InternatIonal MyeloMa FoundatIon
ASCO 2006
Highlights
for Physicians
by Lynne Lederman, PhD
Publication funded by an unrestricted educational grant from Celgene Corporation and Cytogen Corporation.
ASCO 2006 Highlights for Physicians
by Lynne Lederman, PhD
News from the 2006 ASCO Meeting
highest tolerable level up to 400 mg per day, with a
median dose of 200 mg per day and median duration
New and updated data on the use of novel therapeutics
of treatment of 11 months. The study included patients
as single agents and in combination therapy in patients
65 to 75 years of age; 41% of patients were at least 70
with newly dosed or relapsed/refractory multiple
years old. Median follow-up time was 32.2 months. As
myeloma were presented at the 2006 meeting of the
shown in Table 1, patients receiving the MPT treat-
American Society for Clinical Oncology (ASCO), June
ment had a higher response rate than patients receiving
2 through 6 in Atlanta, Georgia. For the first time at
standard MP, increased time to disease progression, and
ASCO, myeloma was featured in the Plenary session.
increased overall survival.
In addition, there were reports on the use of bone-tar-
geting agents, new investigational agents, and preclini-
MPT was associated with higher toxicities than MP,
cal studies. Some of the newer agents affect different
including thrombosis and neuropathy.
pathways in myeloma cells, so the use of these agents
in combination may eventually result in even higher
In a discussion of this presentation, Kenneth Ander-
response rates than the current standards of care.
son of the Dana-Farber Cancer Institute, Boston, Mas-
sachusetts, called the results "a wonderful example of
Novel Agents in Patients
with Newly Diagnosed Myeloma
progress in our disease," and noted that MPT should
be considered as an option for a standard comparator to
Thierry Facon of the University of Lille, France, pre-
use in future trials of novel therapies for the treatment of
sented the results of the Intergroupe Francophone du
elderly, newly diagnosed patients with myeloma. How-
Myelome (IFM) study comparing standard melpha-
ever, other investigators feel that since patients receiving
lan plus prednisone (MP) therapy with thalidomide
MPT experienced more side effects than those receiv-
(T) added to MP (MPT) or with high-dose melpha-
ing MP, including a higher rate of thrombosis, and that
lan (MEL100) followed by stem cell transplantation
neuropathy associated with thalidomide required dose
(SCT) in patients with newly diagnosed myeloma
reductions, further studies are required to establish the
at the Plenary session. Thalidomide was dosed at the
role of MPT for elderly patients. Follow-up studies are
needed to evaluate better-tolerated regimens with pro-
Table 1
phylaxis for thrombosis and infectious complications.
IFM 99-06
In the meantime, MP will remain the comparator of
MP
MPt
Mel100
choice, for example, in an upcoming trial of MP versus
Revlimid-MP (see Palumbo below). In addition, fur-
Number of patients
191
124
121
ther studies are required to evaluate double stem cell
Complete response
2%
15%
17%
transplant with reduced-dose melphalan (100 mg/m2)
90% response
7%
49%
41%
versus MPT in eligible patients, including patients less
50% response
40%
81%
72%
than age 65 years.
Progression-free survival,
months*
17.2
29.5
19.0
Another late-phase study in patients with newly diag-
nosed myeloma was presented by Vincent Rajkumar
Overall survival, months
30.3
not reached
38.6
of the Mayo Clinic, Rochester, Minnesota. He noted
* p <.0001 for MPT compared with MP
that although the response rates were higher in patients
p =.0008 for MPT compared with MP
3
treated with thalidomide up to 200 mg (median dose
The overall response rate with bortezomib as a single
not known) plus dexamethasone (TD) than with dexa-
agent was 40%, making bortezomib the most active
methasone (dex) alone, the time to disease progression
single agent in myeloma. Richardson acknowledged
has not yet been reached, and the differences in over-
that bortezomib will probably be used primarily in
all survival between treatments at about 2 years of fol-
combination therapy, although it does offer a steroid-
low-up are not significant. Potentially fatal thrombotic
sparing option, and no incidents of thrombosis were
events, including deep vein thrombosis (DVT) and pul-
observed. Sundar Jagannath from St. Vincent's Cancer
monary embolism (PE) occurred at a much higher rate
Center, New York, New York, in discussing Dr. Rich-
in patients receiving TD; myocardial and cerebrovascu-
ardson's data, indicated that it confirmed prior pub-
lar ischemia occurred at slightly higher rates in patients
lished data, and that current studies with bortezomib in
receiving TD. These findings led to the use of prophy-
combination with dexamethasone and/or other agents
lactic aspirin. Thalidomide also caused neutropenia.
are necessary to offer response rates higher than 40%
for newly diagnosed patients, and to ensure a durable
Antonio Palumbo, University ofTorino, Italy, presented
response. Several combinations, including bortezomib
an earlier-phase study of lenalidomide (Revlimid)
plus MP, R-MP, and MPT have produced responses in
plus MP (R-MP) in patients with newly diagnosed
80 % to 90% of patients in the frontline setting.
myeloma. In this dose-finding study, dose-limiting
toxicities included neutropenia, thrombocytopenia,
Bart Barlogie of the Myeloma Institute for Research
and thromboembolism, resulting in the use of aspirin.
and Therapy, University of Arkansas for Medical Sci-
Overall response rates were 100% in for 41 patients
ences, Little Rock, Arkansas, presented early results of a
receiving R-MP for a median of 7 cycles compared
trial investigating the incorporation of bortezomib into
with 81.3% in 129 historic controls receiving MPT;
total therapy 3 (TT3) in patients with newly diagnosed
event-free survival was 87% at 16 months vs. 71% at
myeloma. TT3 has been developed to improve on the
18 months, respectively. Further studies are needed.
results of TT2, and consists of a shortened course of
induction therapy with DTPACE (dexamethasone,
Bortezomib was also studied in the front-line setting
thalidomide, cisplatin, Adriamycin, cyclophospha-
as a single agent. Paul Richardson of the Dana Farber
mide, and etoposide) plus bortezomib followed by
Cancer Institute, Boston, Massachusetts, reported on
stem cell collection and tandem SCT. Patients also
the study, which included an analysis of neuropathy in
received thalidomide plus dexamethasone (thal-dex)
patients before, during, and after treatment. The study
before and after the high-dose melphalan and SCT, as
also evaluated ways to treat neuropathy if it occurred. In
well as bortezomib plus DTPACE until the end of the
this study, 50% of the patients had small fiber periph-
first year of treatment. During year 2, patients received
eral neuropathy at enrollment, and 9% had baseline
monthly bortezomib plus thal-dex, and thal-dex alone
large-fiber peripheral neuropathy, although in the sci-
during years three and four of therapy. The 18-month
entific literature only 10% of patients with myeloma
estimates suggest that the response rates for TT3 are
were thought to have clinical neuropathy at diagno-
higher than for TT2, and that responses occur ear-
sis. Peripheral neuropathy that arose during bortezo-
lier in the course of therapy. Patients who are over age
mib treatment was manageable and mostly reversible.
Management of neuropathy involved bortezomib dose
Table 2
modifications and step-wise pharmacologic interven-
Number of patients
66
tions, including vitamins, nutritional supplements,
Complete response
10%
antiseizure medications, antidepressants, and serotonin
Partial response
30%
reuptake inhibitors. Study results are summarized in
Median time to progression
6 months
Table 2.
Duration of response
8.5 months
4
65, have higher lactate dehydrogenase (LDH) levels,
that patients treated with len-dex had significantly
abnormal cytogenetics, or more advanced disease, are
higher response rates, longer time to progression, and
more likely not to respond to TT3. LDH, a marker for
increased overall survival, as compared to patients
high-risk myeloma indicative of hyperproliferative dis-
treated with dex alone, as shown in Table 3.
ease, appears to be a key factor in determining overall
survival in a multivariate analysis. Side effects with TT3
Weber noted that not all of the analyses are complete.
appear to be lower than with TT2. The risk of grade
Although some side effects, such as neuropathy, consti-
2 or higher thrombosis/embolism for TT2 was 37%;
pation, and fatigue, are less frequent with lenalidomide
it was 27% for TT3, and although significantly lower
than with thalidomide, lenalidomide is associated with
than the risk for TT2, all patients received prophylactic
increased hematologic toxicities, resulting in anemia,
low molecular weight heparin (LMWH). Barlogie sug-
neutropenia, and thrombocytopenia. Lenalidomide
gested that some patients who had withheld LMWH
also causes thrombotic events at about the same rate
due to thrombocytopenia may have experienced
as thalidomide, which will probably require some pre-
thrombotic events after their platelet counts recovered
ventative therapy. The rates of thrombosis were differ-
but before LMWH prophylaxis was reinstituted.
ent in the North American (MM-009) and European
studies (MM-010), and the reasons for this discrepancy
Ruben Niesvizky, Weill Cornell Medical College of
are not known. Ruben Niesvizky gave an analysis of
Cornell University, New York, New York, presented
both studies that showed that there was an increased
results of a Phase II trial of len-dex in combination
risk of thrombosis in patients receiving lenalidomide in
with clarithromycin (BIRD) in patients with newly
combination with dexamethasone and erythropoietin.
diagnosed myeloma. This combination appears to safe
The effect of erythropoietin was independent of hema-
and well tolerated at approximately one year of follow-
tocrit and hemoglobin. Increased patient age, higher
up, allowing eventual SCT in some patients, although
numbers of plasma cells, and a decreased performance
15% of patients had thrombosis even with low-dose
status were also associated with an increased rate of
aspirin prophylaxis. The initial complete response
thrombosis. Although aspirin use appeared to protect
(CR) rate was 23% and there were 17% near (n)CR,
against thrombosis, Niesvizky said a prospective, ran-
10% very good partial response (PR), giving an overall
domized clinical trial was needed to study the effects
response rate of 53%, which is higher than the 38%
of aspirin and other prophylactic agents, and that the
overall response rate seen for len-dex alone. The average
use of erythropoietin should be minimized for patients
time to CR was 145.5 days The study group suggests
receiving len-dex.
that this combination be investigated further.
Novel Agents in Patients with Relapsed
Table 3
Myeloma
MM-009
More results of the North American study (MM-009)
len-dex
dex
p-value
of lenalidomide plus dexamethasone (len-dex) com-
Number of patients
171
170
pared with dexamethasone (dex) alone in patients with
Complete response
12.9%
0.6%
relapsed myeloma were presented by Donna Weber,
Overall response
59.4%
21.1%
<.001
M.D. Anderson Cancer Center, Houston, Texas. This
Overall response after
is a companion study to one conducted in Europe
prior bortezomib
66.7%
10%
<.001
(MM-010) for which results were presented last winter
Time to progression,
at the American Society of Hematology (ASH) confer-
median months at interim
ence. As in the companion study, this study showed
analysis
11.1
4.7
<.0001
Overall survival, months
29.6
20.1
<.0001
5
M. Wang discussed a companion analysis of the
cantly higher CR rates, and longer times to disease pro-
MM009 and MM-010 studies, which attempted to
gression than patients receiving dexamethasone (dex)
determine if prior treatment with thalidomide had an
whether or not they had received prior SCT, as summa-
effect on the response to len-dex. Because the groups
rized in Table 4 below. Patients receiving SCT as part
receiving and not receiving thalidomide did not have
of their only line of prior therapy also had longer time
comparable histories of prior therapy and course of
to progression and overall survival, and higher response
disease, it was not possible to answer this question.
rates with bortezomib than with dexamethasone.
Another analysis of these two studies, presented by
Edward A. Stadtmauer, Abramson Cancer Center,
Results of weekly treatment with bortezomib in patients
University of Pennsylvania, Philadelphia, Pennsylva-
with previously treated myeloma who had received
nia, concluded that the time to progression was longer
1 or 2 prior treatment regimens were reported by T.
for patients who received len-dex earlier at first relapse,
Anthony Greco for the Minnie Pearl Caner Research
rather than later as salvage therapy.
Network. In this Phase II trial, the overall response
rate was 47% and median progression-free survival
A final analysis of the IFM 01-02 study of low (100
was 11.8 months, similar to that for patients receiving
mg) vs. high (400 mg) doses of thalidomide plus
twice-weekly bortezomib. The weekly dosing was well-
dexamethasone (at 3 months if disease was stable, or
tolerated and active, although the number of patients
at progression) and pamidronate was presented by
in this study was small (N=40).
I.Yakoub-Agha, Lille, France. Patients receiving the
lower dose of thalidomide required dexamethasone
Results of a small preliminary study evaluating bort-
more frequently, and there was no difference in the two
ezomib in 51 patients with cancer and impaired kidney
treatment groups for overall survival at 1 year (44% and
function was reported by D. Mulkerin for the National
46%, respectively), although the lower dose was better
Cancer Institute (NCI) Organ Dysfunction Working
tolerated. There was a discussion of the best starting
Group. The study included 13 patients with myeloma
dose of thalidomide; no consensus was reached.
and showed that bortezomib at the approved dose and
schedule was well tolerated in patients with varying
Additional data analyses were reported for the APEX
degrees of impaired kidney function (creatinine clear-
Phase III clinical trial of bortezomib vs. dexamethasone
ance ³20 mL/min per 1.73 m2), including patients
in patients with relapsed/refractory myeloma. Dan
on dialysis. Bortezomib clearance was independent of
Vogl of the University of Pennsylvania Cancer Center,
renal function. Enrollment is continuing for patients
Philadelphia, Pennsylvania, presented an evaluation of
with creatinine clearance <20 mL/min per 1.73 m2 and
the impact of prior autologous SCT on response. The
dependence on dialysis, although accrual is expected
analysis showed that patients receiving bortezomib (btz)
to be difficult given the commercial availability of
had significantly higher overall rates of response, signifi-
bortezomib.
Table 4
APEX: effect of prior SCT
Prior SCt
p-value
no prior SCt
p-value
Btz
Dex
Btz
Dex
Number of patients
222
229
110
107
Time to progression, months
6.2
3.5
<.0001
5.5
4.2
.009
Overall survival, months
NE*
22.8
.0122
22.88
24.3
.41
Overall response rate, %
41.3
17.8
<.0001
32.4
18.4
.034
*NE = not estimable
6
Agents Affecting Bone Metabolism
activity markers such as N- or C-telopeptide cross-links
(NTX or CTX) In order to draw any conclusions.
James Berenson, Institute for Myeloma and Bone Can-
cer Research, West Hollywood, California, presented
Shachar Peles, Washington University School of Medi-
results of a Phase I trial of a radioactive, bone-seek-
cine, St. Louis, Missouri, presented the results of a
ing compound, samarium (Sm153) lexidronam (Sam)
prospective study on the effects of weekly bortezomib
in combination with bortezomib in 12 patients with
on bone markers in patients with myeloma. Patients
relapsed/refractory myeloma. Bortezomib is given in 8-
received bortezomib pre-SCT after induction, and as
week cycles in order to reduce the potential side effects
consolidation following SCT. Patients did not receive
of the combination therapy. Sam targets remodeling
bisphosphonates for 42 days before SCT and for the first
bone that may be the sites of myeloma cell activity.
3 cycles of consolidation therapy. Bortezomib inhibited
Myeloma cells are sensitive to radiation, and Berenson
bone resorption by osteoclasts, even in patients whose
feels that bortezomib increases this radiosensitivity. So
myeloma cells did not respond to bortezomib. It was
far the combination of bortezomib and Sam appears
suggested that bortezomib may provide an alternative
to be well-tolerated, with transient thrombocytopenia
and/or adjunct to bisphosphonates, which have been
and transient neutropenia and no dose-limiting tox-
associated with long-term side effects in patients with
icities. There have been 2 patients responding and 4
myeloma, including renal toxicity and osteonecrosis of
with stable disease. Berenson expects the non-overlap-
the jaw.
ping side effect profiles of the two drugs to contribute
to patient quality of life. Additional patients are being
Early Clinical Trials
enrolled in the last 2 dose cohorts for this study.
A Phase I trial, reported by Asher Chanan-Khan,
Berenson also presented the results of a study looking
Roswell Park Cancer Institute, Buffalo, New York,
at the survival of patients with multiple myeloma who
evaluated the combination of KOS-953 (17-AAG in
received 4 mg zolendronic acid, a bisphosphonate that is
Cremophor) plus bortezomib in patients with relapsed
indicated for treatment of bone metastases. Survival of
refractory myeloma. KOS-953 inhibits heat shock pro-
107 patients receiving zolendronic acid was compared
tein 90 (HSP90), which is required for the function of
with that of 102 patients receiving 90 mg pamidronate,
key oncogenic proteins including protein kinases and
another bisphosphonate. The researchers also looked
transcription factors. As a single agent, KOS-953 is
at the levels of bone alkaline phosphatase (BALP), a
not very active; in combination with bortezomib, bet-
marker of bone metabolism, at baseline. At 25 months,
ter responses were seen whether patients had received
the survival was significantly higher for patients receiv-
prior bortezomib or not, and whether or not they had
ing zolendronic acid compared with pamidronate (76%
responded to bortezomib without KOS-953. There
vs. 63%; P=.038). For patients with low baseline BALP
were no additive toxicities. The study is continuing to
levels (<146 U/L), survival was similar in both treat-
enroll patients.
ment groups. However, for patients with high baseline
BALP (³146 U/L), which may be a marker of more
Martha Lacy, Mayo Clinic, Rochester, Minnesota,
aggressive bone disease, survival was significantly higher
described a Phase I trial of a monoclonal antibody,
for those who received zolendronic acid than pamidro-
CP-751,871, which reacts with the insulin-like growth
nate (82% vs. 55%; P=.048). Another risk factor in
factor 1 receptor (IGF-1R), in relapsed or refractory
addition to high baseline BALP is a history of skeletal
myeloma. The antibody was safe and well tolerated as a
related events, such as bone fractures. Comments from
single agent and in combination with dexamethasone,
the audience indicated the need for a prospective ran-
and the combination showed potential anti-myeloma
domized trial incorporating testing of established bone
activity.
7
S.E. Biehn, University of North Carolina at Chapel
It is still not known what treatments to use as mainte-
Hill School of Medicine, Chapel Hill, North Carolina,
nance therapy for patients whose myeloma is in remis-
presented follow-up data for a Phase I trial of bortezo-
sion, and this question, too, will need to be answered
mib and pegylated liposomal doxorubicin in patients
using clinical trials. Anderson pointed out that there
with myeloma. This combination significantly increased
is no conventional maintenance therapy for multiple
both time to progression and time to retreatment com-
myeloma, and that every-other-day steroids and inter-
pared with patients' previous treatment. The patients'
feron have not yielded good results.
red blood cell and platelet counts, performance status,
and level of response were associated with outcome, and
The best measure of response was also an issue for some
might be predictive, although a larger study is needed
investigators. Barlogie believes that complete response
to confirm this.
(CR) is an important surrogate for improved survival,
whereas Berenson believes that paraprotein production,
Other studies are listed in Table 5, next page.
used as a marker for CR, is probably not produced by
the population of cells responsible for fatal disease.
Nonclinical Studies
However, at this time, there isn't a better marker for
those cells.
The results of preclinical studies in myeloma cells or in
animal models are summarized in Table 6, page 10.
As new agents are developed that act against myeloma
Unanswered Questions and Future
in different ways, combinations of new and established
Directions
therapies should continue to result in increased num-
bers of patients with complete responses that are main-
Although the problem of blood clots associated with
tained for longer periods of time.
both thalidomide and lenalidomide was discussed,
there was no consensus on the best way to prevent them.
Lynne Lederman, PhD, is a medical writer based in
Preventative therapy may include the use of aspirin or
Mamaroneck, New York
other clot-preventing drugs, such as Coumadin or low
molecular weight heparin, depending upon a particular
patient's risk factors. Factors that increase the risk of
clots include the use of certain chemotherapy agents,
for example, doxorubicin and melphalan, and the use
of erythropoietin, whereas patients taking high doses of
corticosteroids, such as dexamethasone, appear to have
a lower risk of clots if it is not given in combination
with lenalidomide or thalidomide.
Given the encouraging results with bortezomib,
lenalidomide, and thalidomide, additional clinical tri-
als combining these agents and with some of the more
traditional agents are expected. The best combinations
and courses of therapy still need to be determined. Rich-
ardson suggested that physicians should "be thoughtful
in the selection of combinations, so that efficacy won't
be lost to toxicity." Anderson expects couplet and trip-
let therapy "predicated upon scientific principles."
8
Table 5
Ongoing Clinical Trials Presented at ASCO, 6/06
author
treatment or Study design
Conclusions
James Berenson
Combination arsenic trioxide, bortezomib,
Objective response in 27% of 22 patients;
and ascorbic acid in patients with relapsed or
additional trials suggested
refractory MM
W. Poenisch
Bendamustine in combination with
Combination well tolerated; additional
University of Leipzig,
thalidomide and prenisolone in patients
trials suggested
Leipzig, Germany
with relapsed or refractory MM
S.S. Farag
Temsirolimus (CCI-779) as a single agent in
Anti-myeloma activity seen; warrants
Ohio State University,
patients with relapsed or refractory MM
further study alone and in combination
Columbus, Ohio
Maurizio Zangari
Effect on survival of treatment-associated
Development of DVT in newly diagnosed
University of Arkansas
deep vein thrombosis (DVT) in patients with
patients treated with chemotherapy ± tha-
for Medical Sciences
newly diagnosed myeloma
lidomide had no effect on overall survival;
patients not exposed to thalidomide who
developed thrombosis during therapy had
longer event-free survival
D. Candelaria
Thrombin generation measured in patients
Thalidomide therapy increases thrombin
University of New Mexico,
with myeloma treated with thalidomide
generation significantly in patients with
Albuquerque, New Mexico
(n=9) vs. not (n=13)
myeloma
F. Sayani
Retrospective analysis of effect of CR pre- and
No effect seen
University of Calgary,
post-SCT on overall survival in 88 patients
Calgary, Alberta
with myeloma
H. Ege
Retrospective analysis of effect of absolute
ALC is an independent prognostic factor
Mayo Clinic, Rochester, Minnesota
lymphocyte count (ALC) on survival in 1835
when compared with the International
patients with myeloma
Staging System (ISS)
D.E. Reece
Update of melphalan 280 mg/m2 plus
Treatment regimen was well tolerated;
Princess Margaret Hospital,
amifostine cytoprotection before SCT for
response rate = 62%; warrants further
Toronto, Ontario
newly diagnosed patients with MM (N=24)
study, possibly as part of tandem trans-
plant or combination therapy with novel
agents
R. Carrion Galindo, Sr.
Busulfan plus melphalan-140 vs. MEL200 as
Busulfan plus melphalan-140 associated
Hospital Gregorio Maranon, Madrid
conditioning regimens
with higher toxicity and mortality
L.R. Mileshkin, Peter MacCallum
Patterns of occurrence of neuropathy with
Majority of patients treated with tha-
Cancer Centre, East Melbourne,
thalidomide treatment and role of electro-
lidomide develop peripheral neuropathy
Australia
physiologic monitoring
with sufficient duration of therapy; nerve
electrophysiologic studies did not provide
a benefit over careful clinical evaluation
S. Kumar
Correlation of bone marrow angiogenesis
Baseline bone marrow microdensity
Mayo Clinic
and response to thalidomide in patients with
and tumor cell expression of angiogenic
newly diagnosed myeloma
cytokines do not predict resistance or
response to thal-dex or dex
9
Table 6
Pre-clinical Study Results Presented at ASCO, 6/06
author
Study design
Conclusions
J.D. Shaughnessy
Gene expression profiles (GEP) on paired
Up-regulated microenvironment (ME)
Myeloma Institute for Research
purified plasma cells (PC) and bone
associated genes were identified, includ-
and Therapy,
marrow biopsies from 46 patients before
ing osteoinductive and angiogenic-related
Little Rock, Arkansas
and after a single dose of bortezomib
genes. Growth response, Krupple-like factor,
and nuclear receptor genes were down-
regulated; these PC and ME changes were
observed in patients with-low risk disease
I. Breitkreutz
Effect of lenalidomide and bortezomib on
Lenalidomide and bortezomib inhibit osteo-
Dana-Farber Cancer Institute
osteoclasts in healthy donors and patients
clast growth and survival and block growth
with myeloma
and survival of myeloma cells
co-cultured with osteoclasts
E.P. Neri
Model to evaluate GEP of myeloma cells
Bone marrow ME modulates GEP of
Dana-Farber Cancer Institute
after interaction with ME
myeloma cells
L.D. Anderson, Jr., Fred Hutchinson
Identification of potential T-cell epitopes
T-cells recognizing myeloma-related epitopes
Cancer Research Center,
in candidate myeloma antigens
are present in the normal
Seattle, Washington
T-cell repertoire and can be isolated and
expanded; are identifying additional
epitopes that may be useful for vaccination
or adoptive T-cell therapy
10
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