The Comprehensive Guide to Salamanca
An overview of the
IXth International
Workshop on
Multiple Myeloma
International Myeloma Foundation
International Headquarters
12650 Riverside Drive, Suite 206
North Hollywood, California 91607
Salamanca, SPAIN
800 452 CURE (2873) Fax: 818 487 7454
TheIMF@myeloma.org
www.myeloma.org
IMF
May 23-27, 2003
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure.
© 2003 International Myeloma Foundation
TABLE OF CONTENTS
Introduction
4
Susie Novis, President (IMF)
Salamanca Review
5
Brian G.M. Durie, M.D.
Doxil-Based Regimens In The Management Of Multiple Myeloma
7
Mohamad Hussein, M.D.
Current Clinical Trials and Future Directions
9
James Berenson, M.D.
Thalidomide and the IMiDs in Multiple Myeloma
13
S. Vincent Rajkumar, M.D.
Molecular insights into the Subtypes and
17
Progression of Myeloma
Gareth Morgan, M.D.
Impact on Diagnosis and Therapy
21
Hervé Avet-Loiseau, M.D.
Role of T Cells in Myeloma
23
Douglas Joshua, M.D.
Criteria for Diagnosis of Plasma Cell Disorders
25
Robert A. Kyle, M.D.
Endothelial Cell-Tumor Cell Interactions in MM
29
Ivan Van Riet, Ph.D.
Role of PET/MRI in Disease Monitoring
33
Brian G.M. Durie, M.D.
Optimising Treatment for Anemia
36
Prof. Heinz Ludwig, M.D.
Has Autologus Stem Cell Transplantation (ASCT)
39
Become the Gold Standard Treatment in MM?
Jean-Luc Harousseau
Autologous Stem Cell Transplantation in Special Situations
41
Morie A. Gertz, M.D.
Signal Transduction Pathways and Cytokine Networks
45
Alan Lichtenstein, M.D.
PS341-VELCADE For the Treatment of Myeloma. Results to Date
47
Paul Richardson, M.D.
What is the role of Allogeneic Stem Cell Transplantation in Multiple Myeloma?
51
Henk Lokhorst, M.D.
INTRODUCTION
Susie Novis, President
International Myeloma Foundation
Dear IMF Member:
The International Myeloma Foundation (IMF) is proud to present The Comprehensive Guide to
Salamanca: Understanding the IX Myeloma Workshop.
The International Myeloma Workshop is a bi-annual medical meeting dedicated exclusively to multiple
myeloma. Experts come together and exchange information regarding the latest developments in the
treatment, management, and prevention of myeloma.
The IMF recognizes that, while the meeting is intended primarily for clinicians and researchers, this
information is of great interest to everyone within the myeloma community. As always, we are working hard
to ensure that you, our valued members, are kept abreast of any and all new information. The IMF has
recruited a cadre of top researchers/advisors/clinicians to analyze the impact of the Salamanca presentations.
The Comprehensive Guide to Salamanca provides concise summaries from various presentations made at the
IXth International Myeloma Workshop. For the readersí convenience, the material has been organized to cover
the basic scientific material, followed by first conventional, and then more experimental approaches to treat-
ment.
The Comprehensive Guide to Salamanca has been made possible, in large part, thanks to the time and the
talent of myeloma experts who each agreed to author a summary paper detailing the workshop session in
which they were involved. While each paper has been edited for clarity and consistency, we have strived to
maintain the individual "voice" and writing style of each author. As a result The Comprehensive Guide to
Salamanca is meant to be read as a collection of individual summary papers.
We encourage you to share The Comprehensive Guide to Salamanca with your treating physician so that
you may both benefit from the many exciting developments that emerged from the latest International
Myeloma Workshop.
As always, the IMF is committed to providing updates and reporting on the latest myeloma topics in our
newsletter, Myeloma Today, in addition to our weekly email newsletter, the Myeloma Minute.
If you have specific questions about the material covered in The Comprehensive Guide to Salamanca, please
contact the IMF, and answers will be sought and provided. Any generic follow-up issues will be posted on
the IMF website at www.myeloma.org.
As always, we thank you for your support of the myeloma community and of the International Myeloma
Foundation.
Sincerely,
Susie Novis, President
4
SALAMANCA REVIEW
Brian G.M. Durie, M.D., Chairman of the Board
International Myeloma Foundation
Every 2 years the myeloma scientific community gets together to participate in the International Myeloma
Workshop. This year the IXth was in Salamanca, Spain, co-chaired by Professor Jesus San Miguel
(Salamanca) and Professor Joan Blade (Barcelona).
The Salamanca program was packed with invited and submitted presentations starting May 23rd, running
through May 27th 2003. The whole agenda is available at: http://myeloma2003.usal.es.
The core program with invited speakers covered 13 areas, including:
1. Genetics of myeloma cells
2. New molecular techniques/results
3. Immune biology
4. MGUS
5. Signal transduction pathways
6. Bone marrow microenvironment
7. New prognostic systems
8. Mouse models
9. Maintenance and supportive care
10. The role of auto transplantation
11. Allogeneic transplantation
12. Novel therapies
13. Vaccine strategies
The submitted abstracts, numbering over 500, cover a wide range of topics, which were largeley present-
ed in poster sessions between the oral sessions. This made for an extremely busy schedule. The two best
submitted abstracts in each of the 13 topic areas were selected for oral presentation.
Other corporate and foundation meetings added to the schedule while in Salamanca. On Friday the 23rd,
corporate symposia included arsenic trioxide (Trisenox®: CTI); thalidomide and analogs (Celgene);
ArediaTM/ZometaTM (Novartis).
The International Myeloma Foundation had several scheduled programs, including:
1
IMF Working Group Dinner Meeting Thursday, May 22nd
1
IMF Scientific Advisors Lunch Meeting Saturday, May 24th
1
European Patient Support Group Leaders meeting Sunday, May 25th.
The most interesting new topics covered at the Salamanca workshop included:
Core Program Many of the topics in the core program are always discussed and updated at each
International Workshop. This year the greatest anticipation surrounded presentations about new molecular
information. The other really new aspects were:
5
Gene Expression Profiling Evaluation of hierarchical classification (to match clinical
classifications) as well as expression of specific RNAs and proteins linked to myeloma features
such as bone disease and anemia. There was excitement about expression of a protein called
DKK1, which is linked to the suppression of osteoblasts and therefore interruption of bone heal-
ing in myeloma patients. There has been an exponential increase in understanding of the mole-
cular biology of bone disease in myeloma and details were presented as part of several sessions.
Immune Biology As for molecular biology, the complexity of the processes being uncovered is
impressive. Just how to modulate this complexity of immune regulation to the advantage of the
myeloma patient is a challenge.
Myeloma classification, prognosis and staging New systems for classification, prognosis assess-
ment, and staging have been under development in the past 2 years and the results were presented
at the Salamanca meeting. These systems, which are the cornerstone of all programs for myeloma
patient management, can provide a reliable framework for international clinical research efforts.
Signal transduction and bone marrow microenvironment Thus far, the research has been
retrospective in that after it was discovered that thalidomide and its analogs as well as VELCADETM
were very effective treatments, researchers began to explore the potential mechanisms of action.
This type of retro research is interesting, but not automatically productive in the development of
further therapies. Mouse model systems may help, and several were discussed.
Auto transplantation This may have beeen a watershed meeting with regard to auto transplant.
For the last decade, the role of auto transplant has been under scrutiny. At this meeting, several
groups including the French (IFM), U.K. (MRC), Spanish (GEM/Pethema) and U.S. (UAMS:
Barlogie) presented long-term follow-up data for panel discussion. In addition, tandem transplant,
and transplant in special circumstances, such as renal failure, older patients, and systemic amyloidosis
were addressed. The panel focused on the question: "Has autologous stem cell transplantation
(ASCT) became the gold standard treatment in multiple myeloma?" The overall outcome with
ASCT is definitely superior in the majority of trials/studies presented. Can ASCT now be routine-
ly recommended for all patients? Is ASCT especially recommended for good and/or poor risk
subsets of patients? These and other questions were actively debated. The additional role of
"mini-allo" (non-myeloablative) transplant was discussed in a separate roundtable.
Novel Therapies Strangely, most of the results with the ì novel î therapies, such as thalidomide,
RevimidTM, ActimidTM and VELCADE® are already widely known. Thalidomide is now one of
the most widely used drugs in the myeloma community in the U.S., despite the fact that it is not
FDA approved in this setting. The widespread use has been well documented at the IMF Patient
and Family Seminar Interactive Sessions (e.g., Seattle and Los Angeles). VELCADE®, which
recently received FDA approval in the United States for use in relapsing/refractory myeloma, was
the focus of attention in Salamanca despite being "not so novel." Follow-up data and discussions
with regard to the future integration of these drugs into overall myeloma management, including
ASCT, was also included during that session.
Salamanca Analysis and Impact The IMF recruited a cadre of top researchers/advisors/clinicians
to analyze the impact of the Salamanca presentations. The "Salamanca Guide" is the end result of
their collaborative efforts. In addition, the "Myeloma Minute" has had all the breaking news
stories and any additional new information. Find back issues of the "Myeloma Minute" archived
on the IMF web site: www.myeloma.org.
6
Doxil-Based Regimens In The Management
Of Multiple Myeloma
Mohamad Hussein M.D.
liposomal doxorubicin (40 mg/m2), vincristine (2.0
mg, Day 1), and oral or intravenous dexamethasone
Cleveland Clinic, Cleveland, OH
(40 mg/day 4 days) every 4 weeks for a minimum
of 6 cycles and/or 2 cycles after the best response.
Overall response rate was 88%: 4 (12%) patients
Patients with multiple myeloma (MM) have achieved a complete, 18 (55%) a major, and 7
increased bone marrow angiogenesis, relatively
(21%) a minor response. Three (9%) had stable
low plasma cell labeling index, and multidrug
and 1 (3%) had progressive disease. Median time to
resistance (the primary cause of chemotherapy
progression was 23.1 months, with 2-year and 3-
failure). The increased angiogenic process carries a
year progression-free survival of 42% and 23%,
poor
prognostic
respectively. Median survival is estimated at 5 years.
The challenges to be influence; conver-
Moreover, anti-angiogenic activity was noted in all
sely it could be uti-
addressed with this
patients. The disappearance of the angiogenic
lized at least theo-
activity did not influence the PFS, however. No
regimen were to
retically by certain
patients discontinued treatment due to adverse
agents to expose
improve the quality
events. Myelosuppression did not result in any hos-
the
malignant
pital admission for fever, neutropenia and parenter-
of response among
environment
to
al antibiotic therapy. The most common toxicities
high effective con-
the newly diagnosed,
were grade 3 palmar-plantar erythrodysesthesia,
centrations of the
mucositis, and neutropenia. The majority of the
and to improve the
active
agents.
cases of PPE occurred in the first 9 patients.
Pegylated liposo-
response rate as well
Following focused patient education only 2 of the
mal
doxorubicin
next 24 patients experienced grade 3 PPE toxicity.
as the quality of
(Doxil®/CAELYXTM)
Preliminary results have been reported from 2
outflow through
response.
prospective, randomized phase III clinical trials of
abnormal angio-
the DVd regimen vs VAD in the United States and
genic vessels in the bone marrow has the poten-
Europe, confirming the results of this phase II trial.
tial of exposing the myeloma cells to high con-
Even though the response rates, quality of response,
centrations of the anthracycline, and because of
and tolerability of this regimen in the newly diag-
the long half life, this exposure lasts for a signifi-
nosed patients was adequate, there were several
cantly prolonged period of time. Unfortunately,
challenges that need to be addressed; the quality of
although single-agent dexamethasone is associat-
response continues to be inferior to the results
ed with rapid responses, the responses are not
obtained with bone marrow transplantation, and
durable. The addition of other chemotherapeu-
the disappearance of the abnormal angiogenic
tic agents is generally required to produce more
process in the bone marrow did not translate in to
durable responses.
In a study conducted by
a PFS or an overall survival. Moreover, when this
Facon et al, single-agent dexamethasone pro-
regimen was applied to relapsed/refractory multi-
duced response rates similar to those of melpha-
ple myeloma patients, the response rate (utilizing
lan or interferon monotherapy; however, dexam-
SWOG criteria) was limited to only 22% of the
ethasone-treated patients had a significantly
patients, with the durability limited to only the
shorter duration of response compared with the
patients who achieved near complete remission
other treatment regimens.
(unpublished data). In summary, the regimen pro-
duced a significant decrease in the abnormal bone
We therefore initiated a phase II trial substitution of
marrow angiogenic process, yet failed to improve
pegylated liposomal doxorubicin for doxorubicin
progression-free survival. The challenges to be
in the VAD regimen. Reducing the dose of dexam-
addressed with this regimen were to improve the
ethasone in patients with MM improved the safety
quality of response among the newly diagnosed,
profile and convenience of the treatment regimen
and to improve the response rate as well as the qual-
without compromising efficacy. Briefly, this study
ity of response. Our group felt that if the anti-
was conducted at the Cleveland Clinic Myeloma
angiogenic effect of the regimen is maintained, it
Center where thirty-three newly diagnosed patients
could translate into improved progression-free, and
with active MM received intravenous pegylated
7
possibly overall, survival.
In view of the results and challenges noted above,
toxicity. Overall, 26/35 patients (74%) achieved a
we embarked on a phase II trial designed to deter-
response to therapy according to the Southwest
mine whether the addition of thalidomide to DVd
Oncology Group (SWOG) criteria (é>50%
(DVd-T) increases the rate and quality of response
decrease in M-protein). Notably, three patients
of therapy in patients with relapsed/refractory
(9%) achieved a complete response and another
multiple myeloma Since the antiangiogenic effect
13 patients (37%) achieved a near-complete
of thalidomide prevents the formation of new
response. The median time to initial response was
blood vessels (rather than reversing angiogenesis)
1.0 month (range, 0.7-5.6 months) and the medi-
it was hypothesized that thalidomide may be able
an time to best response was 2.7 months (range,
to maintain the responses produced by DVd. In
0.9-6.3 months). The preliminary results of this
addition, it was hypothesized that the addition of
study suggest that DVd-T is an effective regimen
thalidomide may increase the sensitivity of the
for the treatment of relapsed/refractory multiple
myeloma cells to chemotherapy.
myeloma and has an acceptable toxicity profile
with the appropriate supportive care measures.
The DVd was administered as previously described
The response rate and quality of response observed
by our group where on the first day of each cycle,
in this trial is higher than that seen in previous
patients received pegylated liposomal doxorubicin
studies evaluating DVd or thalidomide/dexam-
40 mg/m2 IV over 2-3 hours and vincristine 2 mg
ethasone. In particular, the quality of response
IV. Dexamethasone 40 mg/day was administered
produced by DVd-T is remarkable. We have initi-
on days 1 to 4 of each cycle. Thalidomide was ini-
ated a phase I trial to evaluate the role of Revimid
tiated at 50 mg/day, increasing by 50 mg/day every
in combination with this regimen, and are in the
week to the maximum tolerated dose not to exceed
process of a phase III to confirm the results of the
400 mg/day. The regimen was repeated every 4
current (DVd-T) trial.
weeks for a minimum of six cycles and for two
cycles after the best response. After the completion
Rajkumar SV, Leong T, Roche PC, Fonseca R, DispenzieriA, Lacy
of chemotherapy, patients were maintained on
MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, and Greipp PR.
prednisone 50 mg every other day plus the maxi-
Prognostic value of bone marrow angiogenesis in multiple myelo-
mum tolerated dose of thalidomide until the onset
ma. Clin. Cancer Res. 6 (8):3111-3116, 2000.
of disease progression or toxicity. Based on the
experience of other investigators, an algorithm to
Facon T, Mary JY, Attal M et al. Melphalan-prednisone versus dex-
monitor for the development of deep vein throm-
amethasone-based regimens for newly diagnosed myeloma patients
bosis (DVT) and to allow for dose reductions for
aged 65-75 years. Safety analysis of the IFM 95 trial on 457 patients
those experiencing neuropathy was included. The
[abstract]. Blood 1999;94(10 suppl):309b.
protocol was also amended after an increased inci-
dence of neutropenia, infection, oral herpes sim-
Hussein M, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, and
plex activation, and DVT developed among the
Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin,
first 20 patients enrolled on the relapsed/refractory
vincristine, and reduced-dose dexamethasone combination therapy
arm of the study. A prophylactic regimen consist-
in newly diagnosed multiple myeloma patients. Cancer 95
ing of amoxicillin 250 mg twice daily and acyclovir
(10):2160-2168, 2002.
400 mg twice daily until the completion of
chemotherapy was included to prevent infectious
Hussein MA, Tonda ME, George S et al. A phase III randomized
complications. Patients also received granulocyte-
trial of Doxil/CAELYX, vincristine, and dexamethasone (DVd) ver-
macrophage colony-stimulating factor (GM-CSF)
sus vincristine, Adriamycin, and reduced-dose dexamethasone
or granulocyte colony-stimulating factor (G-CSF)
(VAd) in the treatment of patients with newly diagnosed multiple
for white blood cell counts <5000/ml on day 1 of
myeloma (n-MM) [poster]. Presented at 38th Annual Meeting of
therapy and aspirin 81 mg/day for antiplatelet
the American Society of Clinical Oncology; Orlando, FL; May 18-
activity. Patients with hemoglobin <10 g/dl were
21, 2002.
started on epoietin alpha at a dose of 40,000 U to
80,000 U administered subcutaneously once-week-
Dimopoulos M, Pouli A, Zervas K et al. Prospective randomized
ly until hemoglobin increased é>2 g/dl, at which
comparison of VAD administered as intravenous bolus injection
time the dosing frequency was reduced to maintain
and of VAD with liposomal doxorubicin (Doxil) as first line treat-
hemoglobin between 12 g/dl and 14 g/dl.
ment in multiple myeloma [abstract]. Blood 2001;98(11 suppl, pt
1):165a.
Currently, 40 patients with relapsed/refractory
multiple myeloma have been enrolled in the trial,
Hussein MA, Elson P, Tsoe EA et al. Doxil (D), vincristine (V),
with a median age 63.5 years, and a median per-
decadron (d) and thalidomide (T) (DVd-T) for relapsed/refractory
formance status (Hussein et al 2002). Median 2-
multiple myeloma (RMM) [abstract]. Blood 2002c;100(pt 1):403a.
microglobulin and albumin values were, respec-
Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and
8
tively, 4.6 mg/dl and 3.2 mg/dl. Of the 40 patients
thalidomide therapy for multiple myeloma. N Engl J Med. 1999 Nov
enrolled to date, 35 were assessable for efficacy and
18;341(21):1565-71.
TRISENOX® (arsenic trioxide) in Multiple Myeloma:
Current Clinical Trials and Future Directions
James Berenson, M.D.
nance of the myeloma bone marrow microenvi-
Institute for Myeloma & Bone
ronment. The inhibitory effect of arsenic trioxide
on NF-B results in a blockade of IL-6 and VEGF
Cancer Research, Los Angeles, CA
transcription. Arsenic trioxide inhibits NF-B by
binding to the enzyme (IB kinase) responsible
for releasing NF-B from its inhibitor (IB) to
HIGHLIGHTS
which it is normally bound. This prevents NF-B
from relocating to the nucleus where it exerts its
The symposium "Trisenox (arsenic trioxide) in intracellular activity.Dr.Berenson noted that one
Multiple Myeloma" was designed to highlight
of the interesting properties of arsenic trioxide is
current clinical trials and future directions involv-
that it appears to have an increased cytotoxic
ing the use of this novel agent. This included pre-
activity in chemotherapy-resistant cells. This may
sentations on the mechanism of action of arsenic
be because myeloma cells exposed to multiple
trioxide, clinical experience with single-agent and
chemotherapeutic agents have been found to have
combination regimens, European experience, new
high levels of NF-B. Other pathways through
directions in the treatment of multiple myeloma,
which arsenic trioxide affects multiple myeloma
and supportive care.
cells include the induction of histone acetylation,
inhibition of STAT3 activation, reduction of JAK-
MECHANISM OF ACTION
STAT signaling, sensitization of chemotherapy-
resistant multiple myeloma cells, and the reduc-
Dr. James Berenson (Institute for Myeloma & Bone
tion of the adhesive properties of myeloma cells.
Cancer Research in Los Angeles, CA) provided an
overview of the scientific rationale and supporting
Notably, the cytotoxicity of arsenic trioxide is atten-
preclinical data regarding the use of arsenic triox-
uated in the presence of glutathione, which is abun-
ide for the treatment of multiple myeloma. Arsenic
dant in myeloma cells. This observation has led to
trioxide is currently licensed in the US and Europe
the addition of agents (eg. ascorbic acid) to arsenic
for the treatment of relapsed or refractory acute
trioxide regimens that reduce glutathione levels in
promyelocytic leukemia (APL). The intracellular
order to increase the cytoxicity of arsenic trioxide.
activity of arsenic trioxide contributes to its three
primary mechanisms of action: 1) induction of
EFFICACY OF ARSENIC TRIOXIDE IN
apoptosis (programmed cell death); 2) induction
MULTIPLE MYELOMA
of cell differentiation; and 3) modulation of the
bone marrow microenvironment.
U.S. Clinical Trials
Arsenic trioxide has been demonstrated to have
The inhibitory effect of arsenic trioxide on the
cytotoxic activity against myeloma cell lines in
transcription factor nuclear factor (NF)-B
vitro at clinically achievable concentrations (2-5
appears to be a key cellular mechanism by which
mM). Dr. Mohamad Hussein of the Multiple
the drug exhibits activity in the treatment of mul-
Myeloma Program at The Cleveland Clinic
tiple myeloma. NF-B is an important mediator in
Foundation in Cleveland, OH, described the initial
the activation, survival, and proliferation of
US study evaluating the clinical efficacy of arsenic
myeloma cells and is involved in immune respons-
trioxide in relapsing multiple myeloma patients.
es, osteoclast activation, oncogenesis, and the
This trial, from the University of Arkansas group,
modulation of drug resistance. NF-B is also asso-
used the dose and schedule indicated for patients
ciated with increased expression of interleukin
with APL. Patients received arsenic trioxide 0.15
(IL)-6 and vascular endothelial growth factor
mg/kg daily for 30 days and if a response was
(VEGF). IL-6 has anti-apoptotic properties and
achieved, the drug was continued for an addition-
promotes the survival and proliferation of myelo-
al 30 days. This study included 14 high-risk
ma cells while VEGF is involved in the mainte-
patients with advanced or previously treated dis-
9
ease, and 3 patients achieved a response. In addi-
bic acid (1000 mg IV) was administered within 30
tion, Dr. Hussein noted that many of the patients
minutes of arsenic trioxide treatment. The study
who were considered non-responders in this study
included six patients who had failed prior
still possibly benefited from arsenic trioxide thera-
chemotherapy. The first three patients received
py. Dr. Hussein also described more recent trials
arsenic trioxide 0.15 mg/kg, for 5 days for 5 weeks,
evaluating arsenic trioxide in the treatment of
followed by a 2-week rest period while the remain-
multiple myeloma which employ more "user-
ing patients received 0.25 mg/kg of arsenic triox-
friendly" regimens of the drug. In a phase II mul-
ide over the same schedule. Among these patients,
ticenter study, 24 patients with relapsed/refractory
2 achieved a partial response with the other 4 hav-
myeloma received arsenic trioxide 0.25 mg/kg/day
ing stable disease. The concomitant use of ascor-
for 5 days (Monday to Friday) for 2 consecutive
bic acid had no effect on the pharmacokinetics of
weeks, followed by a 2-week break from treat-
arsenic trioxide but did produce a decrease in
ment. Treatment cycles were continued until
intracellular glutathione levels. The combination
response was achieved or patients developed pro-
regimen was generally well tolerated with only one
gressive disease or unacceptable toxicity. Eleven of
grade 3 toxicity (hematologic).
24 patients (46%) achieved an objective response.
In addition, there was anecdotal evidence of
There is evidence that arsenic trioxide may have
improvements in patient quality of life.
synergistic effects with other agents commonly
used in the treatment of multiple myeloma. For
Another trial from Los Angeles is ongoing in
example, arsenic
which patients with a current confirmed diagnosis
trioxide appears
of relapsed/refractory stage II/III myeloma and
To date, 7 patients
to
sensitize
measurable disease (based on M-protein or meas-
with extensive prior myeloma cells to
urable plasmacytoma) received arsenic trioxide
the
cytotoxic
treatment (including
0.25 mg/kg twice weekly for 8 weeks followed by a
effects of steroids.
3-week rest. The use of corticosteroids is permit-
bortezomib, stem
Dr.
Hussein
ted for patients with no response or stable disease.
described
an
cell transplantation,
Dose escalation to 0.35 mg/kg is also allowed. To
ongoing phase II
thalidomide) have
date, there are preliminary data on 13 of 16
study evaluating a
enrolled patients with 1 partial response and 3
been treated with
combination regi-
patients with minor responses. In addition, the
men of arsenic
this regimen.
overall survival duration among these patients
trioxide, ascorbic
appears to be promising.
acid, and dexa-methasone (TAD regimen) for
patients with relapsed/refractory myeloma. To
European Clinical Trials
date, 13 patients have completed 2 cycles of thera-
Dr. Heinz Ludwig, director of the Myeloma
py (1-3 cycles planned) with 1 complete, 1 near
Reference Center at the Wilhelminen Hospital in
complete, and 5 partial remissions. Although these
Vienna, Austria described a phase II European
results are promising, longer follow-up is required
multicenter trial currently being conducted in
to determine whether this response will be main-
France, Belgium, and the UK. This study is evalu-
tained.
ating arsenic trioxide (0.30 mg/kg twice weekly for
at least 15 weeks) in 15 patients with
Dr. Berenson reported that arsenic trioxide sensi-
relapsed/refractory,
measurable
myeloma.
tized multiple myeloma cells to the cytotoxic
Response will be assessed using Southwest
effects of melphalan, and based on this observa-
Oncology Group (SWOG) criteria at weeks 8 and
tion, a pilot study evaluating the combination of
16. The study is ongoing and too early for the
melphalan, arsenic trioxide, and ascorbic acid
assessment of results.
(MAC regimen) is currently under way. The objec-
tive of this study is to determine whether the addi-
Arsenic Trioxide Combination Regimens
tion of arsenic trioxide to melphalan can allow
Since ascorbic acid potentiates the cytotoxicity of
therapeutic benefit with reduced toxicity, using
arsenic trioxide and decreases resistance to arsenic
lower doses of melphalan than are typically used in
trioxide by reducing intracellular glutathione lev-
single-agent melphalan regimens. In this study,
els, studies have assessed combination regimens
patients received arsenic trioxide 0.25 mg/kg IV
10
incorporating these two agents. Dr. Hussein
twice weekly rapidly followed by ascorbic acid
described an initial phase I/II trial in which ascor-
1000 mg IV plus melphalan 0.1 mg/kg/day orally
for 4 days every 6 weeks. Patients receiving ongoing
blood collected from patients. These tumor-
steroids prior to the study continued on the same
killing T cells are expanded ex vivo by more than
dose but discontinued the steroid within 1 to 8
1,000-fold over a period of 12 days and re-infused
weeks of initiating the MAC regimen. To date, 7
into patients following standard therapy and
patients with extensive prior treatment (including
autologous stem cell transplantation. This tech-
bortezomib, stem cell transplantation, thalido-
nique is undergoing initial clinical evaluation for
mide) have been treated with this regimen. All 7
patients with relapsed disease. Early results with
patients have experienced a decrease in their M-
the "Xcellerate" technique have been encourag-
protein levels. Furthermore, 4 of these patients
ing; it appears to be well tolerated.
with severe renal dysfunction have shown sus-
tained improvement in renal function. Finally, the
Maintenance Therapy
regimen was well tolerated with the most com-
The role of maintenance therapy is evolving.
monly reported adverse events being leukopenia,
Although single-agent interferon has demonstrat-
fatigue, and anemia. Recently, synergism between
ed no effect on survival, it has been suggested that
arsenic trioxide and the proteasome inhibitor
the addition of interferon to steroid therapy could
bortezomib has been demonstrated. Based on this
be of benefit. However, recent data suggest that
finding, a phase I/II dose-escalating study is
this benefit is more likely due to the steroid alone.
planned for patients with relapsing myeloma. The
Recent studies have demonstrated that prednisone
study will include 3 cohorts of patients (6 patients
produces dramatic improvements in overall sur-
per cohort). Patients receive treatment on days 1,
vival among patients who had responded to con-
4, 8, and 11 of a 21-day cycle. The dosage regimens
ventional therapy. This is in contrast to interferon,
are arsenic trioxide 0.25 mg/kg plus bortezomib
which has only been shown to improve progres-
0.7 mg/m2 (cohort 1), arsenic trioxide 0.25 mg/kg
sion-free survival.
plus bortezomib 1.0 mg/m2 (cohort 2), and arsenic
trioxide 0.35 mg/kg plus bortezomib 1.0 mg/m2
Thalidomide
(cohort 3). This study will assess safety, time to
Thalidomide is a novel agent that has
disease progression, and response rate.
immunomodulatory properties. Initial studies
suggested that approximately one-third of patients
NEW DIRECTIONS OF THERAPY
with multiple myeloma achieve a response after
treatment with thalidomide. More recent studies
Although chemotherapeutic agents used in the
suggest that the response rate is closer to 50% with
treatment of multiple myeloma have been effec-
further benefit observed when thalidomide is com-
tive in producing responses, these regimens have
bined with other agents. In an MD Anderson
produced little effect on overall survival. For
study, 46 patients received thalidomide up to 400
example, despite the initial success of interferon-
mg for more than 3 months. Those who were non-
based regimens in the 1990s, further investigation
responders to monotherapy were treated with
demonstrated that interferon produces little bene-
thalidomide/dexamethasone combination therapy.
fit as a first-line agent in the treatment of multiple
Overall, 50% of patients experienced a response,
myeloma. Therefore, a number of new therapeutic
with partial remission being characterized by a
modalities are currently under investigation in an
>50% reduction in serum M-protein and a >75%
effort to improve clinical outcomes.
reduction in Bence Jones protein. Among patients
not responding to single-agent thalidomide, the
Transplantation
addition of dexamethasone led to responses in
The role of transplantation in the treatment of
approximately one-third of patients.
multiple myeloma remains controversial. For
example, there is conflicting evidence regarding
In another phase II study, 55 patients with newly
whether conventional or high-dose chemothera-
diagnosed myeloma received thalidomide 200mg
py is more effective in transplantation regimens.
plus dexamethasone 40mg on days 1-4, 9-12, and
Dr. Berenson described a newly developed tech-
17-20. Overall, 65% of patients achieved a
nique ("Xcellerate") in which autologous cells are
response, although durability of response is
used to affect antitumor responses instead of the
unknown because most patients went on to
traditional role of replenishing bone marrow
receive transplants. This combination, compared
function. In this technique, a dendritic cell is
with dexamethasone alone, is currently under
replaced by a bead with attached antibodies that
investigation in a phase III trial.
11
acts to nonspecifically activate resting T cells in
Since the macrolide antibiotic clarithromycin has
been demonstrated to potentiate the activity of
Patients with multiple myeloma of >12 months
thalidomide and dexamethasone, this agent has
duration are at particular risk for the development
been incorporated into thalidomide/dexametha-
of osteoporosis. Treatment options include bis-
sone combination regimens. In an initial study, 90%
phosphonates and estrogens (female patients).
of patients achieved a response to this combination.
Calcium and vitamin D supplements may also be
A subsequent study demonstrated 8 of 11 patients
of benefit. Furthermore, treatment with intra-
with relapsing multiple myeloma treated with this
venous bisphosphonates among patients with
regimen achieved a reduction in M-protein with the
multiple myeloma has been shown to reduce the
duration of response exceeding 1 year in 4 patients.
occurrence of hypercalcemia, bone pain, and
However, the combination regimen appeared to be
other osteoporosis-related skeletal changes.
associated with an increase in steroid-related toxici-
ties (myopathy, hyperglycemia, and mood changes).
Depression is a frequent complication of multiple
myeloma, affecting approximately 35% of patients
Bortezomib
who receive 6 months of treatment for multiple
Bortezomib is a novel agent that, like arsenic tri-
myeloma. This results in significant impairment
oxide, is an inhibitor of the NF-B pathway.
of patient quality of life with decreases in physical
Bortezomib acts by preventing the proteasome
and emotional functionality, reduced mental
from degrading IB, resulting in an inhibition of
capacity, and an increased risk of death.
NF-B activation. In preclinical trials, bortezomib
has been shown to have cytotoxic activity when
Finally, patients undergoing transplant following
used either as a single agent or in combination
high-dose chemotherapy experience a loss of phys-
with melphalan. In a phase II study involving 202
ical performance. One study has found that the
multiple myeloma patients who had relapsed after
encouragement of physical activity is associated
first-line therapy and who were refractory to their
with an improvement in many disease- and treat-
most recent therapy, bortezomib produced an
ment-related complications (pain, diarrhea, hospi-
overall response rate of 35%, with 59% of patients
talization stay, and hematological abnormalities).
having stable disease or better.
CONCLUSIONS
SUPPORTIVE CARE
Although multiple myeloma remains a difficult-
According to Dr. Heinz Ludwig, supportive care is
to-treat disease, recent advances in the treatment
an important component to the management
of this disease have produced encouraging results.
strategy of patients with relapsed/refractory mul-
Arsenic trioxide is a novel agent that has been
tiple myeloma. The overall goal of treatment is not
shown to be well tolerated and to have significant
only to control the disease with prolonged remis-
activity in this challenging disease. Ongoing and
sion, but also to maintain the patientís quality of
future studies will help to delineate the appropri-
life and to limit treatment-related toxicity. When
ate role of this promising new agent for patients
possible, patients should receive treatment on an
with multiple myeloma.
outpatient basis and should receive education
regarding their disease and treatments as well as
emotional support.
Common complications of multiple myeloma
include anemia, osteoporosis, and depression.
Appropriate treatment of these complications can
help maintain optimal patient quality of life.
Recombinant erythropoietin (EPO) is commonly
used in Europe to treat anemia. Treatment with
EPO has been shown not only to increase hemo-
globin levels but also to improve quality of life by
improving exercise capacity and decreasing the
need for blood transfusions. It is recommended
12
that EPO be initiated when hemoglobin levels are
<10 g/dl (<12 g/dl for symptomatic patients).
Thalidomide and the IMiDs in Multiple Myeloma
S. Vincent Rajkumar, M.D.
patients with newly diagnosed disease. We will dis-
Mayo Clinic, Rochester, MN
cuss 2 of these agents in this article, namely thalido-
mide and CC-5013 (RevimidTM). We will also
review updates on these two drugs from the IX
Multiple myeloma is a cancer of plasma cells. International Myeloma Workshop in Salamanca,
Plasma cells are cells in the blood and bone
Spain, May 2003.
marrow that are responsible for the production of
antibodies and help us fight viruses and bacteria.
THALIDOMIDE
When these cells
In one study, 50
become cancerous as
Relapsed and refractory myeloma
patients with newly in multiple myelo-
Thalidomide was manufactured by a German
ma, they grow in an
pharmaceutical company, Chemie Grunenthal, in
diagnosed myeloma uncontrolled man- the 1950s. It was first used as a sleeping pill, but
were treated with a ner, and cause signif-
was taken off the market once it was recognized
icant
problems
that is caused serious birth deformities when preg-
combination of
including anemia,
nant mothers took the drug for morning sickness.
thalidomide plus
kidney failure, and
In 1998, researchers at the University of Arkansas
dexamethasone at
destruction
of
reported that thalidomide was effective in the
bones.
The major
treatment of relapsed and refractory myeloma.
the Mayo Clinic.
treatment for multi-
This was an important study because it showed
ple myeloma over the last 3-4 decades is a simple
that thalidomide could be effective even in patients
chemotherapy regimen consisting of two types of
who have exhausted all other therapeutic options
pills: melphalan and prednisone. Treatment with
for multiple myeloma. Since then numerous cen-
melphalan and prednisone is effective in most
ters in the world have confirmed the activity of
patients, but does not cure myeloma.
thalidomide in relapsed and refractory disease.
Numerous presentations were made at the
Over the years, a number of studies tried to
Myeloma Workshop in Spain confirming the activ-
improve on the results of the melphalan and pred-
ity of thalidomide in relapsed and refractory mul-
nisone
regimen
using
various
aggressive
tiple myeloma. Overall, the drug appears to have a
chemotherapy drugs. But none of the standard-
response rate in these patients in the range of at
conventional-dose chemotherapy combinations
least 25-35%. Moreover, responses are relatively
studied was superior in terms of improving survival
long lasting, with duration of response averaging
in myeloma patients. However, since the 1990s, it
approximately 1 year.
has become very clear that high-dose therapy with
stem cell transplantation improves the survival of
Thalidomide in Newly Diagnosed,
myeloma patients compared to conventional-dose
Symptomatic Multiple Myeloma
regimens such as melphalan and prednisone.
Given the activity of thalidomide in relapsed and
Therefore, this approach is now part of the usual
refractory myeloma, the drug was studied as initial
treatment for myeloma in patients who are candi-
therapy for symptomatic multiple myeloma.
dates for such a procedure.
Thalidomide has advantages over other conven-
tional chemotherapy agents used to treat myeloma.
More importantly, over the last 5 years, we have
For example, unlike many chemotherapy drugs,
made significant advances in new agents that target
thalidomide can be taken by mouth as a capsule,
not only the myeloma cell, but also the bone mar-
and it does not cause serious suppression of the
row support structure (microenvironment) that
bone marrow or blood counts. In one study, 50
helps these cancer cells to grow. These new agents
patients with newly diagnosed myeloma were
have shown significant promise in the treatment of
treated with a combination of thalidomide plus
13
patients with refractory myeloma as well as in
dexamethasone at the Mayo Clinic. Thirty-two
patients (64%) had a significant response to thera-
increasingly possible.
py with at least a 50% or higher reduction in tumor
burden (monoclonal protein levels, bone marrow
Based on this, thalidomide was studied in patients
involvement). In fact, 92% of patients had at least
with early stage myeloma at the Mayo Clinic to see
a 25% or higher reduction in tumor burden in this
if we can delay progression to symptomatic multi-
study. The results of this study are very similar to
ple myeloma. Of 31 patients studied, 34% had a
another study conducted at the MD Anderson
partial response to therapy indicated by at least a
Cancer Center, which showed that the combina-
50% reduction in tumor burden. Interestingly, at 2
tion of thalidomide plus dexamethasone is effec-
years almost 65% of patients had no evidence of
tive in over 70% of patients with newly diagnosed
worsening myeloma, suggesting that thalidomide
disease. Based on these interesting observations, a
may delay progression from asymptomatic to
large randomized trial was conducted in which half
sy mpt o matic
of the patients received thalidomide and dexam-
A target dose in the
myeloma. The
ethasone and the other half received dexametha-
MD Anderson
range of 200 to 400 mg
sone alone (ECOG trial, E1A00). The results of
Cancer Center
this trial will be available next year. It certainly
is selected and
has
observed
appears that this oral combination of thalidomide
similar results
patients are slowly
and dexamethasone may be an alternative to more
in a similar trial.
conventional intravenous regimens such as VAD
escalated to that target Based on the
(vincristine, adriamycin, dexamethasone) that are
dose of therapy.
pr omising
commonly used to treat patients with multiple
results of these
myeloma.
2 studies, a comparative clinical trial in which half
the patients get the bone strengthening agent zole-
Thalidomide in Early Stage
dronic acid alone and the other half get a combi-
(Smoldering or Indolent) Myeloma
nation of thalidomide plus zoledronic acid is
We know that not all patients with a serum
scheduled to open at the Mayo Clinic. Because
monoclonal protein or increased plasma cells in
thalidomide has several side effects, it is important
the bone marrow have multiple myeloma. In
to do this comparative trial before early stage
fact, there are many patients who have just a
myeloma patients can be advised to take thalido-
serum monoclonal protein increase and are
mide therapy.
considered to have monoclonal gammopathy of
undetermined significance (MGUS).
These
Combination Therapies with Thalidomide
patients need no therapy; follow-up with their
At the Myeloma meeting in Spain, numerous
physician once a year is enough. Some other
groups presented data and studies that looked at
patients have increased bone marrow plasma
thalidomide in combination with other active
cells (10% or more) and increased monoclonal
chemotherapy regimens for the treatment of mul-
protein, but no evidence of organ damage such
tiple myeloma. One such regimen is the thalido-
as bone lesions, renal failure, high calcium lev-
mide plus dexamethasone regimen for patients
els, or anemia. These patients are considered to
with relapsed and refractory disease. As we noted
have early stage myeloma (also called smolder-
earlier, the combination of these 2 drugs is very
ing myeloma or asymptomatic myeloma).
effective in patients with newly diagnosed myelo-
Normally, patients with asymptomatic myelo-
ma. Similarly, in relapsed refractory myeloma,
ma are observed closely by their physicians
more than 50% of patients achieved significant
without any therapy. However, over half the
benefit (response) with this combination in sepa-
patients are expected to progress to myeloma in
rate studies conducted by Dr. Dimopoulos, Dr.
2 years, and so it is important to continue to
Palumbo, and several others. In contrast, thalido-
conduct trials trying to delay the progression
mide as a single agent shows such benefit in only
from asymptomatic myeloma to symptomatic
25-35% of patients. Therefore, the combination of
myeloma. Earlier attempts at these trials were
thalidomide and dexamethasone seems promising.
limited by the fact that the usual chemotherapy
drugs can cause acute leukemia (a fatal blood
Another combination that has been studied is the
cancer) at a later date, and this risk was felt to
cyclophosphamide, thalidomide, plus dexametha-
be prohibitively high. With new agents such as
sone (CTD) regimen. At least 6 clinical trials using
14
thalidomide we do not expect increased risk of
this combination were presented at the meeting in
leukemia, and therefore such studies are now
Spain, although the dosage and duration of thera-
py differed significantly among the trials. Of inter-
fight myeloma.
est, this regimen had response rates (i.e., percent-
age of patients who get benefit with therapy) that
Side effects of Thalidomide
were better than thalidomide alone, or thalidomide
The main side effects are sleepiness, fatigue, consti-
plus dexamethasone. Almost 65% of the patients
pation, and numbness and tingling in the hands
had 50% or greater reduction in tumor burden
and feet. Side effects can be minimized by careful
with this 3-drug combination therapy. This regi-
dose adjustments and supportive care measures.
men thus merits further study and appears to be an
With prolonged use these side effects do occur in a
effective regimen for patients with advanced,
majority of patients. On the one hand, side effects
relapsed/refractory disease.
such as sedation, fatigue, and constipation decrease
with time. On the other hand, side effects such as
Other regimens that were reported include the reg-
neuropathy seem to increase with duration of ther-
imen combining thalidomide and dexamethasone
apy. Besides these common side effects, other more
with clarithromycin. Clarithromycin is an antibiot-
uncommon ones include rash, lowering of the
ic that may act by potentiating the effects of dex-
heart rate, and possibly blood clots. The side
amethasone or thalidomide by affecting their
effects of thalidomide obviously increase when this
metabolism. Another regimen that has been looked
drug is combined with other agents. For example,
at in patients with newly diagnosed disease as well
when combined with steroids, the adverse events
as relapsed/refractory myeloma is the combination
increase and this must be kept in mind. For
of liposomal doxorubicin with thalidomide and
instance, the incidence of blood clots is < 3% with
dexamethasone, and in one of the two trials, vin-
patients receiving thalidomide alone but increases
cristine was added as well. In studies presented at
to over 10% in patients receiving the combination
the meeting by the Greek Myeloma Group and the
of thalidomide and dexamethasone. When adri-
Cleveland Clinic, over 70% of patients receiving
amycin-containing chemotherapy is used in com-
these regimens had significant responses to therapy.
bination with thalidomide, the risk of blood clots
increases further to 25% or higher.
At the
Although the new regimens discussed above
Myeloma Meeting in Spain, there were presenta-
appear interesting and promising, they need fur-
tions made that showed that adequate blood thin-
ther study. One must keep in mind that the
ners (eg., coumadin or low molecular weight
improved responses when thalidomide is used in
heparin) given in conjunction with thalidomide
combination with other regimens is accompanied
and other combination regimens may decrease the
by significant increase in side effects as well.
incidence of blood clots. Blood thinners do have
Further, it is hard to compare results of trials done
side effects and hence are not recommended rou-
at different institutions. Well designed comparative
tinely with thalidomide alone. Nevertheless, when
trials (randomized trials) are needed to determine
thalidomide is used in combination with other
the true value of these combinations. Therefore,
drugs, blood thinners would be something to con-
careful discussions of the pros and cons of combi-
sider.
nations vs single agent therapy need to be dis-
cussed when using these approaches.
Dosage of Thalidomide
When thalidomide was introduced as myeloma
Mechanism of Action of Thalidomide
therapy, the dosage was increased to the maxi-
Unlike usual conventional chemotherapy drugs
mum tolerated dose, as is done with conventional
that are designed to kill cancer cells, thalidomide
chemotherapy drugs. However, this results in
and other newer drugs appear to have effects not
undesirable side effects without possible benefit.
only on the cancer cell, but also on the support-
Therefore, most physicians today are using one of
ive and fertile microenvironment in the bone
two approaches. A target dose in the range of 200
marrow that allows these cancer cells to grow.
to 400 mg is selected and patients are slowly esca-
The precise mechanism of action of thalidomide
lated to that target dose of therapy. Another
remains unknown in myeloma, but appears to be
approach is to use the lowest dose of thalidomide
at least in part related to its effects on the bone
that can produce a response. This may be as low
marrow microenvironment. It appears to have
as 50-100 mg/day. The consensus was to use the
effects on blood vessel formation that supports
best-tolerated dose and to individualize the dose
cancer cell growth (angiogenesis). It also inhibits
for each patient in order to minimize toxicity and
proteins that stimulate myeloma cell growth, and
maximize response. When thalidomide is com-
15
may strengthen the immune system and help it to
bined with other agents, a dose higher than 200 mg
does not appear to be necessary.
that compares CC-5013 plus dexamethasone ver-
sus dexamethasone alone are ongoing in the
CC-5013 (RevimidTM)
United States. The results of these trials will help
Although thalidomide has emerged as the first
confirm the activity of this agent and hopefully get
new active agent for myeloma in over three
this agent approved for clinical use.
decades, it has some undesirable side effects. These
include birth defects, neuropathy, constipation,
Dosage of CC-5013
and sedation. Therefore, efforts are underway to
The current suggested dosage of CC-5013
create analogs of thalidomide which have fewer
(Revimid) in these clinical trials is 25 mg to 30 mg
side effects and perhaps more activity against
taken by mouth once a day for 21 days, followed
myeloma. After a long search one significant ana-
by a 7-day rest period. The regimen is then
log among a group of drugs called ImiDs
repeated monthly.
(immunomodulatory drugs), CC-5013, was intro-
duced to clinical trials. In laboratory studies, CC-
Side-effects of CC-5013
5013 (Revimid) appears several times more pow-
Unlike thalidomide, constipation and sedation do
erful than thalidomide. Therefore, it was moved
not appear to be significant with CC-5013. In con-
to the clinic to treat patients with relapsed refrac-
trast, lower blood counts, particularly low white
tory disease.
cell and platelet counts, occur as the main side
effect. In laboratory studies, Revimid does not
Phase I Trials
appear to cause birth defects in animal models.
Phase I trials are conducted to identify the side
However, significant precautions have been estab-
effects and the correct dose of a given drug. Two
lished to prevent pregnancies while on this thera-
separate phase I trials with Revimid were conduct-
py.
ed, one at the University of Arkansas and the other
at the Dana Farber Cancer Center. In the Arkansas
CONCLUSION
study, 8 of 15 patients (53%) achieved at least a
25% reduction in tumor burden with Revimid
Overall, studies so far, including many studies pre-
therapy. In the Dana-Farber study, 15 of 24 (63%)
sented at the Myeloma Workshop in Spain, show
achieved at least a 25% reduction in tumor burden.
that both thalidomide and CC-5013 offer signifi-
The maximum tolerated dose was identified to be
cant hope for patients with multiple myeloma.
25 mg, and the main side effects of the drug were
Both drugs are being tested extensively alone and
lowering of the blood counts. These 2 phase I
in combination with other active agents in
trials provided evidence that CC-5013 (Revimid)
patients with relapsed and refractory myeloma.
was active even in patients who had failed multiple
Thalidomide is being studied as initial therapy for
other chemotherapy regimens, including thalido-
myeloma; similar trials are also being planned
mide, and set the stage for further trials.
with CC-5013. Although neither of these 2 drugs
appears to cure myeloma, they may help a signifi-
Phase II Trials
cant proportion of patients for whom limited
Based on the success of the phase I trials, a phase II
therapeutic options exist. Moreover, responses
trial of CC-5013 was conducted last year. Phase II
with these agents appear to be durable.
trials are conducted to determine the exact benefit
Thalidomide and CC-5013 have also opened the
that one gets with a given drug for a given disease.
way for other novel agents to enter the treatment
This phase II trial studied 2 dosing regimens of
of multiple myeloma.
CC-5013 (Revimid): 30 mg once per day and 15
mg twice daily. The main side effects of CC-5013
(Revimid) in this trial were low blood counts as
seen in the phase I trials. Of the first 46 patients
treated, 21% of patients achieved at least a 50%
reduction in tumor burden. Moreover, at least 54%
of patients achieved a 25% or higher reduction in
tumor burden with this therapy. These results
show that CC-5013 had significant activity in
patients with relapsed and refractory disease.
16
Based on the results of this trial, a larger Phase II
trial as well as a comparative trial (Phase III trial)
Development of Normal and Malignant Plasma Cells:
Molecular Insights into the Subtypes and
Progression of Myeloma
Gareth Morgan, M.D.
which can look at the patterns of genes expressed
University of Leeds, Leeds, U.K.
as peripheral blood B cells differentiated into plas-
ma cells have shown that this process is associated
with a widespread downregulation of genes, com-
Summary
patible with a process of specialisation. The gene
families that control this developmental process,
U
and that ensure it occurs in an orderly fashion, are
nderstanding the molecular events leading to
often transcription factors. Deregulation of this
the transformation of normal to malignant
type of gene creates good candidates for mediating
plasma cells is crucially important for us to design
the abnormal behaviour of the malignant myelo-
targeted treatments and to design strategies for the
ma cell.
primary prevention of myeloma. Deregulation of
mechanisms maintaining genomic stability are
The transcription factors responsible for control-
important in initiating myeloma and can be split
ling normal plasma cell development are now
into B cell-specific and non-specific. Aberrant
becoming more clearly understood. It is essential
class switch recombination events can lead to
that the transcription
chromosomal translocation and the deregulation
factor
PRD
BF1
of oncogenes which can be specifically targeted
If we are to under- (BLIMP) is upregu-
with small molecules. This is exemplified by the
lated and that PAX5
t(4;14) FGFR3 deregulation and tyrosine kinase
stand how these
and MYC are down-
inhibitors which can kill cells with this transloca-
cells lose their
regulated during plas-
tion.
Expression microarrays combined with
ma cell development.
molecular cytogenetics have provided a tool with
normal function
At the same time the
which to identify new gene families important in
and become
gene XBP1 is upregu-
myeloma. They form the basis for novel classifica-
malignant, it is
lated
and
conse-
tions based on the patterns of genes expressed and
quently B cells com-
are also leading to novel targeted treatments.
essential that we
plete their differentia-
understand the
tion to plasma cells.
The Development of normal and
The exact nature of
control of normal
malignant plasma cells
the critical events
In this report I describe in general terms the ideas
plasma cell devel- underlying plasma
underlying the presentations made in the session
opment.
cell development have
entitled "the development of normal and malig-
recently been pub-
nant plasma cells." Presenters in the session were
lished. It seems that the cytokine IL4 leads to an
Marta Chesi, Lief Bergsagel, Mike Kuehl, Linda
upregulation of XBP1. This in turn increases anti-
Pilarski, Gareth Morgan, and Bernard Klein.
body production and differentiation towards a
plasma cell. This newly formed antibody needs to
Myeloma is a malignancy of plasma cells (the
be processed correctly for it to function properly,
final stage of B cell development), the function of
and this process requires that critical proteins be
which is to produce highly specific antibodies to
made by the cell. Thus, unfolded antibodies in the
protect the body from infection. These cells are
endoplasmic reticulum signal back to XBP1 via
thus highly specialised and have a unique natural
IRE1a, which cleaves the RNA to give rise to
history and eventually become specialised facto-
XBP1s, a modified smaller form which further
ries for the production of large quantities of anti-
mediates the differentiation towards a plasma cell.
body. If we are to understand how these cells lose
XBP1s upregulates IL6, a crucial cytokine for plas-
their normal function and become malignant, it is
ma cells, and provides a growth and survival signal
essential that we understand the control of normal
for the cell. At the same time as upregulating the
17
plasma cell development. Microarray experiments
"unfolded protein response," which allows the
newly formed antibodies to be correctly processed,
strong control regions of the antibody genes,
the B cell completes its differentiation to an anti-
"enhancer regions" which are normally necessary
body-producing plasma cell. These processes are
to produce the large amounts of antibody which
clearly different in normal compared to malignant
are required.
plasma cells, and as such are an interesting thera-
peutic target manipulation which could lead to
There are only limited numbers of recurrent chro-
either terminal differentiation or cell death.
mosomal translocations in patients with myelo-
ma.
These are the t(4;14) which deregulates
A prerequisite for malignant transformation of a
FGFR3, the t(6;14) which deregulates IRF4, the
cell is the development of an unstable genome, i.e.
(14;16) which deregulates cmaf, the t(11;14)
the processes that repair the DNA do not keep up
which deregulates cyclin D1, and the t(1;14) which
with the amount of damage occurring. As a con-
deregulates MUM1. In order for a translocation
sequence the DNA is damaged and eventually
to form, the DNA must break in two places.
oncogene and tumour suppressor genes are affect-
Subsequently, the DNA ends must swap location
ed, leading to malignant transformation. The gene
and be joined back together. Understanding how
families that con-
this happens would allow us to understand one of
trol this type of
the basic mechanisms leading to myeloma. A first
A prerequisite for
process are called
step in this process is to look at the structure of the
malignant transfor- "caretaker genes."
breakpoints and see whether this can help us
Much of the life
understand the mechanism. Examination of the
mation of a cell is
cycle of B cells is
structure of the breakpoints in myeloma suggests
the development of
devoted to the pro-
that they are mediated by aberrant "class switch
duction of specific
recombination," i.e. there is a mistake made dur-
an unstable genome, antibodies and the ing normal plasma cell differentiation. The junc-
i.e. the processes
cellular processes
tions can either be simple, involving straightfor-
that repair the DNA necessary to gener-
ward rearrangements, or complex, involving 3-
ate these antibod-
way rearrangements or inversions.
These
do not keep up with ies can also con- rearrangements in patient materials should be dis-
the amount of dam- tribute to the
tinguished from the highly complex events seen in
instability of the
cell lines and normally associated with deregula-
age occurring.
DNA that charac-
tion of the expression of cMYC, which is a cell line
terises malignant myeloma cells. These processes
phenomenon.
Thus aberrant gene rearrange-
often involve direct changes in the pattern of DNA;
ments mediated via class switch recombination
if they are not tightly controlled, they can lead to
mechanisms represents one form of ongoing DNA
the DNA being damaged, which in turn leads to
instability in myeloma plasma cells.
malignant transformation. During leave develop-
ment, the genes which will go on to produce anti-
The other commonly encountered feature of
body are rearranged. Subsequently a process called
genomic instability is a failure to maintain the cor-
"affinity maturation," which occurs in the germi-
rect number of chromosomes. When the number
nal centre, increases the activity of antibody by a
of chromosomes increases, it is known as hyper-
process of mutation induction. This process is
diploidy. The processes that maintain chromo-
called "somatic hypermutation." A further process
some number are different from those that cause
that can go wrong occurs when antibodies change
mutation and chromosome translocation. One
their functional activity by altering their structure.
gene product that binds to the centrosome and is
This process is called class ì switch recombination,î
important in chromosomal segregation, a mecha-
in which antibodies switch their constant regions
nism that could lead to abnormal chromosome
from IgM to either IgG, IgA, or IgE. All of these
numbers, is RHAMM. RHAMM is expressed in
processes involve rearrangement and mutation of
myeloma cells. Splice products have been suggest-
the germline DNA, and so potentially can go
ed to effect prognosis. In this respect it is interest-
wrong, giving rise to the activiation of oncogenes.
ing that a reciprocal relationship was noted
In myeloma, it is a class switch recombination that
between myeloma cases with hyperdiploidy and
goes wrong most frequently, giving rise to "gross
those with translocation events. Only 10% of
chromosomal rearrangements" and chromosomal
cases with hyperdiploidy have a chromosomal
18
translocations.
As a consequence of these
rearrangement, whereas the figure is around 70%
rearrangements oncogenes can be activated by the
for the remainder of cases. This finding suggests
that myeloma can be split into two distrinct
data identifying the protein product of this recip-
groups of cases based on the nature of genomic
rocal translocation was presented, but the defini-
instability that is present: those with transloca-
tive interpretation of this data requires further
tions and those with hyperdiploidy. The prognos-
experiments to clarify the situation.
tic and therapeutic importance of these two
groups is the subject of ongoing investigation but
Expression microarray experiments, which can
it is likely that these groups do behave differently
look at all the genes expressed in the cell provide
and will need to be treated differently.
an interesting way of looking at the gene patterns
that are abnormal in myeloma plasma cells, and in
A number of studies have looked at the signifi-
myeloma cells carrying the t(4;14) in particular. A
cance of cases carrying specific translocations. The
distinct pattern of genes is expressed in the cases
most obvious of these and the best studied to date
with a t(4;14), suggesting that it is a distinct sub-
has been the t(4;14). The t(4;14) occurs in approx-
type of myeloma. Other patterns can be seen in
imately 10-15% of cases of myeloma and has been
the genes expressed when many cases of myeloma,
suggested to confer a poor prognosis, but the num-
which may have different molecular origins, are
ber of cases analysed is too few to give firm con-
using computer programmes capable of recognis-
clusion at this time. It has been suggested that the
ing the patterns. Taken together with previous
gene that is critical to the pathogenesis of the dis-
genetic data, a putative new classification system
ease and is deregulated by the translocation is
was proposed based on the distinct molecular sig-
FGFR3. However, it has recently been suggested
natures identified in the array experiments. The
that cases can be identified by FISH which have the
t(4;14) deregulates FGFR3 and is present in 18%
translocation but seem to lack FGFR3 expression,
of cases. cMAF is deregulated in 6% of cases. The
suggesting that while FGFR3 expression may be
t(11;14) deregulates cyclin D1, and when taken
critical early in the disease process, it may not be
together with cases with upregulated cyclin D1
later in the diseaseís natural history. The other
that lack a translocation, accounts for 50% of
explanation is that FGFR3 may not be the target
cases. Cyclin D2 is deregulated in 20% of cases.
gene and another uncharacterised gene may be
The remaining cases are cyclin D1 low. The clini-
more relevant. Data was presented showing that
cal significance of this classification approach was
small molecule drugs that switch off FGFR3 are
not available, but it does provide a novel classifici-
able to kill myeloma cells with the translocation.
ation of myeloma that can be prospectively tested
This result provides a basis for truly targeted treat-
in clinical trials.
ment in myeloma -- that in which a specific drug
is given to patients with specific molecular abnor-
Other array data identified a number of gene
malities. This therapeutic potential has led investi-
pathways that may be deregulated in myeloma.
gators to wish to characterise the molecular events
FRZb is a gene that is frequently upregulated in
underlying the translocation further.
array studies and implicates the WNT signalling
pathway in the process of myeloma. The exact
Work characterising the reciprocal t(4;14) translo-
mechanism underlying this involvement is uncer-
cation has been carried out, and the sites of break-
tain; FRZb inhibits WNT signalling and could
points in both patient and cell lines have been pre-
inhibit this pathway in the maligant plasma cell
sented. These may occur in the 5' region of the
itself. It is interesting that an active signalling
MMSET gene or in the next gene, LETM1. All of
pathway has recently been described in myeloma
the breakpoints characterised to date occur
plasma cell lines. The other possibility is that
upstream of exon 6 of MMSET in the promoter
secreted FRZb could affect WNT signalling in
region of the gene. JhMMSET hybrid transcripts
nearby cells in the bone marrow microenviron-
are ubiquitous, but the role of the protein in
ment. In particular, it could affect signalling in
myelomagenesis is uncertain. The sequence of
osteoblasts, thus exacerbating bone disease. The
MMSET has many stop codons and the number of
array data was further analysed looking for upreg-
open reading frames is limited. However, cryptic
ulation of other members of the WNT pathway, in
start site could result in theoretical transcripts.
particular of the FZ, frizzled receptor, through
Understanding whether a protein product is actu-
which the WNTs signal. LRP5, the FZ co-receptor,
ally made from this reciprocal translocation is very
was not upregulated, but DKK1, another secreted
important, as small molecules targeting FGFR3 are
molecule inhibiting the WNT pathway, was, fur-
being developed and may not work clinically if
ther implicating WNT signalling in the impair-
19
MMSET is the critical abnormal gene. Preliminary
ment of bone formation in myeloma patients.
These initial findings now need confirmation in
addressed is the attempt to understand the factors,
specific experiments looking at the underlying
either inherited or in the environment, which pre-
mechanisms and roles of these proteins.
dispose individuals to develop myeloma. The
caretaker function of certain gene families has
The results of expression array experiments can
been outlined above. Inherited variation affecting
also be used to define new targets for therapy. One
these pathways could readily increase the likeli-
such target is hepann binding epidermal growth-
hood of a cell developing DNA damage. Genes
like factor (HB EGF). Ongoing work targeting
that repair DNA damage have this caretaker func-
this pathway is being developed. This molecule
tion and are a good place to begin to address the
signals via the ErbB receptors. It has shown that
question of inherited DNA instability as a predis-
these receptors are expressed in MM cells and that
posing factor for the development of myeloma.
HB-EGF acts as a growth factor for myeloma cell
The type of variation being examined is called a
lines. Targeting this pathway can kill myeloma
single nucleotide polymorphism, or SNP, and is
cells; combinations with IL-6 antibodies and dex-
common in the population. SNP variants affect-
amethazone can potentiate these effects.
ing class switch recombination have been deter-
mined. They have been used to look both at
Thus considerable progress has been made in
patients with myeloma and at controls from the
understanding the processes involved in deregu-
population who have not developed myeloma. If
lation of normal plasma cell development and
the variants are seen more frequently in the
transformation to
patients than in the controls, it is likely that they
The type of
a malignant plas-
contribute to an increased risk of developing
variation being
ma cell.
These
myeloma. The problem with this type of study is
processes can be
that many hundreds of cases and controls need to
examined is called a integrated into a
be examined. This problem is being addressed by
single nucleotide
model in which
the IMF, which is sponsoring a project, Bank On A
the acquisition of
Cure (BOAC), which aims to assemble a series of
polymorphism, or
genetic instability
10,000 cases. This will be a very important tool to
SNP, and is common is an early event in
allow investigators to study predisposition to
in the population.
myeloma.
The
myeloma and will open the way to primary pre-
path to malignan-
vention of this distressing illness. Until such time
cy can be mediated by a number of molecular
as prevention is a reality, the same changes can be
processes including the B cell-specific mecha-
used to look at the impact of inherited changes on
nisms of class switch recombination, aberrant
disease outcome. The same inherited DNA vari-
double strand break repair, and impairment of
ants can be used to assess 1) cases of disease treat-
apoptosis. The inevitable consequence is the
ed in a similar fashion; 2) the impact of inter-indi-
acquisition of mutations in other pathways.
vidual variation on treatment response; and 3)
Expression arrays are beginning to identify these
side effects. An example of this is variation in
pathways.
Good candidates as pathways are
GSTP1, an enzyme that can affect the response to
those involved in normal embryonic develop-
chemotherapy and the risk of developing therapy-
ment and patterning. These genes are under
related AML.
tight control, are expressed during limited time
windows, and control many downstream genes.
If expressed at the wrong time, they would mis-
programme the cell, leading to a cell with the
characteristics of malignancy. Examples of such
genes identified by expression arrays include the
WNT and "sonic hedgehog," or SHH, family
members. These types of genes constitute good
targets for therapy, since targeting one gene will
potentially affect multiple downstream genes
either reversing the malignant behaviour or by
causing differentiation and extinction of the
abnormal cells.
20
The other important area that is beginning to be
Genetic Heterogeneity in Multiple Myeloma:
Impact on Diagnosis and Therapy
Hervé Avet-Loiseau, M.D.
differentially overexpressed genes, they iden-
Institut de Biologie, Nantes, France
tified 2 genes coding for secreted factors
FRZB and DKK1. These two genes belong to
the WNT pathway, and represent both nega-
Whereas multiple myeloma (MM) has tive regulators of this signaling pathway.
been thought to be a homogeneous dis-
Interestingly, these 2 genes were not overex-
ease, several pieces of evidence now suggest
pressed in 45 plasma cell samples from nor-
that MM represents a heterogeneous entity,
mal donors. In contrast, some patients lack-
masking several diseases. A full session was
ing bone lesions on X-ray did present an
devoted to this novel view of MM, entitled:
overexpression of DKK1 and/or FRZB. To
"Genetic heterogeneity in MM: impact on
further understand these correlations, the
diagnosis and therapy." The first communi-
authors did include MRI data. Because some
cation, presented by Dr. Shaughnessy (Little
patients did present abnormalities on MRI
Rock, AR), reported on the molecular path-
scans, but lacked lytic images on X-ray, they
ways involved in
combined these 2 groups of patients as an
Patients with MM
one of the most
"MRI-defined lytic lesions" group. The
frequently present
prominent clini-
application of the same analyses to these
cal
aspects
of
novel groups (with MRI-defined bone
activating muta-
MM, bone lesions.
lesions versus no MRI lesion) led to the iden-
tions of the RAS
It is well known
tification of 107 differentially expressed
that
bone
is
genes. In this second analysis, DKK1 overex-
family oncogenes,
destroyed in MM
pression was even more striking in the group
which play a key
by a deregulation
with bone lesions. This study suggests that in
role in prolifera-
of the osteoclast-
MM, osteoclasts might be activated by the
osteoblast
bal-
malignant plasma cells' secretion of the
tion activation.
ance, leading to
WNT pathway antagonists DKK1 and FRZB.
unregulated osteoclast activation.
Because
bone resorption foci are close to malignant
The second communication was given by Dr.
plasma cells, this osteoclastic activation has
Van Ness (University of Minnesota), and was
been linked to the secretion of "osteoclasto-
devoted to the impact of several growth con-
genic" factors by the plasma cells. In order to
ditions on plasma cell gene regulation. The
further understand these mechanisms, John
authors tested the influence of 3 different
Shaughnessy et al. analyzed 170 patients with
growth factors: IL-6, stromal cells, and acti-
MM using microarray technology. They
vating NRAS mutations. IL-6 has been shown
selected two populations of patients, 87
to play a major role in the proliferation and
without evidence of bone disease, and 83
survival of plasma cells. Similarly, in vitro
with more than 3 lytic bone lesions. After
co-cultures of malignant plasma cells with
selection of the plasma cells in these
bone marrow stromal cells stimulate plasma
patients, they examined the expression of
cell proliferation. Patients with MM fre-
approximately 12,000 genes, and searched for
quently present activating mutations of the
genes differentially expressed in the 2 patient
RAS family oncogenes, which play a key role
populations. A total of 367 genes were iden-
in proliferation activation. In order to
tified, 229 being overexpressed and 138 being
decrypt the respective roles of these 3 fac-
underexpressed in patients with lytic bone
tors, they studied the molecular conse-
lesions. Several genes involved in prolifera-
quences of malignant plasma cell activation
tion were upregulated in the group of
(ANBL-6 myeloma cell line) by each of them,
patients with bone disease. Apart from these
using microarray technology. Hierarchical clus-
21
"proliferative" genes, and among the most
tering enabled them to identify gene expres-
sion patterns specific for each of the prolifer-
bined their data for their respective commu-
ative signals, demonstrating that even
nications. Dr. Avet-Loiseau presented the
though common proliferative pathways do
most recent view of the molecular classifica-
exist, each factor activates its own signaling
tion of MM. Because of the low proliferative
pathway. Brian Van Ness then presented an
index observed in plasma cells, chromosomes
analysis of DNA polymorphisms. Individuals
are obtained in only a subset of patients
differ at the DNA level by many variations in
(about one third), preventing an extensive
the DNA sequence, known as "single
knowledge of chromosomal changes in MM.
nucleotide polymorphisms," or SNPs. These
The recent use of molecular cytogenetics
DNA variations may explain the variability
(FISH) circumvents this pitfall, enabling a
in sensitivity of plasma cells to anti-myeloma
dramatic improvement in our comprehen-
drugs, or in the toxicity to these drugs. Dr.
sion of MM oncogenesis. Three major chro-
Van Ness discussed a large international
mosomal changes have been identified:
research
program
supported
by
the
hyperdiploidy, chromosome 13 abnormali-
International Myeloma Foundation, called
ties (CA13), and translocations involving the
"Bank On A Cure (BOAC)." The aim of this
14q32
region
program is to establish a DNA bank of sever-
(t(14q32)), each of
al thousands of samples, enabling support
Since CA13 are
them
being
efforts in population-based studies of genet-
observed in 3/4 of observed in about
ic variants in MM.
half of the patients.
patients with non- Recent studies have
The third speaker was Dr. Keith Stewart
hyperdiploidy, the enabled us to corre-
(Toronto), who presented data on the molec-
late these abnor-
respective prog-
ular profiles characterizing different plasma
malities,
defining
cell stages (normal and malignant). As previ-
nostic value of
several
categories
ously reported by his group, they used a ded-
each abnormality of patients. CA13
icated "Myeloma-chip" containing approxi-
are especially asso-
is unknown.
mately 4300 genes expressed in MM. Using
ciated with non-
this array, they analyzed 25 cell lines (either
hyperdiploidy (three quarters of cases), ver-
MM or other hematopoietic malignancies),
sus only 1/3 of patients with hyperdiploidy.
45 MM patients, as well as 13 normal plasma
Similarly, t(14q32) are especially seen in
cell or B cell specimens. Several genes (essen-
non-hyperdiploid patients (80-90% of the
tially genes involved in the plasma cell differ-
cases, versus only about 1/3 of hyperdiploid
entiation) discriminated MM cell lines from
patients). Interestingly, recurrent and ì ran-
non-MM cell lines. Among patients with
domî t(14q32) present a different distribu-
MM, several groups of patients were identi-
tion. Whereas at least 80% of recurrent
fied, according to their resemblance to nor-
t(14q32), i.e., t(4;14), t(11;14), and t(14;16),
mal cellular counterparts. A group of
are observed in non-hyperdiploid patients),
patients clustered with normal plasma cells,
non-recurrent t(14q32) are essentially seen
whereas a second one clustered with normal
in non-hyperdiploid patients. Whether the
B cells. Analysis of the genes characterizing
first represent primary events and the latter
this latter signature revealed that several
secondary rearrangements is a currently
genes involved in proliferation were up-regu-
unanswerable question. Finally, CA13 do also
lated. These data further supported the actu-
correlate with some t(14q32), and especially
al view of MM as a heterogeneous disease,
t(4;14) and t(14;16), which are associated
possibly regrouping several entities differen-
with CA13 in 85% to 90% of the cases. These
tiated by molecular and/or genetic character-
data allow us to propose an oncogenesis
istics.
model: a first group of patients (about half
of them) would present with hyperdiploidy.
The last two communications were devoted
In these patients, t(14q32) are observed in
to the molecular cytogenetics of MM,
only 1/3 of the cases, and are essentially ran-
regarding either classification of MM, or the
dom translocations, raising the hypothesis of
prognostic significance of this classification.
secondary events. Similarly, CA13 are also
22
Dr. Hervé Avet-Loiseau (Nantes, France) and
seen in 1/3 of the cases. In contrast, the sec-
Dr. Raphael Fonseca (Mayo Clinic) com-
ond group of patients is non-hyperdiploid,
and displays t(14q32) in 80% to 90% of the
as
proliferation.
Similarly,
recurrent
cases, especially recurrent translocations.
t(14q32) have been shown to bear specific
prognostic value: t(4;14) and t(14;16) are
The last communication was given by Dr.
associated with a short survival. However, we
Raphael Fonseca, who reported on the prog-
have to keep in mind that both transloca-
nostic value of the most frequent chromoso-
tions are combined with CA13 in 85% to
mal changes. Several recent series have
90% of the cases, and that the prognostic
demonstrated the poor outcome associated
value might be related to CA13 rather than
with non-hyperdiploidy. However, these
the t(14q32). In contrast, t(11;14) has been
studies are based on cytogenetics, i.e., in
associated with a longer survival, especially
patients with proliferation. Whether these
in
patients
treated
with
high-dose
observations remain true in all the patients
chemotherapy.
will require further experiments. Similarly,
many reports have now shown the high prog-
Thus, as in other hematopoietic malignan-
nostic value of CA13. Since CA13 are
cies, cytogenetic abnormalities are defining
observed in 3/4 of patients with non-hyper-
several subgroups in MM. The use of more
diploidy, the respective prognostic value of
global techniques such as gene expression
each abnormality is unknown. Nevertheless,
profiling should contribute to the identifica-
comparative studies have demonstrated a
tion of novel entities in MM, enabling us to
stronger prognostic power of CA13 identi-
offer specific risk-adapted therapies to
fied by cytogenetics than of CA13 identified
patients.
by FISH. This probably reflects the addition-
al prognostic effect of other parameters, such
Immunobiology:
Role of T Cells in Myeloma
Douglas Joshua, M.D.
phenotypic differentiation of normal and malig-
Royal Prince Alfred Hospital
nant plasma cells has allowed minimal residual
disease assays to be performed by flow cytometry.
Campersdown, NSW, Australia
Immunology - Understanding myeloma growth
IMMUNOLOGY
- The role of CD45 expression
It is now clear that CD45 expression is related to
T
myeloma growth, with the CD45+ plasma cells
he importance of immunobiology and our
being highly proliferative and perhaps representing
understanding of the functional role of the
a more malignant phenotype.
Lack of CD45
immunophenotypic profiles in myeloma have
expression is characteristic of mature plasma cells
greatly advanced in recent years. In addition,
with low proliferative capacity. Lack of CD45 is
understanding of the host-myeloma T cell
more frequently observed in myeloma than nor-
response and the identification of expanded cyto-
mal plasma cells and in late and extramedullary
toxic T cells in patients with myeloma and their
relapse of myeloma rather
than at diagnosis.
possible role in control of myeloma cell prolifera-
CD45 expression could be of strong adverse prog-
tion provides new avenues for therapeutic manip-
nostic signficance (R Bataille).
ulation of the immune response and disease con-
trol. Current avenues of investigation include
Myeloma cells have been shown to be heteroge-
analysis of the role of bioinformatics and immun-
nous both morphologically and phenotypically
odominance of the idiotypic peptides and
and this heterogeneity appears to be present in
cytokine receptor expression in plasma cells.
most patients. Relationship between maturation
Myeloma cell growth and maturation has been
of plasma cells and the ability to respond to IL-6
23
related to antigen expression on plasma cells, and
has also been clearly demonstrated and activation
of the src family kinases associated with CD45
ties of stimulating cytotoxic T cells with immuni-
expression appears to be a prerequisite for the
sation protocols (F Caligaris-Cappio).
proliferation of myeloma cells. It is possible that
understanding the relationship between CD45
Other immune mechanisms of killing myeloma
expression and proliferation will lead to the devel-
cells relate to induction of apoptosis in multiple
opment of chemotherapies targeted to the tyrosine
myeloma. Novel means for re-establishing apopto-
phosphatase activity represented by the CD45 anti-
sis in myeloma by exposure to interferon may be a
gen (M Kawano).
mechanism by which myeloma cells can be sensi-
tised to FAS-induced apoptosis (K Nilson).
Host-tumour interactions in myeloma -
the role of T cells
Finally, data on the expansion of T cells from the
The role of T cells in myeloma is explored by a
peripheral blood of the patient with multiple
number of papers. Expanded T cell clones are
myeloma using the XcellerateTM process have been
present in myeloma and the recognition that the
developed, and clinical trials to evaluate the activi-
presence of these clones conveys a good prognosis
ty of such expanded T cells in myeloma are in
has been documented. The phenotype of these
progress. Studies are also ongoing on the identifi-
clones is CD 8+, CD57+, CD28-, CD27-, perforin-
cation of T cells that reside in the tumour micro-
positive. By making immunodominant idiotype-
environment, as these have been demonstrated to
derived tetramers from peptide fragments with
have oligoclonal restriction and show a greater
high immunodom-
expansion and enhanced response to plasma cells
Expanded T cell
inant scores based
compared to peripheral blood lymphocytes
clones are present
on bioinformatic
(R Vescio, K Noonan).
programmes, it has
in myeloma and the been
clearly
Immunoprofiling by flow cytometry -
recognition that the demonstrated that
identification of malignant plasma cells
the expanded T cell
Immunoprofiling of multiple myeloma using flow
presence of these
clones
do
not
cytometry with specific signature immunopheno-
clones conveys a
recognise idiotype
types for the malignant clone has been document-
good prognosis has but have the char-
ed by a number of investigators. These techniques
acteristics of cyto-
allow minimal residual disease to be identified in
been documented.
toxic T cells that
multiple myeloma. In addition, phenotypic differ-
are seen in chronic viral infections, especially
ence between normal and clonal plasma cells from
CMV, and are unlike the chronic viral infections
patients with monoclonal gammopathy can be
associated with HIV, hepatitis C, and EBV. This
determined, as clonal plasma cells from patients
suggests that protective immunity in myeloma is
with monoclonal gammopathies constantly dis-
associated with similar mechanisms to chronic
play higher abnormal levels of CD56, CD86 and
CMV infection. Tetramer staining using the
CD126, together with lower amounts of CD38 (A
immunodominant pp65 CMV peptide show that
Orfao, L Galvano).
CMV-positive cells are not numerically in accord
with the expanded T cell clones, documenting that
Expression of cytokine receptors in myeloma can
CMV is not the main causative factor of T cell
be correlated with clinical status; two studies indi-
expansion (D Joshua).
cated that myeloma cells were shown to have vari-
able patterns of chemokine receptors and that
T cell dysfunction is evident in myeloma, espe-
migration properties in vitro appeared to be relat-
cially in the advanced stages, and these factors
ed to their expression. The cytokine receptors such
must be taken into consideration when developing
as VEGF and Rank Ligand (RANKL), are present
cellular therapeutic approaches, especially vacci-
in myeloma cells and may play a role in determin-
nation. The addition of various cytokines to
ing bone and possibly angiogenic status in vivo
improve T cell dysfunction may be needed and
(A Alegre, L Trentin, U Heider).
this may also apply to dysfunctional dendritic cells
that are present in myeloma (H Mellstedt).
Antibody-based therapy in myeloma
Investigations regarding the immune reactivity of
The development of antibody-based strategies for
T cells to autologous myeloma cells suggest that
the treatment of myeloma has been hampered by
24
they are only present in early phase disease and are
the fact that suitable plasma-specific antigens are
lost as disease advances, complicating the difficul-
not yet available. However a new antigen, Wue-1,
has been generated and a single chain antibody,
as an immunodominant antigen has emerged
Wue-1xCD3, has been shown to be able to lyse
from bioinformatic programmes and it may be
both normal and malignant plasma cells. This
possible to expand selective T cell populations
holds great promise as a potential agent for the
in patients with multiple myeloma.
treatment of myeloma (D Honenemann).
Cytokine expression in patients with myeloma
SUMMARY
and its correlation with clinical behaviour allows
the possibility of targeting novel therapies to
In summary the immunobiology of myeloma
important cytokines. New data on immunpheno-
has advanced greatly over the last few years. It
typing has clearly identified the ability to detect
is now clear that activated cytotoxic T cells exist
minimal residual disease in myeloma and identify
in patients with myeloma and may be able to be
those malignant from non-malignant plasma cells
stimulated by vaccination. New techniques for
in patients with MGUS.
their isolation have been developed and the
identification of a cell responsible for the pro-
Understanding the immunobiology of the disease
tective effect of the expanded T cell clones has
and the host-tumour reactions that occur will
been identified and shown to be similar to the
allow both more directed vaccination pro-
expanded cytotoxic T cells associated with CMV
grammes to be developed, and the myeloma-asso-
infection. However, it is present in CMV-nega-
ciated defects in dendritic cell and T cell function
tive individuals, and CMV tetramer studies
to be corrected for optimal vaccination and stim-
show that CMV-positive cells do not account for
ulation of anti-tumour cytotoxicity.
all these expanded cells. A much more thor-
ough understanding of the role of the idiotype
From MGUS to Symptomatic Multiple Myeloma:
Criteria for Diagnosis of Plasma Cell Disorders
Robert A. Kyle, M.D.
Most patients with multiple myeloma require
Mayo Clinic, Rochester, MN
chemotherapy at diagnosis because of symptoms
due to pathologic fracture, anemia, renal impair-
The session opened with definitions of the ment, or hypercalcemia. Approximately 20% of
monoclonal gammopathies, which are a
patients who fulfill the usual criteria for multiple
group of disorders associated with monoclonal
myeloma are asymptomatic and are designated as
proliferation of plasma cells. The International
having smoldering or asymptomatic myeloma.
Myeloma Working Group has reviewed the crite-
These patients have a serum M-protein é 30 g/l
ria for diagnosis and classification with the aim of
and/or bone marrow clonal plasma cells é 10%
producing simple, easily used definitions based
but no end organ damage. In an effort to clarify
on routinely available investigations. Monoclonal
the prognostic features of these patients Weber et
gammopathy of undetermined significance
al. (P4.2, 2003) have identified low-, intermedi-
(MGUS) was defined as having a monoclonal
ate-, and high-risk groups based on three vari-
protein < 30 g/l and bone marrow clonal plasma
ables (M-protein > 30 g/l, IgA protein type, and
cells < 10% with no evidence of multiple myelo-
Bence Jones proteinuria > 50 mg/day). The fea-
ma, other B-cell proliferative disorders, or amy-
tures evaluated included serum M-protein level,
loidosis. Patients with MGUS must have no relat-
2 microglobulin, marrow plasmacytosis, levels
ed organ or tissue impairment (ROTI) (end organ
of uninvolved immunoglobulins, M-protein
damage); which is typically manifested by
type, level of Bence Jones proteinuria (BJP), age,
increased calcium, renal insufficiency, anemia, or
serum albumin, and hemoglobin. For patients
bone lesions (CRAB) attributed to the plasma cell
with an available MRI of the spine, the impact of
proliferative process.
Symptomatic myeloma
this test was also assessed. Univariate analysis
requires evidence of ROTI (Kyle et al. P4.1 2003).
revealed abnormal MRI, M-protein > 3 g/dl,
25
2M > 2.5 mg/L, marrow plasmacytosis > 25%,
and suppression of uninvolved immunoglobu-
Kaufmann et al. (094, 2003) studied 34 patients
lins < 30 mg/dl to be indicators of a shortened
with multiple myeloma that developed after
time to progression. Multivariate analysis was
recognition of MGUS. Twenty-four patients had
limited to 72 patients with complete information
overt myeloma requiring therapy and 10 patients
for all five variables. Three risk categories were
had smoldering myeloma. Deletion of chromo-
identified for time to disease progression and
some 13q14 was detected in 14 of the 24 treated
were identified as follows: low risk (33 patients) -
patients and in only 2 of the 10 smoldering myelo-
normal MRI, and serum M-protein < 3 g/dl
ma patients. Chromosome 13q14 deletion was
(median time to progression [TTP] 79 mos);
detected in 17 (32.7%) of 52 patients with MGUS.
intermediate risk (28 patients) - abnormal MRI
They emphasized that deletion of 13q14 and IgH
or M-protein > 3 g/dL (median TTP 30 mos);
translocations were early events in monoclonal
and high risk (11 patients) abnormal MRI and
gammopathies and did not appear at the time of
M-protein > 3 g/dL (median TTP 17 mos) (p <
progression from MGUS to multiple myeloma.
.01).
Because MRI was not available for all
patients and a previous model had included BJP,
Rajkumar (P4.4 2003) reported that circulating
a multivariate analysis was performed eliminat-
plasma cells in MGUS was a risk factor for pro-
ing MRI and including BJP (109 patients with
gression. Three hundred thirty persons with
complete data for all five variables). In addition
MGUS who had been evaluated at the Mayo
to serum M-protein level the only covariate that
Clinic between 1984 and 1997 were analyzed.
contributed significantly to the model was
The presence of plasma cells was determined by a
immunoglobulin type, with a higher risk associ-
slide-based immunofluorescence
technique.
ated with IgA type. Three risk categories were
Thirty-eight patients (12%) progressed to either
identified: low risk (50 pts) - serum M-protein
multiple myeloma (23 pts), smoldering multiple
< 3 g/dL and IgG type (median TTP 52 mos);
myeloma (11 pts), primary systemic amyloidosis
intermediate risk (51 pts) M-protein > 3 g/dL
(AL) (3 pts), or Waldenström's macroglobuline-
and IgA type (median TTP 25 mos); and high
mia (1 pt) dur-
risk (8 pts) M-protein > 3 g/dL and IgA type
They also pointed
ing follow-up.
(median TTP 9 mos) (p < 0.1).
Patients
with
out that microarray
circulating plas-
Jakob et al. (087, 2003) evaluated 32 untreated
analysis might be
ma cells were
patients with multiple myeloma who had no
useful in separating
twice as likely
osteolytic lesions with conventional radiography.
(RR 2.2) to have
MGUS from multiple
Serum levels of carboxy-terminal telopeptide of
progression to
type-1 collagen (ICTP) were significantly elevat-
myeloma but that
another plasma
ed in patients with an abnormal bone MRI com-
cell
disorder
two studies failed to
pared to those with a normal bone MRI.
compared to the
distinguish the two
remainder (P =
Facon and colleagues (P4.3 2003) performed flu-
entities.
0.02).
When
orescence in situ hybridization (FISH) with
c o nsider ing
probes directed to 14q32 and 13q14 chromoso-
only those with > 0.5 x 109/l plasma cells, the rel-
mal regions. The incidence of 14q32 rearrange-
ative risk of progression was 2.5 (P = 0.016). The
ment was 48% of 143 MGUS patients compared
median overall survival was lower for those
to 73% of 653 multiple myeloma patients. The
patients with circulating plasma cells compared
presence of t(11;14) was found in 13% of 147
to the remainder (P = 0.03). In a separate study
MGUS patients and in 16% of 669 multiple
of 400 patients with plasma cell disorders seen at
myeloma patients. Chromosome 13 deletion was
the Mayo Clinic: MGUS (76 pts), smoldering
found in 21% of 147 MGUS patients and in 43%
MM (112 pts), newly diagnosed, untreated MM
of 669 multiple myeloma patients. Thus, dele-
(99 pts), relapsed MM (26 pts), and AL (87 pts)
tion of chromosome 13 is an early event in onco-
high grade angiogenesis was present in 0% of
genesis of multiple myeloma but the issue of
controls and AL, 1% of MGUS, 3% of SMM, 29%
whether del(13) is of importance in progression
of MM, and 42% of relapsed MM (P < 0.001).
is debatable. They also pointed out that microar-
ray analysis might be useful in separating MGUS
Lust and Donovan (P4.5 2003) measured IL-1b
26
from multiple myeloma but that two studies
functional activity with a bioassay using IL-6
failed to distinguish the two entities.
production by bone marrow stromal cells as a
sensitive surrogate marker. IL-1b-specific IL-6
Haug et al. (084, 2003) reported trends correlat-
production showed that myeloma patients
ing the expression of VEGF, bFGF, and their recep-
induced a 2.2 ñ 24.1-fold increase in IL-6 that
tors and the degree of bone marrow angiogenesis.
was statistically different from the 0.25 ñ 1.9-fold
However, there was no significant difference in
increase by normal or MGUS patients (P <
expression of VEGF, bFGF, and their receptors by
0.001). The SMM patients
plasma cells in MGUS, smoldering multiple
MGUS was
fell into two groups: stable
myeloma, or newly diagnosed symptomatic multi-
disease (n = 31) and those
ple myeloma. In another report IL-6, sIL-6R,
diagnosed in that progressed to active TNF, and HGF values were higher in patients
434 patients MM (n = 14). The SMM
with multiple myeloma than in MGUS (Herndez
patientsí stable disease gen-
Martin 085, 2003). The authors concluded that
in a single
erated a 0.63 ñ 6.91-fold
the serum concentrations of these cytokines were
institution
increase in IL-6 production
useful for discriminating the patients with multi-
from
and was statistically differ-
ple myeloma from those with MGUS.
ent from the 1.62 ñ 33.16-
September
fold increase by the SMM
Seidl et al. (089, 2003) demonstrated that methy-
1970 to
patients that progressed to
lation of several genes occurred frequently in
January 2001 active MM (p = 0.001).
multiple myeloma. They reported that methyla-
The stromal cell IL-6 pro-
tion of CDH1 was not detected in MGUS but was
duction could be inhibited with an IL-1 inhibitor
present in multiple myeloma patients and in an
by > 90% in 41/53 patients tested. Sixty-two
even higher percentage of patients with plasma
patients with SMM were followed for at least one
cell leukemia suggesting that CDH1 methylation
year or progressed during that time. The plasma
was an indicator of disease progression.
cell labeling index, percent bone marrow plasma
cells, serum albumin, M-protein level, 2
MGUS was diagnosed in 434 patients in a single
microgloblin, creatinine, calcium, hemoglobin,
institution from September 1970 to January 2001
and stromal cell IL-6 production were evaluated.
(BladÈ et al. 2003). All had an M-protein < 30
Only stromal cell IL-6 production and bone mar-
g/l. IgG accounted for 67%, IgA 19%, and IgM
row plasma cells were found to be significant in
12%. Light chain and biclonal proteins were
predicting progression of SMM to MM.
found in 1% each. The median M-protein size
Seventeen patients with SMM had increase of
was 15.6 g/l. The median percentage of bone
< 1.6-fold and none progressed to active myelo-
marrow plasma cells (BMPC) in 305 patients was
ma. In contrast, 14 of 28 SMM patients with a é
4.6% (range: 0.4 ñ 25). After a median follow-up
1.6-fold increase progressed to active MM with a
of 5.2 years, 50 patients (11.5%) developed either
median time of progression of approximately 2.5
multiple myeloma (44 pts), Waldenstr ^ mís
years.
macroglobulinemia (5 pts), or AL amyloidosis (1
pt). The median time to progression was 5.4
Dring et al. (091, 2003) analyzed plasma cells from
years (range: 1.4 ñ 16.9 yrs). The risk of progres-
5 normal persons, 5 MGUS patients, and 31 mul-
sion was 15.4% at 10 years and 34% at 20 years.
tiple myeloma patients following CD138+ selec-
The variables associated with a higher risk of
tion and SMART PCR-based amplification using
transformation were IgA type, light chain,
an Affymetrix U95 Av2 gene chip comparing
amount of M-protein (< 15 vs. > 15 g/l; p =
12,000 known expressed sequences. Three hun-
0.005) and the percentage of BMPC (< 5% vs. >
dred eighty genes separated normal plasma cells
5%; p = 0.007). In summary, the type of M-pro-
from myeloma plasma cells whereas 263 genes
tein (IgA or ) and the size of the M-protein as
separated normal plasma cells from MGUS plas-
well as the percentage of bone marrow plasma
ma cells. Interestingly, the majority of genes were
cells predicted progression.
downregulated. The authors concluded that gene
array analysis highlighted the differences in gene
Goldaniga et al. (080, 2003) retrospectively evalu-
expression levels between normal, MGUS, and
ated 300 patients with asymptomatic IgM mono-
myeloma plasma cells. Genes involved in the con-
clonal gammopathy. Patients requiring therapy, as
trol of transcription and developmental pathways
well as those with an autoimmune disorder, cryo-
were important in the transition of MGUS to
globulinemia, or amyloidosis were also excluded.
myeloma.
The 300 patients were followed for a median of 55
27
months during which time 43 (14.7%) required
chemotherapy for either symptomatic Waldenström's
P4.1). Hematol J 2003 Suppl 1;4:S31.
macroglobulinemia (70%), non-Hodgkinís lym-
Weber DM, Wang LM, Delasalle KB, Smith T,
phoma (18.5%), amyloidosis (7%), or peripheral
Alexanian R. Risk factors for early progression of
neuropathy (4.5%). The progression-free survival
asymptomatic multiple myeloma (Abstract P4.2).
was 91% at 5 years and 78% at 10 years. The vari-
Hematol J 2003 Suppl 1;4:S31.
ables correlating with evolution to an overt lym-
phoproliferative disease were serum IgM concen-
Jakob C, Zavrski I, Heider U, Fleissner C, Eucker J,
tration, Bence Jones proteinuria, hemoglobin, IgG
Possinger Sezer O. Serum levels of carboxy-termi-
level, serum albumin, and male gender. In multi-
nal telopeptide of type-1 collagen (ICTP) are ele-
variate analysis serum IgM concentration, hemo-
vated in patients with multiple myeloma with
globin, and male gender were significant variables.
skeletal abnormalities in MRI, who lack osteolyses
The relative increased risk of progression in males
in conventional radiography (Abstract 087).
(vs. females) was 4.1 while an increase in serum
Hematol J 2003 Suppl 1;4:S127.
IgM was 2.68. Using the three prognostic vari-
ables the authors developed a prognostic index
Facon T, Avet-Loiseau H, Leleu X, Bataille R.
that separated those with low and high risk for a
Cytogenetic changes in the evolution of mono-
malignant evolution.
clonal gammopathy of undetermined significance
(MGUS) to multiple myeloma (Abstract P4.3).
Montañés et al. (081, 2003) reported that 639
Hematol J 2003 Suppl 1;4:S32.
(33%) of 1,906 patients with MGUS developed
cancer.
Higher incidences of cancer were
Kaufmann H, Ackermann J, Nösslinger T,
observed among the MGUS patients compared
Gisslinger H, Wieser R, Kromer E, Ludwig H,
to the general population.
Drach J. Multiple myeloma evolving from MGUS:
high incidence of chromosome 13q deletions,
Rosiñol et al. (095, 2003) described 53 patients
which are invariably associated with IgH transloca-
with smoldering multiple myeloma from a single
tions (Abstract 094). Hematol J
2003 Suppl
institution. The overall survival from diagnosis
1;4:S130.
was 8.3 years. They described ì evolvingî smol-
dering myeloma in 23 patients with a progressive
Rajkumar SV. Circulating plasma cells, labeling
increase in serum M-protein.
Twenty-five
index, and angiogenesis in MGUS and smoldering
patients had "non-evolving" smoldering myelo-
multiple myeloma (Abstract P4.4). Hematol J
ma with long-lasting stable M-protein that
2003 Suppl 1;4:S33.
abruptly increased when symptomatic myeloma
developed. Patients with "evolving" disease had
Lust JA, Donovan KA. Cytokines in MGUS: thera-
an earlier transformation than those with "non-
peutic interventions to prevent progression
evolving" smoldering myeloma (60% and 90%
(Abstract P4.5). Hematol J 2003 Suppl 1;4:S34.
vs. 16% and 15% at 2 and 5 years, respectively).
However, no significant differences were
Dring A, Davies FE, Li C, Rawstron AC, Shammas
observed in survival between both groups (6.4 vs.
MA, Fenton JA, Hideshima T, Chauhan D, Rees K,
8.9 yrs). Thirty-four of the 53 patients developed
Gonzalez-Castro D, Auclair D, Wong WH, Munshi
symptomatic multiple myeloma.
Thirty-one
NC, Morgan GJ, Anderson KC. Characterisation of
patients were treated. In both groups the pattern
the transition of MGUS to multiple myeloma
of progression consisted of anemia and/or lytic
using expression microarrays (Abstract 091).
lesions but no renal failure, hypercalcemia, or
Hematol J 2003 Suppl 1;4:S129.
extramedullary plasmacytomas. Although the
response rate to therapy was poor, the survival
Haug JL, Kumar S, Witzig TE, Thompson MA,
from transformation to symptomatic multiple
Wellik L, Timm MM, Greipp PR, Rajkumar SV.
myeloma was 3.5 years.
Expression of angiogenic cytokines by plasma cells:
a comparison of MGUS, smoldering myeloma and
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28
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Utility of serum cytokines in the study of mono-
Goldaniga M, Gobbi P, Cortelazzo S, Broglia C,
clonal gammopathies and bone disease of multiple
Guffanti A, Oldani E, Stelitano C, Brozino B, Calori
myeloma (MM) (Abstract 085). Hematol J 2003
R, Pogliani E, Merli F, Baldini L. Clinical evolution
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tomatic IgM monoclonal gammopathy (Abstract
Seidl S, Ackermann J, Kaufmann H, Zielinski CC,
080). Hematol J 2003 Suppl 1;4:S123.
Drach J, Zöchbauer-Müller S. Aberrant methyla-
tion of tumor suppressor genes in patients with
Montañés MA, Franco-Garcia E1, Martos C2,
multiple myeloma and monoclonal gammopathy
Garcia-Capintero G2, Recaséns V, Gomez-López
of undetermined significance (Abstract 089).
L2, Giralt M, Rubio-Félix D, Giraldo P. Incidence
Hematol J 2003 Suppl 1;4:S128.
of solid tumors in cohort of patients with mono-
clonal gammopathies of undetermined signifi-
Bladé J, Rozman M, Rosiñol L, Nadal B, Giné E,
cance along twenty years (Abstract 081). Hematol
Aymerich M, Esteve J, Cervantes F, López-
J 2003 Suppl 1;4:S124.
Guillermo A, Bosch F, Nomdedeu B, Montserrat E.
Monoclonal gammopathy of undetermined signif-
Rosiñol L, Bladé J, Esteve J, Aymerich M, Giné E,
icance (MGUS): clinical predictors of malignant
Montoto S, Nadal E, Rozman M, Queralt R, Filella
transformation in 434 patients from a single insti-
X, Carrió A, Montserrat E. Smoldering multiple
tution with a long follow-up (Abstract 079).
myeloma pattern of progression and subsequent
Hematol J 2003 Suppl 1;4:S122.
outcome in 53 patients from a single institution
(Abstract 095). Hematol J 2003 Suppl 1;4:S131
Role of Microenvironment:
Endothelial Cell-Tumor Cell Interactions in MM
Ivan Van Riet, Ph.D.
findings in relation to the development of new
Department Hematology-
therapeutic interventions.
Immunology
INTERACTIONS WITH BONE
Free University, Brussels, Belgium
MARROW ENDOTHELIUM
It is believed that MM cells in the BM can re-enter
Therestrictedlocalizationandgrowthof multi- the blood circulation and migrate to distant bone
ple myeloma (MM) cells in the bone marrow
marrow sites, contributing to disease spreading
(BM) compartment is the result of specific molec-
and evolution. According to the migration of nor-
ular interactions between the tumor cells and their
mal circulating leukocytes, it can be assumed that
microenvironment. Tumor cells do not only inter-
MM cells express several molecules that allow
act with the BM endothelium during the homing
them to bind to and migrate through BM endothe-
process but communicate, once arrived in the BM,
lium during the extravasation process (migration
with different cell types in the BM stroma leading
from blood to bone marrow). Dr. I. Vande Broek
to different events which are directly linked to the
(Free University Brussels, Belgium) presented data
pathogenesis of this malignant disease. These
showing that human MM cells have the capacity to
include prevention of apoptosis, stimulation of
degrade the basement membrane of endothelium
proliferation, and acquisition of drug resistance in
and that BM endothelial cells can stimulate the
the tumor cells and induction of osteolysis and
invasive capacity of the MM cells. Moreover she
angiogenesis. During the last MM workshop in
showed that BM endothelial cells enhance the pro-
Salamanca several presentations focused on new
duction of the metalloproteinase MMP-9 in the
aspects of these tumor-host interactions and illus-
tumor cells through secretion of hepatocyte
trated, in some cases, the importance of these new
growth factor (HGF). Myeloma cell-produced
29
MMP-9 seems to be directly involved in basement
(line PI-3K/Akt and Raf/MAPK), decrease of pro-
degradation since this protease degrades collagen
apoptotic proteins, increased activity of the tran-
IV, a major component of the basement mem-
scription factor NF-B, and increased expression
brane. Dr. M. Parma-Cabanas (Centro de
of proliferation-stimulating proteins. Interestingly,
Investigaciones Biologicas, Madrid, Spain) demon-
many of these events were also noticed when the
strated the involvement of a second metallopro-
tumor cells were previously treated with IGFs
tease in the invasion of MM cells, i.e. MT-MMP. In
(Insulin-like
Growth
Factors),
important
addition she showed that the migration of human
cytokines which are, like Il-6, produced by BM
MM cells through endothelium can be stimulated
stromal cells in MM patients.
by SDF-1, a chemokine produced by BM stromal
cells, through transient upregulation of the adhe-
SDF-1 is a chemokine that not only has the capac-
sion molecule a4b1. Dr. N. Gonzalez-Paz (Mayo
ity to stimulate the migration of tumor cells but
Clinic, Rochester) presented data showing that
also prevents apotosis and stimulates tumor prolif-
SDF-1 production is significantly increased in
eration in several neoplastic diseases. SDF-1 binds
MM, both by analyzing transcript-expression in
to CXCR-4 on the target cell and the activation of
BM stromal cells and protein secretion in BM plas-
this last receptor is normally controlled by SOCS
ma. This increased production might contribute to
(Suppressors of cytokine signaling). Dr. N.
an enhanced migration of circulating MM cells to
Gonzalez-Paz (Mayo Clinic, Rochester) showed
the BM. Dr. R. U. Holt (Norwegian University of
that in BM stroma of MM patients, there is no
Science and Technology, Oslo, Norway) showed
expression of SOCS mRNA (in contrast to BM
that the migration of human MM cell lines is not
stroma in normal and MGUS patients). This indi-
only stimulated by SDF-1 but also by HGF and
cates that interactions between SDF-1 and CXCR-
IGF-1 (Insulin-like Growth Factor-1). In addition
4 are in MM unchecked, which will result in con-
she showed that this migration involves the adhe-
tinual activation of the receptor and uncontrolled
sion molecule a4b1.
tumor growth.
The first form
INTERACTIONS WITH BONE
Dr. M. Alsina, from
involves soluble
the group of Dr. W.
MARROW STROMA
cytokines like IL-6, Dalton (University
of South Florida,
secreted by stromal
Once entered in the bone marrow compartment,
Tampa) presented
myeloma cells will receive the appropriate signals
cells. The second
data showing that
to survive and to grow. This process is found to be
drug resistance of
form requires
the result of a functional interplay between the
myeloma cells is
direct cell to stroma
myeloma cells and the surrounding microenvi-
not only mediated
ronment, involving the action of various
contact and has
by
endogenous
cytokines, adhesion molecules, and metallopro-
molecular mecha-
been given the term
teinases. It is believed that stromal cells will not
nisms but that the
cell adhesion medi-
only activate the myeloma cells but that also the
tumor
cell
tumor cells will instruct and stimulate the stromal
ated drug resistance microenvironment
cells. Dr. F. Caligaris-Cappio (University of
also influences how
(CAM-DR).
Milano, Italy) stated that the acquisition of the
a
myeloma
cell
capacity to activate endogenous stromal cells
responds to cyto-
might be the most important event that initiates
toxic drugs. She showed that two different forms of
the transition from the pre-malignant condition,
tumor cell-microenvironment interaction could
called MGUS, to real MM.
explain how some myeloma cells survive initial
drug exposure and eventually express classical
Dr. C. Mitsiades (Dana-Farber Cancer Institute,
mechanisms of drug resistance. The first form
Boston) showed that co-culturing human MM
involves soluble cytokines like IL-6, secreted by
cells (MM-1S cell line) with pre-cultured BM stro-
stromal cells. The second form requires direct cell
mal cells results in the alteration of expression of
to stroma contact and has been given the term cell
numerous genes in the tumor cells, as demonstrat-
adhesion mediated drug resistance (CAM-DR).
ed by oligonucleotide microarrays and proteomics
Moreover it was demonstrated that adhesion of
30
analyses. These changes included activation of sig-
MM cells to fibronectin (FN), a major component
naling pathways that support tumor cell survival
of the extracellular matrix of bone marrow stroma,
or to bone marrow stromal cells (via integrins 1),
of Innsbruck, Austria) provided evidence that MM
contributes to a reversible de novo drug resistance
cells produce a factor which sensitizes normal bone
or CAM-DR. This process induces reversible
cells to apoptosis induced by TRAIL (TNF-related
genomic changes that predispose cells to survive
apotosis-inducing ligand), a molecule produced by
initial drug exposure and allows for the ultimate
bone marrow stromal cells.
acquisition of resistance to drugs including mel-
phalan. Dr. T. Landowski from the same group
Some presentations focused on the expression and
reported that exposure of MM cells to FN induces
role of OPG in MM. Dr. Y. Li from the group of Dr.
the upregulation of 53 different genes, as assessed
R. Pearse (Cornell University, New York) reported
by microarray analysis. Some of these genes are
that MM cells produce brain-derived neurotroph-
specific for well-characterized myeloma survival
ic factor (BDNF) and that this molecule is involved
factors (like IL-6 and cIAP-2) and their expression
in the MM cell-mediated down-regulation of OPG
is regulated by the transcription factor NF-B. It is
in the BM stroma. E. De Leenheer, working in the
believed that activation of NF-B by FN also con-
group of Dr. P. Croucher (Oxford University, UK)
tributes to the CAM-DR phenotype.
demonstrated in the 5T33MM mouse model that
BM-EC produce OPG but that this production is
Within the bone marrow environment, myeloma
downregulated when the EC are in close contact
cells also mediate bone remodeling by activation of
with 5TMM tumor cells. This observation might
osteoclasts, inhibition of osteoblasts, and secretion
represent an additional mechanism that con-
of bone-degrading proteases (like MMP-9).
tributes to the myeloma cell-mediated develop-
Recently it was suggested that the Receptor
ment of bone disease. Dr. C. Shipman, from the
Activator of NF-B (RANK) a molecule central to
same group, reported that OPG does not only reg-
osteoclast generation, plays an important role in
ulate bone resorption but may also function as a
MM-induced osteolysis. RANK is predominantly
paracrine survival factor of MM cells by inhibiting
expressed on osteoclast precursors and mature
apoptosis in the tumor cells which is induced by
osteoclasts whereas its cognate ligand (RANKL) is
TRAIL.
expressed by stromal cells and osteoblasts. In vivo
the biological activities of RANKL are blocked by
Several studies have shown that MM plasma cells
osteoprotegerin (OPG). MM cells seem to trigger
secrete factors that cause upregulation of RANKL
osteoclastogenesis by disrupting the balance
by stromal osteoblasts, but it remains controver-
between RANKL and its natural inhibitor OPG.
sial whether MM cells express RANKL themselves.
MM cells can increase RANKL and decrease OPG
Dr. A. Farrugia (University of Adelaide, Australia)
production by stromal cells. In this way a paracrine
reported that primary MM cells express both
loop is created, in which the MM cells stimulate the
RANKL transcripts and protein. Moreover, it was
generation of osteoclasts and the latter degrade
shown that RANKL expressed by MM cells is
bone matrix, resulting in the release of several
functional and can induce the formation of osteo-
cytokines (like IL-6 and IGFs) that can support the
clast-like cells. Also Dr. S. Yaccoby observed in his
growth of the tumor cells. Dr. Yaccoby (University
study that primary MM cells express RANKL on
of Arkansas, Little Rock) demonstrated that osteo-
their surface and that this molecule is directly
clasts stimulate the proliferation and survival of
involved in osteoclastogenesis.
MM cells, by direct cell-to-cell contact. A similar
finding was also documented by Dr. M. Abe
RANKL exists principally as a membrane-bound
(University of Tokushima, Japan) demonstrating
molecule, although a soluble form (sRANKL) can
that osteoclasts produce osteopontin (OPN), a
be produced as well. Dr. P. Croucher (Oxford
molecule that enhances myeloma cell growth in
University) presented the results of some experi-
concert with IL-6.
ments that were performed in the in vivo 5T2MM
mouse model, in which the development of
Dr. Yaccoby also reported that co-culturing with
myeloma is, as in the human situation, associated
osteoclasts induces altered expression of numerous
with the occurrence of increasing osteolytic
genes (at least 41) in human MM cells and not in
lesions. He demonstrated that tumor-bearing ani-
normal plasma cells. Some of these genes are
mals have increased serum concentrations of
involved in cell cycle progression, oncogenesis and
sRANKL and unchanged OPG levels. In contrast,
adhesion. Moreover he also showed that bone for-
mice that were injected with the variant line
mation in MM is triggered by induction of apop-
5T33MM did not develop osteolytic disease and
31
tosis of osteogenic cells. Dr. I. Tinhofer (University
had no detectable sRANKL in their serum but had
increased OPG. These data provide evidence that
poster showing that MVD in the BM of MM
the balance between a soluble form of RANKL and
patients decreased significantly after treatment
OPG may play a critical role in regulating osteo-
with the combination of VAD containing liposo-
clast formation and bone disease in myeloma.
mal doxorubicin plus thalidomide. The same
Using the 5T2MM model Dr. P. Croucher also pre-
author showed data that indicate that the bone
sented data showing that treatment of mice with a
marrow MVD is also increased in patients with
recombinant murine RANK-murine Fc fusion
Waldenström's Macroglobulinemia.
protein (RANK.Fc) could inhibit the development
of osteolytic bone disease in this model. This rais-
Several presentations addressed the molecular
es the possibility that targeting the RANKL/RANK
mechanisms that underlie the neovascularisation
interaction could be a valuable approach to treat-
process in MM. Dr. I. Van Riet (Free University
ing myeloma bone disease.
Brussels, Belgium) presented data showing that
MM cells not only produce the well-characterized
The group of Dr. Roodman (University of
angiogenic factors, VEGF and bFGF, but that
Pittsburgh) demonstrated previously that MM
PDGF (Platelet-derived growth factor), another
cells produce a chemokine, i.e. MIP-1, that is
pro-angiogeneic molecule, is also expressed.
involved in MM bone disease since it can directly
Moreover PDGF production seems to be upregu-
activate osteoclast precursor cells. During this
lated in both MM cells and EC when both cell
workshop he presented data indicating that
types are in contact with each other. In the in vivo
abnormal transcriptional regulation of MIP-1
5T33MM mouse model it was shown that the use
in MM is due to imbalance between the expres-
of the angiogenesis inhibitor SU11657 results in a
sion levels of the acute myeloid leukemia-1A
strong reduction of the MVD to the value observed
(AML-1A) and AML-1B transcription factors.
in tumor-free animals. Since SU11657 inhibits the
Moreover this imbalance also increases the
receptors for VEGF and PDGF, it can be assumed
expression of some other genes that have impact
that these two angiogeneic molecules play an
on the prognosis of the disease, such as IL-3,
important role in the in vivo regulation of the
which will enhance tumor proliferation.
angiogenesis process in MM. Dr. A. Vacca
(University of Bari, Italy) reported that bone mar-
A few presentations reported on the mode of
row endothelial cells in MM patients have differen-
action of the biphosphonate, zoledronic acid
tial phenotypic and morphological characteristics
(ZOL), that is currently used extensively to treat
as compared to their normal counterparts. He also
the skeletal manifestations of several malignan-
observed an antigenic phenotypic heterogeneity
cies, including MM. This molecule can induce
among the endothelial cells in MM bone marrow.
apoptosis in osteoclasts but has also some direct
He concluded that the extended vessel network in
effects on osteoblast-like cells. Dr. B. Pan
bone marrow of MM patients results from both
(University of Adelaide, Australia) demonstrated
angiogenesis and embryonic vasculogenesis.
that this molecule has the potential to stimulate
Dr. N. Mitsiades (Dana-Farber Cancer Institute,
the differentiation of human adult bone-derived
Boston) presented data indicating that the protea-
cells in vitro. In a separate study, the same group
some inhibitor PS-341 stimulates VEGF synthesis
demonstrated that ZOL can increase the produc-
in MM cells. He also reported that this inhibitor
tion of OPG protein while it reduces membrane
causes direct anti-proliferative and apoptosis-
RANKL protein expression in primary human
inducing effects on endothelial cells which over-
osteoblast-like cells. Dr. A. Corso (University of
come the increased production of VEGF and result
Pavia, Italy) reported that ZOL also has direct
in net inhibition of angiogenesis.
anti-proliferative and pro-apoptotic activity in
vitro on bone marrow stromal cells.
At last Dr. J. Bahlis (University of Miami) provided
evidence that in the bone marrow microenviron-
Several clinical observations indicate that the pres-
ment, MM cells might also interact with dendritic
ence of myeloma cells within the bone marrow
cells by cell-to-cell contact-mediated activation of
compartment is associated with increased activity
the CD28 molecule on the tumor cells. This activa-
of endothelial cells, resulting in neovascularisation.
tion results in upregulation of NF-B activity in
Bone marrow microvessel density (MVD) is signif-
the myeloma cells, which might stimulate the
icantly increased in MM patients and is a predictor
tumor proliferation as well.
32
of poor survival. Dr. Hatjiharissi (Theagenion
Cancer Center, Thessaloniki, Greece) presented a
New Prognostic Criteria for
Classification and Monitoring MM:
Role of PET/MRI in Disease Monitoring
Brian G.M. Durie, M.D.
serum 2 microglobulin and serum albumin
Cedars-Sinai Comprehensive
emerged as the best predictors of survival dura-
tion from the start of treatment. The IPI index or
Cancer Center, Los Angeles, CA
International Myeloma Group Staging System
(IMWG SS) is shown in Table 1.
This session included 6 plenary topics. P7.1-P7.6.
Table 1
The topics and authors are:
P7.1: Development of an international prognostic
International Prognostic Index (IPI)
index (IPI) for myeloma: report of the interna-
Staging for Multiple Myeloma
tional myeloma working group. Greipp PR, San
Miguel JF, Fonseca R, Avet-Loiseau H, Jacobson
JL, Rasmussen E, Crowley JJ, and Durie BGM.
STAGE 1
2M < 3.5
ALB
3.5
P7.2: The major prognostic value of cytogenetics
in myeloma. G Tricot.
STAGE 2
2M < 3.5
ALB < 3.5
P7.3: The importance of imaging in myeloma
Or
staging, prognostic classification and monitoring.
2M 3.5 - 5.5
Durie BGM, Waxman AD, DíAgnolo A, and
Williams CM.
STAGE 3
2M > 5.5
P7.4: Role of serum free light chain measure-
ments in disease diagnosis and monitoring.
Footnote: 2M = serum 2 microglobulin in mg/dl
Bradwell AR, Mead, GP, Drayson MT, Kyle RA,
ALB = serum albumin g/dl
and Katzmann JA.
P7.5: Investigation of residual disease by quanti-
Good and Poor Risk Groups
tative PCR in multiple myeloma. Corrandini P,
Age is the only additional factor that significantly
Carrabba M, Ladetto M, Montefusco V, and
impacts outcome.
Gahrton G.
Survival for > 5 years is associated with age < 60
P7.6: Immunophenotypic investigation of mini-
years.
mal residual disease in multiple myeloma. Mateo
G, Orfao A, Montalban MA, Blade J, Lahuerta JJ,
Survival for < 2 years is associated with age > 60
and San Miguel JF.
years. Other correlations in this category include:
platelet count < 130,000/mm3 and LDH serum
The six presenters indicated the current role of a
level above normal.
broad range of clinical tests in assessing myeloma
stage and prognosis. Dr. Philip Greipp, presenting
Cytogenetics do significantly influence outcome,
for the International Myeloma Working Group (a
however, chromosome 13 deletion and presence of
research committee of the International Myeloma
complex chromosome abnormalities do not add to
Foundation), summarized the results of a collab-
the impact of age, 2M and ALB in multivariate
orative analysis involving 17 centers from Asia,
and tree regression analyses.
Africa, Europe, North America and South
America, incorporating 11,179 patients studied
This is very similar to the recently published
between 1981 and 2002. Using a multivariate
SWOG staging system. The most important advan-
33
technique and a regression tree analysis model,
tages of this IMWGSS are listed in Table 2.
Table 2
There is little doubt that within their 1,475
patients the presence of abnormal cytogenetics is a
Advantages of IMWG SS
poor prognostic factor. Presence of chromosome
13 deletion, an ìMDS genotypeî (-5/-5q; -7/-7q;
1 2 simple tests, which are widely
+8; t (1; 7); -20q) as well as simply hypodiploidy
available and cheap
correlated with median survival of 18-24 months
1Ability to classify and compare
(overall) versus 56 months for patients with no
international treatment study result
detected abnormalities (i.e., successful cytogenetic
1Potential identification of patients
testing with no abnormalities found).
for selected new treatment protocols
In P7.3, Dr. Brian Durie summarized the role of
imaging in staging and prognostic classification.
In that the system subsumes a diagnosis of multi-
Using CT scanning, MRI, and nuclear imaging
ple myeloma requiring treatment, it is actually
techniques, more accurate staging is achieved ver-
more of a prognostic system than a tumor mass
sus use of x-rays alone. True staging information is
staging system, per se. Patients with low tumor
critical for appropriate clinical decision making.
burden can have poor prognostic features, patients
Results with whole body FDG/PET were used to
with high tumor burden can have good prognostic
illustrate the importance of full staging, both pre-
features and live for over 10 years. There is there-
treatment and with serial follow-up. Pre-treat-
fore still a need to precisely diagnose myeloma and
ment, MGUS, solitary plasmacytomata, and smol-
anatomically stage the disease as noted below.
dering/indolent myeloma can be distinguished
from active myeloma requiring systemic therapy.
In the new IMWG system, several other parameters
In patients with active myeloma, areas of unsus-
proved to be important in multivariate analyses
pected disease are detected. These additional sites
including age (< or > 60) serum creatinine (< or >
in about 25% of patients change the stage or diag-
2mg/dl); LDH (low/high) and platelet count
nosis demand alternate or additional therapy
(> 130,000/mm3 or < 130,000/mm3). Although
and/or
indicate
a
different
prognosis.
S2M and S. Alb alone adequately classify patients,
Extramedullary disease noted in 20-25% of
a number of other systems can be derived from this
patients has previously gone unrecognized. In
very large international data base, which have sta-
view of these findings, bone marrow biopsy is not
tistical validity e.g., s. creatinine substituting for
a sufficient anatomic staging or restaging proce-
S2M or avoiding S2M and s. creatinine and
dure. Extra-medullary disease, especially at
using a combination of age, LDH, and platelets.
relapse, coexists with a normal bone marrow. In
There is therefore considerable flexibility in match-
patients with non-secretory myeloma, FDG/PET
ing classification systems with new clinical trials in
and/or serum Freelite may be the only tools avail-
which, for example, renal function and/or blood
able for careful serial monitoring. Overall, the crit-
count values may influence treatment selection.
ical need for imaging to determine true stage was
emphasized. As noted in a recent report by Bauer
Further analyses are underway to determine the
et al, there is significant value in a ì Durie plusî
risk likelihood of very good or very poor survival
staging system outlined in Table 3, which inte-
in particular patient subsets. Chromosome analy-
grates new imaging techniques.
ses will be included in these follow-up studies. The
precise prognostic value of chromosome 13 dele-
Dr. Brian Durie summarized the
tion, hypodiploidy, and other features in predicting
reduced likelihood of survival >5-10 years will be
role of imaging in staging and
assessed. Conversely features of patients most like-
prognostic classification. Using
ly to live > 5-10 years will be delineated.
CT scanning, MRI, and nuclear
In P7.2, Dr. Guido Tricot presented results from
imaging techniques, more accurate
Little Rock, Arkansas, summarizing the prognostic
staging is achieved versus use of x-
34
value of cytogenetics in their very large data set.
rays alone.
TABLE 7
Durie/Salmon PLUS Staging System**
CLASSIFICATION
PLUS
NEW IMAGING
MRI AND/OR FDG PET
1MGUS
ALL NEGATIVE
(Table 2)
1Stage IA*
CAN HAVE SINGLE
(Smoldering or indolent)
PLASMACYTOMA
(Table 3)
AND/OR LIMITED
DISEASE ON IMAGING
1MULTIPLE MYELOMA
STAGES IB*, IIA/B*, IIIA/B*
(Table 1)
Stage I B*
· < 5 FOCAL LESIONS;
MILD DIFFUSE DISEASE
Stage II A/B*
· 5-20 FOCAL LESIONS;
MODERATE DIFFUSE DISEASE
Stage III A/B*
· > 20 FOCAL LESIONS;
SEVERE DIFFUSE DISEASE
* A
· serum creatinine < 2.0 mg / dl
· no extramedullary disease (EMD)
* B
· serum creatinine > 2.0 mg / dl
· extramedullary disease (EMD)
** See:
1
Bauer et al. Magnetic Resonance Imaging as a Supplement for the Clinical Staging
System of Durie and Salmon? Cancer. Vol. 95, No. 6, September 15, 2002; 1334-1345.
2
Durie et al. Whole-body F-FDG PET identifies high-risk myeloma. J Nucl Med.
Vol. 43, 2002; 1457-1463.
In P7.4, Professor Bradwell summarized the clini-
FreeliteTM test may replace the 24-hour urine
cal utility of the serum FreeliteTM test, a recently
method. However, 24-hour testing is still required
available assay for measuring serum free light
to assess renal function, especially any potential
chains as compared to prior assays, which detected
nephrotic status (i.e., abnormal loss of urine
both free light chains and those bound to IgG, IgA,
Albumin), which can occur, for example, with
IgM and/or other immunoglobulins. Several
amyloidosis and/or bisphosphonate toxicity.
points were made:
1 Approximately 70% of patients with so-
1 In patients with Bence Jones (mono-
called non-secretory myeloma have positive results
clonal light chain) myeloma, the serum Freelite test
with the new FreeliteTM test. Thus 70% of such
is more sensitive and reliable than standard 24
patients can now be monitored in a quantitative
hour urine testing. With further testing, the
fashion and be eligible for clinical trials.
35
1 In using the FreeliteTM test, both the
residual" disease. This can allow for optimizing or
actual values as well as the kappa/lambda ratio are
individualizing post transplant immunotherapy
important. As light chain levels start to increase at
approaches and reduce the risk of unnecessary
a low level (within the normal range), the ratio
GVH effects.
may change first, giving the first indication of an
abnormality. Since the half-life of light chains is
In P7.6, Dr. Mateo, from the Salamanca Group,
short (2-6 hours) versus whole monoclonal pro-
showed that studying the immune phenotype of
teins (e.g., IgG/IgA 21-25 days), a drop in light
myeloma cells persisting after therapy can be prog-
chain level occurs very rapidly in responding
nostically important. Presence or absence of abnor-
patients and gives the first indication of treatment
mal plasma cells using CD38/CD56/CD19/CD45
benefit. Further evaluation of the utility of
combination typing was compared with disappear-
FreeliteTM testing in this setting is required.
ance of the myeloma monoclonal protein by
immunofixation (IFE). Patients with 85% recovery
1 Monitoring of light chain levels can also
of normal phenotype in the bone marrow had
be useful using FreeliteTM in patients with systemic
longer remission of 32 months PFS versus 20
amyloidosis, light chain deposition disease, and
months: P=0.03. Further studies are ongoing.
Waldenstrmís macroglobulinemia.
Monitoring of minimal residual disease using these
immunological techniques is clinically useful.
In P7.5, Dr. Corrandini presented results of molec-
ular monitoring of patients treated with allogeneic
The P7 session was one of the best attended of the
transplantation using bone marrow PCR tech-
whole Salamanca meeting. The data presented sum-
niques. Basically, the PCR technique allows moni-
marized many details, which are very important for
toring below the usual detection limits and illus-
up-to-date management of multiple myeloma.
trates the therapeutic impact of the graft versus
Results from these various studies have definite
myeloma effect in further reducing the tumor bur-
implications for upcoming clinical trials as well as
den in patients with residual low level or "minimal
individual patient management around the world.
Chemotherapy, Maintenance,
Treatment, and Supportive Care:
Optimizing Treatment for Anemia
Prof. Heinz Ludwig, M.D.
available tools. The goals that have been pursued
Department of Medicine and
by studies presented at the workshop focused on
improvement in outcome in terms of response
Medical Oncology,
rate, survival, and importantly for patient com-
fort, ease of application and quality of life.
Wilhelminenspital, Vienna, Austria
Results of the recent VIIIth MRC myeloma trial
showed that substituting cyclophosphamide plus
Conventional chemotherapy with presently prednisolone for ABCM induction chemotherapy
available means has come close to its limits in
in newly diagnosed myeloma patients allows spar-
multiple myeloma. In the future, substantial
ing of anthracyclines and of the nitrosourea
improvement may be achieved by applying
BCNU, both of which tend to be more toxic than
genomics and proteomics for individualization of
cyclophosphamid. Both regimens resulted in simi-
cytotoxic therapy. This might lead to selection of
lar survival, but data on quality of life and toxicity,
patients who are most likely to respond to a given
which would allow evaluation of a possible superi-
therapy. It might also help to select the appropri-
ority in terms of subject benefit of one or the other
ate dose and schedule and to exclude those who
regimen, were not collected.
are unlikely to benefit from a specific treatment.
Until these options become available, trials are
Another interesting study compared oral
36
warranted to optimize therapy with presently
Idarubicin-dexamethasone (ID) with the standard
VAD regimen, which requires a central venous line
or Port-A-Cath for the 96-hour continuous infu-
Two trials tested whether modification of gluco-
sion. The oral regimen was found to be similar in
corticoid treatment within well established
effectiveness (response rate 62%) to VAD
regimes improves outcome. The Spanish PETHE-
(response rate 73%) with 51% of the ID and 62%
MA group (Martin, JMH and colleagues) com-
of the VAD patients proceeding to high-dose ther-
pared dexamethasone in combination with mel-
apy. VAD patients had central line problems, main-
phalan (MD) with standard melphalan-pred-
ly infections, but infections were also quite fre-
nisone (MP) in newly diagnosed patients above
quent in patients on ID due to greater myelotoxic-
age 65. Treatment was given for six cycles, and in
ity. The need for hospitalization was similar in
case of any response, continued with additional
both groups. In general, the results show that the
six cycles. Although the overall response rate did
ID combination is feasible and of comparable
not differ between both groups (MD: 65% vs. MP:
activity to VAD. Similar observations have already pre-
65%) a higher proportion of patients on MD
viously been reported by others.
achieved CR (both after 6 and 12 cycles), in addi-
tion, PFS was significantly prolonged with MD (35
Two trials
Quality of life was
mos. vs. 26 mos. on MP). Overall, in responding
measured using the
patients, survival was slightly better on MD (56
tested whether
EORTC QLQ-C30
mos vs. 34 mos. on MP), but when all patients
modification of
questionnaire
in
(responsive or non responsive to initial treat-
glucocorticoid
patients on VAD/C-
ment), were analyzed, results were almost compa-
CAMP and in those
rable. Extrahematological toxicity, namely infec-
treatment within
on standard alky-
tions and hyperglycemia, were more frequent with
well established
lating agents or
the MD regimen. MD may be the preferred treat-
regimens improves ABCM (Crofts, SE
ment in patients with adequate dexamethasone
outcome.
and
colleagues).
tolerance, but should be withheld in those with a
Interestingly, QOL,
propensity for severe dexamethasone side effects.
in particular cognitive functioning, pain, and
fatigue tended to improve more during VAD/C-
The study by the CEMSG group (Ludwig, H and
CAMP. Although this was a non randomized study
colleagues) tested whether continuous pred-
on a small number of patients, the findings are in
nisolone treatment is able to improve outcome
line with clinical experience that dexamethasone
compared to standard prednisolone in combina-
improves subjective well being.
tion with VMCP/IFN as first line treatment in eld-
erly patients. Overall, continuing prednisolone
When single agent dexamethasone was compared
treatment during the entire induction phase (Pred
with VAD for induction therapy in a Mayo study
40mg orally, d 1-7, and 25mg orally, TIW, d 8-28,
(Kumar, S and colleagues), dexamethasone turned
vs. Pred 40mg orally, d1-7 and 25mg orally, d8-14),
out to be similarly effective in inducing remission
did not increase response rate, PFS or OS. There
(Dex: 74% vs. VAD: 86%). Patients on Dex collect-
was significantly less grade III and IV anemia but
ed significantly more CD34 cells. As patients on
more episodes of hyperglycemia with escalated
Dex do not need indwelling catheters and showed
prednisolone therapy.
a lower risk for neutropenic infections and throm-
botic events, monotherapy with dexamethasone is
Interferon (IFN) maintenance treatment was
an attractive alternative to VAD, particularly in
looked at by two groups. Authors from the Czech
patients who are planning to undergo autologous
Republic (Hajek, R and colleagues) compared IFN
stem cell transplantation.
(3 MicU, TIW) with IFN plus dexamethasone
40mg, d 1-4, 10-13, 20-23 in 183 patients who
A retrospective analysis (Ross, DM and colleagues)
completed autologous transplantation (single if
of the impact on time to response during VAD
CR after transplantation, or tandem in those not
treatment revealed that patients responding with a
in CR after 1st transplantation). In contrast to a
>50% reduction of M-component after the first
previous SWOG study that showed superior
VAD cycle benefited from a significantly better
results for patients on interferon-prednisone, the
event-free survival (EFS at 3 years 53% vs. 12%).
present study revealed a tendency towards the
The authors explained the lack of significant dif-
other direction. Patients on IFN maintenance
ference in overall survival by the relatively small
showed an EFS of 44.6 months compared to 35.5
37
number of patients studied.
months in those on IFN/Dex; (not significantly
different). The Royal Marsden Group (Sirohi, B
study. Philip Greipp will explore the potential of bis-
and colleagues) evaluated whether maintenance
phosphonate therapy within the Eastern Oncology
treatment with pegylated interferon (P-IFN) once
Group in high-risk MGUS, plasmacytomas, and
weekly subcutaneously is associated with better
indolent myelomas. He plans to compare thalido-
QOL than therapy with conventional interferon
mide and ZometaTM with Zometa in the latter group
(IFN) given subcutaneously TIW in patients
of patients and to investigate whether these treat-
responding at least with minimal response to
ments will slow or halt transformation into active
prior chemotherapy. A crossover design with 3
disease.
months on one drug followed by cross over to the
other was applied. The results clearly showed a sig-
Thomas Delea and colleagues calculated the life-
nificant better global QOL score under P-IFN. The
time cost of skeletal events in myeloma as $10,247
functional scales for physical activity, emotional
per
patient.
and social function, and pain were significantly
A crossover design
Skeletal
events
better, but patients had less appetite while on P-
with 3 months on
were defined as
IFN. Taken together, the overall rating was superi-
pathologic
frac-
one drug followed
or for P-IFN and the authors conclude that P-IFN
tures, spinal cord
should become the future standard for mainte-
by cross over to the c o mpr ession,
nance treatment.
hy per calc emia,
other was applied.
bone
surgery,
Bone involvement is the most common and fre-
The results clearly
radiotherapy,
or
quently most severe complication in myeloma.
showed a significant initiation of opioid
The use of bisphosphonates significantly slows
analgesic medica-
better global QOL
progression of bone disease and skeletal related
tion. Median sur-
events such as fractures, need for local radiothera-
score under P-IFN.
vival from first
py, surgical intervention, and pain medication.
skeletal event was
James Berenson presented an overview on the
28 months. This figure underlines the high lifetime
present state of prophylaxis and treatment.
costs of skeletal events and suggests also that due to
Bisphosphonates, in particular pamidronate and
economic considerations, ample use of treatment
the more potent zolendronate, exert various bio-
should be undertaken to postpone or prevent these
logical effects in vitro which might be advantages
complications.
in vivo. They induce the mevalonate pathway and
as a result decrease the prenylation of the onco-
Kyphoplasty is a relatively new intervention that
gene ras and of other GTPases. Other effects com-
utilizes minimally invasive balloon tamps. These
prise inhibition of IL-6 production, induction of
tamps are inserted into a collapsed vertebral body
myeloma cell apoptosis, and synergism with sever-
and subsequently inflated and filled with methyl-
al anti-myeloma drugs. In addition, amino-bis-
methacrylate for stabilization of the body. The
phosphonates (including pamidronate and zolen-
indications for this procedure are either restoration
dronate) stimulate immunoregulatory cells. In
of height and/or pain resistant to radiotherapy,
spite of this impressive array of biological effects
explained Isador Liebermann from the Cleveland
observed in vitro, clinical data have as yet not
Clinic. Patients need to be carefully selected for this
revealed a substantial anti-myeloma activity, as
intervention, which is safe and associated with sig-
there was no difference in survival seen in a major
nificant functional improvement. Similar findings
randomized trial comparing pamidronate with
with an average height reconstitution of about 30%
placebo. Only in a subgroup of patients, namely
were reported by Josef M. Lane and colleagues.
those enrolled after failure of first-line chemother-
apy, a better outcome on pamidronate therapy was
With the advent of erythropoietin as effective treat-
seen. Still there is hope that bisphosphonates can
ment for anemia in myeloma, anemia and its com-
impede progression of MGUS and of indolent
plications and consequences have received
myeloma into active disease.
increased interest. A large Italian study (Palumbo,
A and colleagues) on more than 1000 patients
James Berenson reported that he has launched a
investigated the relationship between anemia, sta-
trial in individuals with MGUS. Zometa will be
tus of disease, treatment, gender, age, and QOL.
administered every three months. Bone mineral
The authors used an instrument which has been
38
density and transformation to a malignant plasma
designed to specifically evaluate the impact of ane-
cell dyscrasia will be important endpoints of this
mia on QOL (FACT-An scale). Low hemoglobin
was directly related with fatigue and generally low
patients with myeloma. Similar response rates
FACT-An scores. In addition, QOL as assessed by
(once weekly: 69% vs. TIW: 78%) and times to
FACT-An was lower in older patients (particularly
response (once weekly: 71 days vs. TIW: 57 days)
women), in patients with no response or relapse,
were obtained with both regimens. The treatment
and in those with concurrent disease.
was well tolerated. A similar approach using 40,000
Similar findings were obtained by the Nordic
U once weekly is already common practice in the
Myeloma Study Group (Wisloff, F and colleagues)
US and is becoming more common in Europe as
utilizing the EORTC Q30 instrument, which
well. In addition to these trials, smaller studies
measures global QOL. They confirmed that hemo-
were presented during the meeting, which con-
globin is an independent predictor for some QOL
firmed the well documented positive effect of ery-
variables, most notably fatigue, dyspnea, and
thropoietin therapy on QOL and the fact that it is
physical functioning. In their analysis, the extent
well tolerated.
of bone disease at time of diagnosis was found to
be the strongest predictor of QOL, while during
In conclusion, some of the data presented during
treatment, the response to therapy was primarily
this session allow further fine tuning of conven-
predictive of QOL. In these situations anemia
tional and maintenance treatment and substantiate
remains associated with QOL, but its impact is less
the rationale for treatment of bone disease with
that of behind bone disease and the response to
bisphosphonates. Anemia impairs QOL and can
anti-myeloma therapy.
successfully be treated with erythropoietin, but
other determinants of the status of an individual
Mario Cazzola and colleagues compared once-
patient, such as extent of bone involvement and
weekly 30,000 U erythropoietin beta with 10.000 U
response to anti-myeloma therapy, outweigh ane-
TIW in a prospective randomized trial in anemic
mia as a factor impacting QOL.
Has Autologous Stem Cell Transplantation (ASCT)
Become the Gold Standard Treatment in MM?
The French Experience (IFM)
Jean-Luc Harousseau
trial comparing high dose therapy (HDT) plus
Institut de Biologie
autologous bone marrow transplantation and
conventional chemotherapy (CC). The results of
Nantes, France
this important IFM-90 trial were published as
early as 1996 in the New England Journal of
Summary
Medicine (1). They showed the superiority of
HDT in terms of remission rate, event-free sur-
F
vival (EFS), and overall survival (OS).
ifteen years after the introduction of high-dose
therapy plus autologous stem cell transplanta-
Since this publication, ASCT has been widely used
tion in the field of multiple myeloma, it is now
in the up-front therapy of younger patients with
clear that this procedure is superior to conven-
newly diagnosed MM. However these results have
tional chemotherapy and should be considered as
been questioned, especially because the follow-up
the standard of care, at least for younger patients.
was still short at the time of publication, and
because the number of patients was only 200. As
In Salamanca a full session was devoted to autolo-
the other French group, MAG, reported two nega-
gous stem cell transplantation and was entitled
tive trials (2-3), the results of other large multi-
"Has autologous stem cell transplantation become
center randomized trials were expected with great
the gold standard treatment in multiple myelo-
interest. In this session J.L. Harousseau first pre-
ma?" (MM). It was divided into 3 roundtable dis-
sented the updated results of the IFM-90 trial. In
cussions and the first one addressed the long-
this trial, at the time of diagnosis, 200 patients 65
debated issue of "ASCT versus conventional
years of age or less with Durie-Salmon stage II or
chemotherapy." The Intergroupe Français du
III, were randomly assigned to receive either CC or
MyÈlome was the first to conduct a randomized
HDT. CC consisted of alternating cycles of
39
VMCP/BVAP administered at 3-week intervals for
dence interval, 33.1 to 51.6]). There was a trend
12 months for a total of 18 cycles. HDT was
toward a greater survival benefit group of patients
administered after four to six cycles of
with a poor prognosis, as defined by a high 2-
VMCP/BVAP to all patients with WHO perform-
microglobulin level (more than 8mg/l).
ance status of 2 or less, a serum creatinine level less
than 150 mmol/l and more than 2 x 108 nucleated
In the third talk, J. Blade presented the results of a
cells/kg in the marrow collected and unpurged.
randomized trial performed by the Spanish group
Patients were prepared with HDM (140 mg/m2)
PETHEMA. The objective of this study was differ-
and total body irradiation (TBI 8 Gy). Interferon
ent and was to compare ASCT and continued CC
alpha (IFN) was administered at a dose of 3 x 106
in patients responding to their initial treatment.
U/m2 3 times a week until relapse in both arms of
From May 1994 to October 1999, 216 patients
the study. Comparison of the two therapeutic
(122M/94F), median age 56 yr, stage II or III,
modalities was made on an intention-to-treat
ECOG < 3, were registered. The diagnosis was
basis, with all patients studied in their assigned
made according to the criteria of the Chronic
treatment groups. None of the initial characteris-
Leukemia Myeloma task force. The initial
tics differed significantly between treatment
chemotherapy consisted of 4 courses of alternating
groups. The response to initial chemotherapy and
BVMCP/VBAP. Responding patients received
the compliance with interferon treatment were
either 8 additional courses of BVMCP/VBAD (arm
also comparable. In this IFM-90 trial, HDT signif-
A) or intensification with ASCT melphalan
icantly improved the response rate: 38% of
140mg/m2/TBI 12 Gys or melphalan 200mg/m2
patients enrolled in the HDT arm achieved a com-
(armB). Maintenance treatment consisted of inter-
plete remission or very good partial remission (>
feron alpha and dexamethasone in both arms. One
90% reduction of the M-component) versus 14%
hundred eighty-five patients responded to initial
of patients enrolled in the CC arm (p< 0.001). An
chemotherapy (CR : 15%, PR : 68%, MR : 17%).
updated analysis of this study confirms that, with a
Twenty-one of these responding patients were not
median follow-up of 7 years, HDT significantly
randomized due to various reasons. Among the
improves EFS (median 28 months versus 18
164 randomized patients, 83 were allocated to con-
months, 7-year EFS 16% versus 8%, p=0.01) and
tinued chemotherapy, and 81 to ASCT. The degree
OS (median 57 months versus 44 months, 7-year
of initial response as well as prognostic features did
OS 43% versus 25%, p=0.03).
not differ in both groups. The results were updat-
ed as of November 15, 2002, after a median follow-
In the second talk, J.A. Child presented the results
up of 44 months from the initiation of treatment,
of the large MRC-VII trial, which were just pub-
and were analyzed on an intention-to-treat basis.
lished in the New England Journal of Medicine (4).
CR (negative electrophoresis) was significantly
In this multicenter study, MRC-VII trial, 407
higher in the ASCT arm (30% vs 11%, p=0.002).
patients with previously untreated multiple myelo-
However, PFS was not significantly different
ma and younger than 65 years of age were ran-
between ASCT and conventional chemotherapy
domized to receive either standard conventional-
(median, 43 vs 34 mos, p=NS) and the OS was
dose combination chemotherapy or HDT and
similar in both groups (median, 62 vs 56 mos,
autologous stem cell transplant. Among the 401
p=NS). This study shows that, as delivered in this
patients who could be evaluated, the rates of com-
trial, ASCT intensification significantly increases
plete response were higher in the HDT group than
complete remission rate but has no significant
in the CC group (44% vs 8%, p<0.001). The rates
impact on PFS and OS in myeloma patients
of partial response were similar (42% and 40%,
responding to initial chemotherapy.
respectively p=0.72), and the rates of minimal
response were lower in the intensive therapy group
Finally B. Barlogie presented the updated results
than in the standard therapy group (3% vs 18%,
of a historical comparison of patients treated at
p<0.001). Intention-to-treat analysis showed a
University of Arkansas with an aggressive
higher rate of overall survival (p=0.04 by the log
approach including tandem ASCT (Total therapy
rank test) and progression-free survival (p<0.001)
I) and patients treated with CC according to
in the intensive therapy group than in the standard
SWOG trials. With a median follow-up of 10
therapy group. As compared with standard thera-
years for all patients, 10-year survival and EFS
py, intensive treatment increased median survival
rate were markedly higher with HDT than with
by almost 1 year (54.1 months [95% confidence
SWOG CC (33% vs 15%, p<0.0001 ; 16% vs 15%,
40
interval, 44.9 to 65.2] vs 42.3 months [95% confi-
p<0.0001). Indeed, according to multivariate
analysis of baseline prognostic variables together
achieving CR with CC? This question will be of
with treatment modality, HDT emerged as the
greater importance with the introduction of novel
single most important variable associated both
agents like bortezomib or IMiDs.
with superior overall and EFS.
2. What is the upper age limit for ASCT ? In the
From the studies presented in this round table as
IFM-90 trial, the benefit of ASCT was significant
well as from other studies presented in part at
only for patients < 60 years of age. In the MAG 91
other meetings or published in the literature
trial there is no survival advantage of ASCT but
(2,3,5) one can conclude:
the median age of included patients is > 60 years.
Therefore is ASCT the optimal treatment in
1ASCT significantly increases complete
patients over 60 years of age?
remission rate in all studies.
These 2 questions were addressed in another
1 ASCT significantly increases EFS in almost all
round table in this session.
randomized trials and OS in two major random-
ized trials (IFM90 and MRC 7 trials). Moreover
survival benefit of ASCT can be underestimated
REFERENCES
since in all studies a number of patients allocated
to the CC arm did receive ASCT at relapse.
1 Attal M, Harousseau J-L, Stoppa A-M et al. N
Engl J Med 1996;335:91-7.
1 Therefore ASCT should be considered as the
2 Fermand J-P, Ravaud P, Chevret S et al. Blood
standard of care at least for younger patients.
1998;92:3131-6.
Two questions remain to be addressed :
3 Fermand J-P, Ravaud P, Katsahian S et al. Blood
1999;94 (Suppl1):396a (abstract).
1. Prolonged survival is strongly correlated to
4 Child JA, Morgan GJ, Davies FE, N Engl J med
achievement of CR. The superiority of ASCT is
2003;348:875-83.
probably mainly due to a better quality of remis-
sion and to a higher incidence of complete remis-
5 Palumbo A, Bringhen S, Rus C et al. Blood
sion. Therefore, is ASCT necessary in patients
2001;98:849a (abstract).
Autologous Stem Cell Transplantation
in Special Situations
Morie A. Gertz, M.D.
will have significant renal impairment, and others
Mayo Clinic, Rochester, MN
will have amyloidosis. The purpose of this session
was to try and determine specific criteria that
would permit consideration of transplantation in
SESSION: Summary Statement
these unique situations.
Randomized trials have demonstrated the survival
INTRODUCTION
benefit of stem cell transplant for previously
untreated younger multiple myeloma patients with
On Monday, May 26, 2003, following round table
adequate renal function. Oftentimes, physicians
discussions on the value of stem cell transplant
encounter patients who have been previously
compared to conventional chemotherapy and the
transplanted or treated with conventional
controversy surrounding single vs. tandem autolo-
chemotherapy and have subsequently progressed,
gous transplants, a discussion with four presenta-
or are older than patients who have been the sub-
tions was held to discuss special situations for stem
41
jects of published studies. Some myeloma patients
cell transplantation. The IFM-90 French study of
conventional chemotherapy vs. transplant and the
plants.
Survival was better for those patients
MRC-VII British study both demonstrated that
whose transplants were spaced by greater than two
stem cell transplant produced a better survival
years. The interpretation is that patients who are
than conventional chemotherapy. However, in the
most likely to benefit from a second transplant are
IFM-90 trial, all patients were less than age 65, and
those patients who derived the greatest benefit
patients had to have well preserved kidney func-
from a first transplant. Itís reasonable to believe
tion as defined by a serum creatinine of less than or
that when a specific therapy, such as transplant,
equal to 1.7 mg/dl. In the MRC-VII trial, all
provides a good first response, re-applying the
patients, once again, were under the age of 65
exact same treatment will be likely to provide a
years, and only a small proportion had significant
good response a second time. Those patients who
impairment in kidney
relapse shortly after transplant (less than one year)
Many myeloma function.
This leaves
likely have aggressive disease biology that will not
unanswered the ques-
be well controlled by the application of high-dose
patients receive tions, "What is the role of therapy and therefore would be better served with
conventional
transplant for patients
some of the new innovative treatments available
over the age of 65?" and
rather than repeating high-dose therapy.
therapy and
"What role does trans-
have not fully
plant play for those
The level of the 2-microglobulin predicted the
discussed the
patients who do not have
time to progression after a second transplant at the
preserved kidney func-
time of transplant. This is quite plausible since 2-
option for
tionóa consequence of
microglobulin predicts outcome both after a first
transplant.
myeloma cast nephropa-
transplant and after conventional treatment. It
thy, i.e. light chain dam-
should therefore be a reasonable measure of the
age to the kidney?"
results following a second transplant. The out-
come with a single transplant followed by a late
Many myeloma patients receive conventional
transplant at relapse resulted in survivals quite
therapy and have not fully discussed the option for
comparable to tandem autotransplantation.
transplant. In many instances, patients following
Applying a stem cell transplant at relapse, many
standard therapy will progress and then will ask
patients are spared an unnecessary second trans-
the appropriate question, "Will transplant play
plant since some of these patients do well for many
any role in my management at this time?" The
years after only one transplant. Those patients who
purpose of the round table discussion was to try
do not benefit from a single transplant are spared
and define the role of stem cell transplant for older
receiving a second transplant that is not likely to
patients, patients with impaired kidney function,
add much value.
previously treated patients, and for the rare subset
of patients who have amyloidosis as the primary
An initial response to induction chemotherapy
clinical manifestation of their bone marrow plas-
is not required for a favorable outcome with
ma cell disorder.
transplant. Some centers will treat patients for
approximately four months prior to stem cell
1. Relapsed and refractory disease.
transplant. Commonly used induction regimens
Drs. Powles and Sirohi first presented on a group
include VAD and thalidomide dexamethasone.
of 96 patients who had previously undergone a
Other regimens that are used include DT-PACE
stem cell transplant and had sufficient stem cells
and C-VAMP. What should be done for patients
collected at diagnosis to permit the option of a sec-
who fail to achieve any response with these
ond later transplant at progression. The average
induction therapies?
time between the first and the second transplant
was 3.2 years. Therefore, these transplants were
The conclusion at the round table was that patients
not tandem, rather one was an early transplant and
who fail induction therapy can achieve very good
one was a late transplant after relapse. In one
outcomes following high-dose therapy and that a
patient, the second transplant followed the first
favorable outcome with induction therapy should
after 11.8 years. The use of a second transplant
not be considered a necessary criterion to proceed
resulted in acceptable response rates with a low
with a transplant. Others have also confirmed that
treatment-related risk. The factor that most favor-
patients with primary resistant disease can benefit
ably predicted for a good outcome with the second
from early high-dose therapy. The group at M. D.
42
transplant was the interval between the two trans-
Anderson published nearly ten years ago that
patients who failed initial therapy still had very
it is a highly desirable agent for conditioning prior
good outcomes following transplant.
to transplantation. The clearance of melphalan is
the same in patients with kidney failure and those
In conclusion, patients who fail induction therapy
with normal renal function. It has a very short half
are candidates for transplant and a second stem cell
life so that stem cell infusion can occur within 24
transplant using stem cells collected early in the
hours of the melphalan dose.
disease course can provide important clinical ben-
efit for patients with multiple myeloma.
Studies have shown that patients with kidney fail-
ure have very adequate stem cell yields when they
2. Use of Transplant in Renal Failure
undergo mobilization. In patients with kidney fail-
Fifteen percent of patients will present with
ure, stem cells can be collected using chemothera-
impaired kidney function at the diagnosis of
py followed by a growth factor or following growth
myeloma. In many instances, impaired kidney
factor alone. In general, mobilization with growth
function is reversible with induction therapy,
factor alone avoids the side effects associated with
which usually includes dexamethasone and may
chemotherapy, which include a reduction in the
include total plasma exchange to reduce the blood
white blood cell count, with an increased risk of
level of circulating light chains responsible for
infection and the need for antibiotic support.
damaging the kidney. In patients who have recov-
Dialysis should be avoided during the day of mel-
ery of kidney function, outcomes are quite similar
phalan administration so that it is not removed
to those patients who present with normal kidney
from the body. Stem cells can be safely re-infused
function. For those who do not, we consider the
24 hours after melphalan. Post transplant recovery
following questions:
How are we to manage
of blood counts in patients with kidney failure
patients who have
occurs with an identical time course as those
The interpretation little or no improve-
patients without kidney failure.
ment in their kidney
is that patients who function after induc- Patients with kidney failure do appear to have a
are most likely to
tion treatment? Are
higher potential for adverse effects during trans-
benefit from a sec- these patients candi-
plant including a higher infection rate and
dates for transplant?
increased problems with mouth and throat sores.
ond transplant are Are special modifica- Lung complications that often require respiratory
those patients who tions required? Dr.
support are also more common in dialysis patients
Sundar Jagannath of
receiving higher doses of melphalan. It is common
derived the greatest St.
Vincentís
to reduce the dose of melphalan from the standard
benefit from a first Co mpre hensive
200 mg/m2 to 140 mg/m2 to reduce these risks.
transplant.
Cancer
Center
Very few renal failure patients receive tandem
reviewed the experi-
transplants. In one study of 81 patients who had
ence of autotransplantation in multiple myeloma
kidney impairment that was not reversible, includ-
patients with kidney failure. Initially, he reviewed
ing 38 on dialysis, the high-dose chemotherapy
the causes of renal failure including high calcium
dose was 200 mg/m2 melphalan, but when the dose
levels and the deposition of light chains in the kid-
was reduced to 140 mg/m2, patient tolerance was
ney tubules. Most published experience with high-
substantially improved. Complete responses with
dose chemotherapy and stem cell transplant either
no detectable myeloma protein were seen in over a
exclude patients with kidney failure or have very
quarter of patients. The consensus of the group
small numbers of patients so that it is difficult to
was that in patients with kidney failure, high-dose
draw firm conclusions.
It is clear that with
therapy is an appropriate option if they had are in
improved supportive care introduced over the last
good general condition but that stem cells are best
ten years, including better mobilization techniques
mobilized using growth factor only, and the condi-
for stem cells and the use of growth factors to
tioning chemotherapy used is melphalan at 140
shorten the period of infection risk, the complica-
mg/m2.
tion rates associated with transplant have been
substantially reduced. Several studies have shown
3. Stem Cell Transplant in Older Patients
the feasibility and effectiveness of using stem cell
The median age of patients seen in major medical
transplant in patients with impaired kidney func-
centers with multiple myeloma is 63. The two
tion.
Because melphalan is not significantly
largest studies of stem cell transplant vs. conven-
43
dependent on kidney function for its metabolism,
tional chemotherapy excluded patients aged over
65. The value of stem cell transplant has not been
of 60, and compared them to 382 patients under
studied in a very large number of patients with
the age of 60. She found no differences in the
multiple myeloma. The third presentation was
complete response rate or overall survival
devoted to the role of transplant in patients above
between the two groups, suggesting that patients
the age of 65. In patients over the age of 70, con-
who are older but in good condition are appro-
ventional chemotherapy continues to play a very
priate transplant candidates.
important role, with excellent outcomes using tra-
ditional doses. High-dose chemotherapy can be
4. Amyloidosis
applied to patients over the age of 70, but it is
Amyloidosis results when the light chain proteins
unclear to what extent outcomes are improved. Dr.
produced by the plasma cells in the bone marrow
Boccadoro and his group from Torino, Italy, pre-
cannot be broken down by the body and ultimate-
sented a strategy for patients between the age of 60
ly become deposited in the tissues. In patients with
and 70 in which they administered lower doses of
amyloidosis, these light chain deposits are typical-
melphalan, 100 mg/m2, half the dose typically used
ly found in the heart, the kidneys, the liver, and the
for transplant, and followed that with peripheral
nerves. The progressive deposition of this light
blood stem cell support. This regimen was very
chain protein causes these organs to dysfunction
well tolerated and produced higher response rates
and lead to complications as a direct result of their
compared to a histori-
presence. Organ-related complications result in a
The value of stem cal group treated with
survival that is shorter than is seen in multiple
cell transplant has oral melphalan and
myeloma. Because patients with amyloidosis tend
prednisone.
Their
to have very small numbers of plasma cells in their
not been studied
results supported the
bone marrow, it was considered reasonable to
in a very large
use
of
melphalan
determine if high-dose therapy would result in a
100/m2 with stem cells
superior outcome. The Mayo Clinic group report-
number of
as superior to conven-
ed on 125 patients with amyloidosis composed of
patients with
tional chemotherapy
light chains. The majority of patients had involve-
multiple myeloma. for patients between
ment of the kidney, but nearly half also had
the age of 60 and 70.
involvement of the heart, and a sixth of patients
Melphalan 100 mg/m2 is less toxic than melphalan
each had involvement of the liver and of the
at 200 mg/m2 and produced comparable survivals.
nerves. The median age of patients was 55, which
In statistical models that look at those factors that
is younger than most patients with amyloid. Stem
predict outcome following transplant, age does not
cells were collected using either growth factor
appear to have an impact on outcome. One cannot
alone or growth factor and chemotherapy. Patients
determine with certainty what degree of survival
received melphalan in a dose of 200 mg/m2, or for
prolongation occurs in patients over the age of 65
patients in weakened condition, 140 mg/m2 or 100
who are transplanted. It is clear that the procedure
mg/m2. Significant impairment of kidney function
can be done with a significant margin of safety.
(creatinine greater than 2) was present in 10%.
Currently, at most centers, older patients are con-
15% had significant liver compromise (alkaline
ditioned with lower doses of melphalan, most
phosphatase greater than 1.5 times normal). 57%
commonly 140 mg/m2. The overall risk of life-
of the patients had over 3 g of protein in their urine
threatening complications is less than 3%. The
for 24 hours, and 2/3 were losing over a gram of
complete response rate appears to be lower in older
protein in 24 hours. A quarter of the patients had
patients receiving transplant, hovering in the 20%
significant heart involvement. Graft function fol-
range. Patients over the age of 70 have been trans-
lowing transplant was excellent and was compara-
planted, and these results have been reported. The
ble to patients with multiple myeloma, achieving a
side effects associated with melphalan 200 mg/m2
neutrophil count of 500 in a median of 14 days and
were considered unacceptable. With a dose of mel-
20,000 platelets at a median of 17 days. Treatment-
phalan 140 mg/m2, more favorable outcomes were
related mortality in amyloidosis is substantially
seen. Autologous transplant can be safely adminis-
higher than seen in multiple myeloma as a result of
tered to older patients, but they need to be in
the associated organ dysfunction. Major risk fac-
robust clinical condition, physically active without
tors for patients going to transplant include a
impaired heart, kidney, or lung function. Dr.
reduction in kidney function, as measured by a
Donna Reece reviewed the experience from the
creatinine level greater than 1.7 mg/dl, or sympto-
44
autologous blood and marrow transplant registry,
matic heart impairment. Patients with amyloido-
comparing outcomes in 110 patients over the age
sis had a response rate of 64%, which exceeds that
which has been previously reported for conven-
improvement in their nerve symptoms. High-
tional chemotherapy. However, the outcome was
dose therapy for patients with POEMS syndrome
directly related to the number of organs involved,
can produce clinically important responses.
and patients with three or more organs involved
were not considered good candidates for stem cell
CONCLUSION
transplant.
This round table summarized the use of stem cell
A very rare manifestation of a plasma cell disorder
transplant in older myeloma patients and myelo-
is the so-called POEMS syndrome. These patients
ma patients with impaired renal function.
usually have a plasmacytoma of bone, which is
Carefully selected patients will have a favorable
referred to as sclerotic. These patients develop
outcome with high-dose therapy. Selected patients
progressive nerve damage manifested by lower
with amyloidosis who do not have excessive car-
extremity numbness and weakness. Treatment of
diac or kidney involvement and do not have three
this disorder with conventional therapy is very
or more organs involved are candidates for stem
frustrating, and the response rates are low. The
cell transplant. Transplantation is a useful therapy
Mayo Clinic experience with high-dose therapy
both in myeloma patients who failed induction
included six patients with the POEMS syndrome
therapy as well as in myeloma patients who had a
ranging in age from 20 to 62. Four patients had
previous bone marrow transplant, particularly
complete eradication of the monoclonal protein,
those whose response lasted longer than two years.
responsible for the nerve damage, and all four had
Signal Transduction Pathways and Cytokine Networks
Alan Lichtenstein, M.D.
known tumor-promoting effects of IL-6, the
myeloma-proliferative, anti-apoptotic and migra-
SUMMARY STATEMENT
tion effects of IGF-1, VEGF, TNF, IL-21 and SDF-1
(stromal cell derived factor-1) were delineated. All
The signal transduction pathways and cytokine in all, by focusing on the interaction between
networks session reviewed several aspects rele-
myeloma cells and the marrow environment,
vant to these areas in myeloma biology. These sub-
which includes stromal cells and extracellular
jects were not addressed in a vacuum but were dis-
matrix proteins, Dr. Anderson demonstrated an
cussed with a constant underlying purpose of
interacting, synergistic, positive feedback loop net-
relating the cellular and molecular biology to
work which promotes myeloma growth.
potential therapeutic exploitation. The implicit
Dr. Andersonís group has made considerable
concept was that identifying activated cytokines or
progress during the last 5-7 years in dissecting the
pathways that were critical to myeloma cell prolif-
major pathways these cytokines trigger to promote
eration, survival or migration could provide par-
myeloma growth, namely the Raf-1/MEK/ERK,
ticularly good molecular targets for future agents.
JAK/STAT, PI3-kinase/AKT and NF-B pathways.
As a corollary, understanding these pathways
Newer data presented suggests that protein kinase
could also explain relative sensitivity versus resist-
C is also an important player as it mediates VEGF-
ance to well established agents.
induced myeloma cell migration. In contrast, the
therapeutic induction of myeloma cell apoptosis is
DR. ANDERSON
not as clearly known. Although some work impli-
cates activation of the related adhesion focal tyro-
Dr. K. Anderson first reviewed the known
sine kinase (RAFTK) in dexamethasone-induced
cytokines that potentially function as myeloma
apoptosis, it is still unclear how the newer agents
growth factors within the marrow microenviron-
such as PS-341, thalidomide, and IMiDs proximal-
ment and the signal pathways they trigger in
ly activate the apoptosis program, although some
malignant plasma cells. In addition to the well
newer data presented by Dr. L Catley (see below)
45
implicates jun kinase. Dr. Anderson also elabo-
that bind to receptors consisting of Frizzled (Fz)
rated on the factors that protect against drug-
family proteins, often associated with LDL recep-
induced myeloma cell apoptosis, including BCL-
tor related protein (LRP 5/6). Pathway activation
XL, MCL-1 and intracellular inhibitors of apopto-
results in b-catenin stabilization, which enhances
sis (IAPs). All agreed that identification of the
gene expression. This pathway has been implicat-
important cytokines and pathways that induce
ed in several solid tumor types but has not yet
myeloma growth and regulate responsiveness to
been studied in B-lymphoid/plasma cell tumors.
agents is critical for optimal future therapy.
By contrasting WNT signaling in B cell lym-
phomas with myeloma cells, Dr. Rudikoff present-
DR. LICHTENSTEIN
ed convincing evidence of WNT signaling specific
to myeloma cells which resulted in b-catenin sta-
Dr. A. Lichtenstein focused on targeting therapy to
bilization, transcriptional stimulation, and
mutated ras and its downstream activated path-
marked activation of the cytoskeleton. When
ways. He noted the high prevalence of these onco-
stimulated with WNT, myeloma cells developed
genic mutations in myeloma (approx 40%) and
filopodia-like processes and attched tightly to sur-
their correlation with aggressiveness. His labora-
faces. If sufficient amounts of WNT are present in
tory attacked mutant ras-containing myeloma
vivo, this pathway may be important in the inter-
cells with two separate strategies. First, farnesyl
action between myeloma cells and marrow stro-
transferase inhibitors (FTIs) were used to prevent
mal cells, and in myeloma cell migration and dis-
the processing of ras, which
semination throughout the skeleton.
Dr.
FTIs are
is required for its proper
Rudikoff ís studies thus identify another potential
localization and function.
molecular pathway for future therapy.
particularly
FTIs are particularly attrac-
attractive
tive agents as they are cur-
DR. CATLEY
agents as they rently in clinical trials. In
vitro, two separate FTIs had
Dr. L. Catley presented new work on the role of
are currently little effect on mutant ras- jun kinase (JNK) as a mediator of myeloma cell
in clinical
expressing myeloma cells in
apoptosis triggered by the agents 2-methoxyestra-
the presence of serum, but
diol (2ME) and PS-341. It is known that under
trials.
induced strong apoptosis in
genotoxic stress, JNK becomes activated, translo-
low serum conditions. Interestingly, induction of
cates to mitochondria, and facilitates mitochondr-
apoptosis was not associated with prevention of
ial release of factors which activate the apoptosis
ras processing, indicating that inhibition of farne-
caspase cascade. As Dr. Catleyís co-worker, Dr. D.
sylation of a yet unknown protein probably medi-
Chauhan, has shown, 2-ME and PS-341 also liber-
ated apoptosis. In the discussion session, it was
ate these factors from mitochondria in myeloma
noted that more potent FTIs might be effective
cells. Thus, Drs. Catley and Chauhan postulated a
even in the presence of high serum concentra-
potential role for JNK activation in myeloma cell
tions. A second strategy followed identification by
apoptosis triggered by these new agents. Indeed,
Dr.
Lichtensteinís
laboratory
that
the
Dr. Catley presented clear evidence for this notion
AKT/mTOR/p70 pathway was hyperactive in
as both drugs were capable of activating JNK and
mutant ras-containing myeloma cells. This path-
inducing its translocation to mitochondria. This
way is important for the effective translation of
was associated with release of apoptosis mediators
critical cell cycle proteins like cyclins and c-myc.
into the cytosol. Most importantly, inhibiting
These results prompted the use of the mTOR
JNK activation pharmacologically or by gene
inhibitors rapamycin and CCI-779, which were
transfer with a dominant negative JNK mutant,
found to be strongly anti-proliferative, specifically
prevented 2-ME and PS-341-mediated myeloma
for mutant ras myeloma cells. As rapamycin is
cell apoptosis. The therapeutic potential of these
FDA-approved for other conditions and CCI-779
findings was significant. Since dexamethasone
is currently in cancer clinical trials, these drugs
induced myeloma cell apoptosis via pathways
may be soon tested in myeloma patients.
independent of JNK, it follows that combining
dexamethasone with these newer agents should
DR. RUDIKOFF
result in heightened apoptosis and anti-tumor
activity.
46
Dr. S. Rudikoff discussed the WNT signaling path-
way in myeloma cells. WNTs are secreted proteins
DR. JELINEK
marked heterogeneity of tumor responsivenss in
treated patients.
Dr. D. Jelinek discussed the concept of receptor
cross-talk in myeloma cells, emphasizing how
DR. ARENDT
such a phenomenon may play a role in disease het-
erogeneity and impact upon therapeutic strategies
In an attempt to identify new potential molecular
targeted to cytokine stimulation and signaling.
targets, Dr. B. Arendt performed genomic profil-
She presented an example of this with work on
ing on myeloma cells following stimulation with
interferon-a (IFN-a)-responsiveness in myeloma
the growth-promoting cytokines IL-6 or IGF-1.
cells. IFN-a is usually inhibitory to myeloma cell
Dr. Arendt and co-workers were able to identify
growth but an atypical response (ie., growth stim-
gene expression specifically induced through the
ulation) was found in a myeloma cell line that sin-
Raf-1/MEK/ERK pathway by concurrent treat-
gularly co-expressed the ErbB3 receptor with the
ment of the myeloma cells with the MEK inhibitor
IFN receptor. Postulating that receptor co-expres-
UO126. As this pathway has been previously
sion and cross-talk was responsible for this atypi-
shown to be indispensable for cytokine-stimulat-
cal growth response, Dr. Jelinek and co-workers
ed myeloma growth, this approach is likely to pro-
demonstrated that IFN-a transactivated ErbB3 in
vide very relevant information on the critical pro-
these cells as well as the IFN receptor. Gene silenc-
teins induced. Dr. Arendtís profiling identified a
ing of the ErbB3 gene prevented the atypical
number of genes induced by these myeloma
response of these myeloma cells.
These data
growth factors in a MEK-dependent as well as
underscore the importance of co-receptor interac-
ñindependent fashion.
Of interest, several
tions in regulating responses to therapeutic
induced genes, which are potentially important
agents. Extension of this work to an assessment of
for cell cycle transit, were found to be MEK-
expression of receptors such as ErbB3 on primary
dependent for the first time. These proteins may
patient material might provide insights into the
provide good targets for future therapy.
PS341-VELCADE For the Treatment of Myeloma.
Results to Date
Paul Richardson
International Workshop on Multiple Myeloma in
Dana-Farber Cancer Institute
Salamanca, Spain.
Boston, MA
BACKGROUND
The proteasome, an enzyme complex that is
SUMMARY
abundant in all cells, is involved in several
processes that regulate cell growth. Bortezomib
At the IXth International Multiple Myeloma selectively inhibits the proteasome, interrupting
Workshop,
myeloma
specialists
and
several cellular processes, which can ultimately
researchers from around the world presented
result in cell death in tumors. Because the protea-
results of laboratory and clinical research sur-
some inhibition caused by bortezomib is
rounding the proteasome inhibitor VELCADETM
reversible, laboratory research indicates that nor-
(bortezomib), recently approved for the treat-
mal cells can recover from its effects.
ment of relapsed refractory multiple myeloma.*
Before clinical trials in bortezomib were initiated,
Several presentations on the promising new ther-
increased tumor cell death and decreased tumor
apy bortezomib (VELCADETM Millennium
cell growth with the proteasome inhibitor were
Pharmaceuticals, Inc.) were made at the IXth
demonstrated in laboratory and animal studies.
47
*Specifically in patients who have received at least 2 prior therapies and whose disease had progressed on the last therapy.
Other preclinical results also showed increased
zomib therapy could be correlated with
cytoxicity when bortezomib was combined with
tumor
genetic
patterns.
This
analysis
other anticancer drugs including dexametha-
revealed that response to bortezomib treat-
sone, doxorubicin, melphalan, Gleevec, and
ment of MM could be predicted with an
immunomodulatory drugs.1-7
accuracy of 71% to 78%, based on the genet-
ic expression of the patientís tumor. It
CLINICAL TRIALS
appears as though differences in the myelo-
ma biology of certain patients tend to pre-
SUMMIT
dict their response to bortezomib therapy.
More samples are being collected and ana-
The 2 clinical trials that led to FDA approval for
lyzed from patients participating in phase III
bortezomib were SUMMIT and CREST. In the
bortezomib trials to further investigate these
SUMMIT trial, 202 patients with MM whose dis-
results and to identify other genetic markers.
ease had relapsed after 2 or more prior therapies
and who were refractory to their last treatment
CREST
received 1.3 mg/m2 of bortezomib on days 1, 4, 8,
and 11 every 3 weeks for 8 cycles. Patients whose
In the CREST trial, 54 patients with MM whose
disease progressed after 2 cycles or whose disease
disease had not responded or who had relapsed
remained stable after the first 4 cycles were per-
during or after front-line therapy received 1.0 or
mitted to add dexamethasone. In this heavily pre-
1.3 mg/m2 of bortezomib on days 1, 4, 8, 11 every
treated patient population, bortezomib as a single
3 weeks for 8 cycles. The major differences in this
agent achieved an overall response rate of 35% by
trial were the randomization to 2 doses and the
an independent review committee, including
earlier time in the treatment course when borte-
patients who achieved complete response, partial
zomib was given. As in SUMMIT, the addition of
response, or minor response.8 Four percent of
dexamethasone was permitted after 2 (for pro-
patients in SUMMIT achieved a complete
gressive disease) or 4 (for stable disease) cycles in
response and 6% a near complete response,
patients who did not respond to therapy.
regardless of the number or type of previous ther-
Complete responses were achieved at both the 1.3
apies they had received. The median duration of
and 1.0 mg/m2 dose levels. A 50% overall response
these responses was 12 months and the median
rate was seen in patients receiving 1.3 mg/m2
length of survival for patients participating in the
bortezomib versus 33% in those receiving 1.0
study was 16 months. Furthermore, after the
mg/m2 bortezomib. A higher incidence of diar-
addition of dexamethasone, additional responses
rhea, nausea, vomiting, and peripheral neuropa-
were seen in 18% of those patients with progres-
thy were observed at the higher dose; however,
sive or stable disease. The most common toxici-
due to the small number of patients in the study,
ties in SUMMIT were nausea, diarrhea, fatigue,
no conclusion can be drawn about response or
thrombocytopenia (decrease in blood platelets),
toxicity at the 2 doses. Additional responses
constipation, vomiting, peripheral sensory neu-
(33%) were seen when dexamethasone treatment
ropathy (loss of feeling in hands and feet), fever,
was added.
and anemia. These toxicities were considered to
be generally manageable.
Ongoing Clinical Trials
Currently, clinical trials are evaluating the use of
Pharmacogenomics in SUMMIT
bortezomib in MM as first-line therapy, as main-
The knowledge concerning the precise ways in
tenance therapy, and before and after stem cell
which bortezomib works against MM is evolving.
transplantation as well as in combination with
In a poster presentation at Salamanca, Dr. George
other chemotherapies. Among the ongoing stud-
Mulligan and associates from the SUMMIT
ies in bortezomib, the international phase III,
Myeloma Study Group displayed the results of a
randomized APEX trial will evaluate the efficacy
pharmacogenomic (studying the relationship
of bortezomib compared with dexamethasone in
between genes and response to therapy) analysis
more than 600 patients.
of patients participating in the SUMMIT trial.
Sixty-two percent of the patients in this study
Bortezomib Combinations
agreed to allow specimens collected from their
Bortezomib and Melphalan
48
bone marrow before the trial to be frozen
Preclinical studies have showed that MM cells
and analyzed to see if response to borte-
that are resistant to some chemotherapies can be
destroyed with much lower dosages when those
effects compared with the standard form of dox-
chemotherapies are combined with bortezomib.
orubicin, and which may overcome resistance of
Therefore Dr. Hank Yang and colleagues from the
cancers to multidrug treatment. So far, 32 patients
Cedars-Sinai Medical Center, UCLA School of
with hematologic malignancies (cancers of the
Medicine, and Millennium Pharmaceuticals are
blood) that did not respond to previous treat-
investigating use of bortezomib and melphalan
ments, 23 of whom had MM, were treated with
combination therapy in 15 patients who did not
intravenous bortezomib at 0.90, 1.05, 1.20, 1.30,
respond to 2 or more previous MM treatments or
1.40 or 1.50 mg/m2 on days 1, 4, 8, and 11 and
who had experienced a relapse.
Investigators
Doxil 30 mg/m2 on day 4 for an average of 4.2
hope to avoid or decrease the side effects associat-
cycles.
ed with melphalan and bortezomib by using
lower dosages of both of these drugs.
Of the 20 evaluable MM patients, 5 achieved
complete response, 2 near complete response, 5
In this trial, all patients are receiving 0.7 mg/m2
partial response, 3 minor response, and 4 stable
bortezomib intravenously on days 1, 4, 8, and 11
disease; whereas disease progressed in 1 patient.
of a 28-day cycle for up to 8 cycles. This is 40% of
Of the 13 patients in this group whose disease had
the bortezomib dosage received per month by
previously been unresponsive to treatment with
patients in a previous trial. At the same time,
anthracyclines, 4 achieved complete response, 1
groups of 3 patients are receiving 1 of 5 different
achieved near complete response, 2 partial
doses levels of melphalan orally, starting with .025
response, 2 minor response, and 3 stable disease,
mg/kg (10% of the standard melphalan dosage)
with 1 patient whose disease progression was pre-
to a maximum of 0.25 mg/kg 4 times per week for
viously noted. During cycle 1, when the maxi-
4 weeks.
mum tolerated dose (the dose level below which a
significant proportion of patients experienced
The first group of patients has received 8 cycles of
serious side effects) was being evaluated, 1 patient
therapy and the fifth group has received 2 cycles.
with Crohnís disease who received 0.90 mg/m2
Preliminary results reported by Dr. Yang indicate
bortezomib experienced grade 3 diarrhea,
that 7 patients (47%) have achieved a partial
hypotension (low blood pressure), confusion, and
response, 4 patients (27%) a minor response, and
syncope (fainting or light-headedness), but no
4 patients (27%) stable disease. These responses
other side effects that would cause investigators to
include 3 partial responses, 1 minor response,
limit the dosage were noted at this level nor at
and 1 incidence of stable disease in patients
1.05, 1.20, or 1.30 mg/m2. At 1.40 mg/m2, 1 patient
whose MM had not responded to previous treat-
had prolonged grade 4 neutropenia (decrease in
ment. Two patients (13%) have relapsed, and the
white blood cells), and 1 patient at 1.50 mg/m2
average time to progression of disease is 104
had grade 3 constipation. More patients are being
days. The type of treatment previously received
entered into this trial to identify dosages that
did not affect the response to this therapy.
would allow patients to complete 6 to 8 cycles of
Treatment has been relatively well tolerated:
therapy with an acceptable level of side effects and
major side effects were related to reduced blood
few delays in treatment caused by side effects, yet
cell count and occurred mainly in patients who
maintain the efficacy results.
had a reduced count at the start of the trial.
Occurrence of peripheral neuropathy has been
Bortezomib and Arsenic Trioxide
minimal. Future studies are planned to expand
The potential ability of bortezomib to overcome
this trial, using bortezomib 1.0 mg/m2 and 3 dif-
resistance to treatment with other cancer thera-
ferent doses of melphalan.
pies was featured in a poster presentation on the
effects of arsenic trioxide on MM cells. Lawrence
Bortezomib and Doxil®
Boise and colleagues from the University of
(doxorubicin HCl liposome injection)
Miami School of Medicine presented data from
Dr. Robert Orlowski and colleagues at the
laboratory experiments showing cytotoxicity in 3
Linbergerger Comprehensive Cancer Center at
different cell lines known to be resistant to treat-
the University of North Carolina at Chapel Hill
ment with arsenic trioxide, when also treated
and Millennium Pharmaceuticals reported the
with bortezomib.
preliminary results of a study of bortezomib and
the anthracycline Doxil, a form of doxorubicin
Further Defining Bortezomib
49
that may be associated with less heart-related side
Mechanism of Action
Laboratory work continues to expand knowledge
the mechanisms by which they resist cancer thera-
concerning bortezomib's effects on cancer. Dr
pies occur in multiple tumor cell pathways.
Reshma Shringapure and associates from our
group at the Jerome Lipper Multiple Myeloma
Bortezomib and Primary Plasma Cell Leukemia
Center, Dana-Farber Cancer Institute, and
(PCL)
Harvard Medical School presented results at
Research is ongoing concerning the use of borte-
Salamanca of the ongoing analysis of laboratory
zomib in the treatment of other types of cancer.
experiments in 2 cell lines (SUDHL-4, SUDHL-6)
Dr. Atanasio Pandiella and colleagues from the
from patients with diffuse histiocytic lymphoma
Center for Investigation of Cancer and the
(DHL). Although both cell lines are extremely
Hematology Division of the Hospital at the
similar genetically, SUDHL-4 is 20 times more
University of Salamanca, published a summary of
resistant to treatment with bortezomib. By defin-
laboratory research in treatment of cells from
ing genetic changes in these 2 cell lines before and
patients with PCL with bortezomib compared
after bortezomib treatment, these researchers
with treatment with dexamethasone and 3 other
hope to identify molecular markers that will ulti-
drugs that, like bortezomib, interfere with tumor
mately point to patients who will be the best can-
cell processes: the Erk pathway inhibitor PD98059,
didates for bortezomib treatment.
the Atk pathway inhibitor LY294002, and the far-
nesyltransferase inhibitor FPTIII. With borte-
Bortezomib works against MM both by directly
zomib treatment, only 20% of the PCL cells
killing MM cells and by affecting changes in the
remained alive, compared with less that 25% with
bone microenvironment, the exact mechanism of
FPTIII. The effect of dexamethasone, PD98059,
which is still under investigation. Cytokines (pro-
and LY294002 on PCL cells was considered mar-
teins that act as mediators between cells) such as
ginal, however, since approximately 70% of cells
interleukin-6 (IL-6), IL-10, IL-15, IL-21, tumor
remained viable after treatment with these agents.
necrosis factor (TNF), or insulin-like growth fac-
These results may indicate hope for the future
tor-1 (IGF-1) may play an important role sepa-
treatment of PCL, a disease that does not usually
rately or in combination with one another in the
respond to standard cancer treatments.
development of MM. Unn-Merete Fagerli and
associates from the Norwegian University of
REFERENCES
Science and Technology published an abstract
reporting the effects of bortezomib compared
1. Hideshima et al. Cancer Res. 2001;61:3071.
with the IB kinase inhibitor PS-1145 on 2 MM
2. Hideshima et al. J Biol Chem. 2002;277:16639.
cell lines that depended on cytokines for survival
3. Hidesima et al. Oncogene. 2001;20:4519.
as well as 1 cell line that did not. Bortezomib was
4. Mitsiades et al. Blood.2002;99:4525.
shown to cause MM cell death regardless of which
5. Mitsiades et al. Blood.2003;101:2377.
cytokines were responsible for cell growth, indi-
6. Mitsiades et al. Blood. 2001;98:795.
cating that it is effective regardless of a particular
7. Pandiella et al. Blood. 2002;100:601a.
MM cellular pathway. This is significant because
8. Bladé et al. Br J Haematol. 1998;102:1115-1123.
the mechanisms by which tumor cells can grow or
50
What is the role of Allogeneic Stem Cell
Transplantation in Multiple Myeloma?
Henk Lokhorst, M.D.
"graft versus leukemia" is shown by the effect of
donor lymphocyte infusions (DLI). DLI is the
infusion of peripheral blood cells from the original
SUMMARY
stem cell donor to the patient who has a recurrence
of the disease after allogeneic stem cell transplanta-
Although progress has been made in recent years
tion. DLI alone, without any other treatment like
with myeloablative allogeneic stem cell transplata-
chemotherapy, may completely eliminate the
tion in patients with multiple myeloma, the overall
malignant cells, resulting in a high percentage of
outcome of this treatment is disappointing due to
cures, as in patients with CML. Also in myeloma
a high chance of fatal complications in patients
there are strong indications that donor cells may
with newly diagnosed disease and ongoing relaps-
eliminate myeloma cells, resulting in the "graft ver-
es even after many years.
sus myeloma effect." This is especially shown by
the favorable effect of DLI in myeloma patients
with a recurrence of their disease after allogeneic
INTRODUCTION
transplantation.
Donor stem cell transplantation (so-called allo-
The presentations at the myeloma congress in
geneic stem cell transplantation, allo-SCT) is the
Salamanca clearly showed that progress has been
treatment of choice for a number of hematological
made in recent years with allogeneic stem cell
malignancies like chronic and acute myeloid
transplantation and that there is further proof for
leukemia. Patients who undergo "myeloablative"
the existence of a favorable graft versus myeloma
allo-SCT receive high-dose chemotherapy, some-
effect even in patients with unfavorable prognostic
times combined with total body irradiation, which
features. However, due to the high incidence of
completely knocks out their own bone marrow.
fatal complications associated with allogeneic
This treatment is immediately followed by infusion
transplantation in patients with multiple myelo-
of donor stem cells derived from a suitable (HLA-
ma, the outcome compares unfavorably with
identical) family or unrelated donor. At present
patients with the same characteristics who under-
mostly donor stem cells are used, which are col-
go autologous stem cell transplantation.
lected from the peripheral blood and not from the
bone marrow. With Allo-SCT 60-70% of patients
Altogether these results do not support a role for
with (otherwise incurable) chronic myeloid
myeloablative allogeneic stem cell transplantation
leukemia (CML) may be cured. This favorable
in multiple myeloma.
effect of allo-SCT is due to the so-called "Graft ver-
sus Leukemia" effect: donor (T) cells from the graft
The Salamanca presentations:
recognize and eliminate the residual leukemia cells
The experience of the European Group for Blood and Bone
in the patient. Donor T cells may also react with
Marrow Transplantation (EBMT)
normal host cells like cells in the skin or the gut,
Since 1983 the EBMT has registered the outcome
resulting in "Graft versus Host Disease," the most
of transplantations performed in European stem
important complication of allo-SCT. Due to the
cell transplantation centers. A case-matched
severe side effects, myeloablative allo-SCT is
study comparing allogeneic and autologous
restricted to younger patients (up to 55 years) only.
transplantation in patients treated up to 1994
showed that although allogeneic transplants had
The importance of donor T cells for the occurrence
a lower relapse rate, the overall survival was
of the graft versus leukemia effect is shown by the
superior for autologous transplants owing to the
fact that removal of T cells from the graft (to avoid
higher transplant-related mortality following
graft versus host disease) results in a much higher
allogeneic transplantation. 41 % of patients died
chance that the disease will return after transplan-
in the 2 years following allogeneic transplant
51
tation. A more direct proof for the existence of
mainly due to infections, lung disease, and graft
versus host disease (GVHD).
Hematology Association) a study was performed
in which allogeneic transplantation was compared
Patients who received their allogeneic transplants
with autologous transplantation. In this study (the
in the period between 1994 and 1998 had a much
HOVON 24 study) all patients initially received the
better outcome (longer survival) than patients
same treatment (VAD as induction therapy fol-
transplanted earlier. This better outcome was
lowed by semi-intensive treatment with intra-
completely due to lower treatment related mor-
venous melphalan) to which 85% of patients
tality, although this was still as high as 30%, 2
responded. After this treatment, patients with a
years after transplant. This better outcome
suitable stem cell donor received myeloablative
seemed to be due to many factors, i.e. earlier
allogeneic stem cell transplantation. The outcome
transplantation and more effective treatment of
of these patients was compared with patients who
infections. There was no difference in outcome
had no suitable stem cell donor and who were
between patients who received bone marrow or
treated with autologous transplantation after the
peripheral blood transplants.
same initial therapy with VAD and Melphalan. The
Careful selection of patients based on good prog-
outcome for the patients who received allogeneic
nostic factors like female gender, young age, low
stem cell transplantation was disappointing. Their
tumor burden, low 2-microglobulin, and
survival was much shorter (24 months) than the
responsive disease could further help to decrease
patients who received an autologous transplanta-
overall mortality. However these favorable char-
tion (48 months). An important reason for this was
acteristics would also indicate a good outcome
the high treatment related mortality: 34% of
with other treatments like autologous stem cell
patients died from fatal complications in the first
transplantation.
year after allogeneic transplantation as compared
to only 5% of patients after autologous transplan-
The experience of the Bologna group
tation. The other reason was that the "remission"
The
early
experience
of
the
Bologna
duration (the time the disease was quiet and under
Transplantation center (Italy) also showed a high
control) was not prolonged after allogeneic trans-
percentage of fatal side effects following allogeneic
plantation, probably also caused by the use of
transplant. Thirty-five % of patients transplanted
donor stem cell transplants from which part of the
in the period between 1990-1995 died within 1
T-cells were removed ("partial T cell depletion") in
year due to transplant complications. Fortunately
order to reduce the toxicity of the treatment.
the percentage of fatal side effects (16 % at 1 year)
was much lower in the 50 patients who received
It should be emphasized that the only difference
their transplant since 1996 in Bologna, probably
between the 2 patient groups was the fact that they
due to better infection prevention and transplanta-
received allogeneic or autologous transplantation.
tion earlier in the course of the disease. Mainly as a
All patients received the same pre-treatment, and
result of this much lower percentage of fatal side
other patient characteristics like age, disease stage,
effects, the survival of the recently transplanted
or presence of unfavorable prognostic factors were
patients (66% of patients were still alive 4 years
comparable in both patient groups. This first
after transplantation) was much longer. In a high
study ever performed in which autologous and
percentage of patients (44%) no signs of myeloma
allogeneic transplantation were compared showed
could be detected even when very sensitive (molec-
that that there seems to be no indication for mye-
ular) methods were used. This suggests that allo-
loablative allo-SCT as part of first line treatment in
geneic transplantation results in a better myeloma
myeloma.
cell elimination as compared to other treatments
like autologous transplantation. However even
Donor Lymphocyte Infusions
patients "free" of myeloma after transplantation
In the Netherlands, 50 patients have been treated
have recurrence of their disease sometimes as late
with donor lymphocyte infusions (DLI) for recur-
as 9 and 10 years following transplantation. This
rence of their disease after allogeneic stem cell
finding raises the question of whether allotrans-
transplantation. 56% of patients responded well to
plantation has the potential to cure myeloma.
DLI, including 25% of patients who achieved a so-
called complete remission. In these patients no
The experience of Dutch HOVON
signs of myeloma can be detected in blood/urine
Allogeneic stem cell transplantation compared
and bone marrow. Also patients with unfavorable
with autologous transplantation
prognostic factors like deletion of chromosome 13
52
Under the auspices of
HOVON (Dutch
(the most important negative prognostic factor in
myeloma) may respond well to DLI, and in sever-
al patients the disease is now undetectable for
many years (5-10 years) after treatment with DLI
alone. The most important side effect of DLI is a
graft versus host disease. In fact the best response
to DLI is seen in patients with long-lasting GVHD.
CONCLUSIONS
Although the outcome of patients treated with
myeloablative allogeneic stem cell transplantation
has improved in recent years, it is still associated
with a high chance of fatal complications. Mainly
as a consequence of this high treatment-related
mortality, the overall outcome of allogeneic trans-
plantation is inferior compared to autologous
transplantation.
The first challenge will be to further reduce the
fatal complications of standard allotransplatation.
One promising method for this is the use of non-
myeloablative allogeneic transplantation. Later
donor lymphocyte infusions directed against the
myeloma cell may prevent the potential risk of
relapse. Such studies are currently performed on a
worldwide scale.
53
The Comprehensive Guide to Salamanca
An overview of the
IXth International
Workshop on
Multiple Myeloma
International Myeloma Foundation
International Headquarters
12650 Riverside Drive, Suite 206
North Hollywood, California 91607
Salamanca, SPAIN
800 452 CURE (2873) Fax: 818 487 7454
TheIMF@myeloma.org
www.myeloma.org
IMF
May 23-27, 2003
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure.
© 2003 International Myeloma Foundation