INTERNATIONAL MYELOMA FOUNDATION
ASH 2009
Multiple Myeloma
Highlights
for Physicians
Summaries of Multiple Myeloma Presentations
from the 51st Annual Meeting
of the American Society for Hematology (ASH)
held in New Orleans, Louisiana,
December 58, 2009
Compiled by Lynne Lederman, PhD
Funded by unrestricted educational grants from Celgene Corporation and Proteolix, Inc.
ASH 2009 Summaries of Multiple Myeloma
Presentations for Physicians
Introduction
on transplantation, venous thromboembolism, stem cell
collection, tumor cell biology, and other topics of interest.
The 51st Annual Society of Hematology (ASH) Annual Meet-
ing was held December 5th through the 8th, 2009, in New
· Three poster sessions featured hundreds of posters about
Orleans, LA. On December 4, the International Myeloma
myeloma and related topics, e.g., pharmacoeconomics,
Foundation (IMF) and the Postgraduate Institute for Medi-
and new drugs in development.
cine sponsored a symposium that provided participants
with an overview of the most recent data from clinical trials
This report summarizes information presented at the 2009
along with expert commentary, analysis, interpretation of
ASH Annual Meeting, organized by topics rather than by ses-
findings, and discussion of implications for current clinical
sions, presenting an overview of information on new drugs
practice in the treatment of myeloma. Dr. Brian G.M. Durie
in development, clinical trial results, treatment by patient
introduced the presenters and topics at the symposium.
characteristics, e.g., transplant eligibility or stage of disease,
risk stratification and staging, and a brief summary of some
Multiple myeloma was the topic of many presentations at
presentations that might be of interest to patients with
ASH, including the following:
myeloma and their families and caregivers.
· The PETHEMA/GEM clinical trial of bortezomib/mel-
phalan/prednisone (VMP) vs. bortezomib/thalidomide/
prednisone (VTP) followed by maintenance therapy with
New Drugs in Development
bortezomib/thalidomide (VT) vs. bortezomib/prednisone
Relapsed Refractory Myeloma: The Role of New Drugs,
(VP) in elderly untreated patients, was presented by María
was presented by A. Keith Stewart, MD, Mayo Clinic, Scott-
Victoria Mateos, Salamanca, Spain. This was one of the six
sdale, Arizona, who chaired the Multiple Myeloma Educa-
talks selected for the plenary session by the ASH program
tion Session. This topic was discussed in depth in a paper
committee as the most groundbreaking abstracts submit-
published in Hematology 2009, which is available through
ted to the meeting.
the American Society of Hematology. Dr. Stewart reviewed
· At the ASH/ASCO Joint Symposium, Sundar Jagannath, St.
clinical trial results and the status of novel emerging thera-
Vincent's Catholic Medical Center, New York, presented
pies. He emphasized the importance of individualizing
the final results of PX-171-003-A0, part 1 of an open-label,
treatment at relapse, taking into consideration the tempo
single-arm, phase II study of carfilzomib (CFZ) in patients
of disease, previous toxicities and responses, duration of
with relapsed and refractory multiple myeloma. This joint
previous remission, pragmatic concerns such as access to
symposium is a review of what the ASH meeting organiz-
drugs as determined by country or insurance, geography,
ers feel represents some of the best science from the
and patient preference. Of hundreds of drugs in preclini-
2009 American Society of Clinical Oncology (ASCO) 2009
cal trials, only a few make it through clinical trials to be
Annual Meeting, which was held in June.
licensed. Some that have shown little or no activity as single
agents in small trials might still be active in combinations.
· An education session was held on how to treat young
There may be subsets of myelomas that could respond to a
patients, old patients, and patients with relapsed/refrac-
given therapy. Advances in gene expression profiling could
tory myeloma.
provide information to enhance the aim of targeted thera-
pies and to define which molecular subtypes of myeloma
· A scientific session was conducted entitled "Scientific
are most susceptible to current therapies and to those in
Linking of Unusual Manifestations of Myeloma."
development. Promising agents still in trials that Dr. Stewart
mentioned include bendamustine, pomalidomide, carfil-
· At least 15 simultaneous oral sessions (comprising about
zomib, perifosine, vorinostat, tanespimycin, and NPI-0052,
6 presentations each) were held specifically on myeloma,
which are discussed below.
with many other sessions presenting related information
3
Proteasome Inhibitors
as of October, 2009, and a safety review was available for
141 patients who received treatment for at least 6 months.
Carfilzomib (PX-171)
Toxicities have been minimal, with lower rates of grade 3
Encouraging results for the second-generation proteasome
and 4 hematologic and non-hematologic toxicities than
inhibitor, carfilzomib, were reported in several talks and at
were seen in the A0 portion of the trial. The rates of periph-
least half a dozen posters. The final results of the phase I
eral neuropathy and acute renal failure have also been low.
study in relapsed and refractory myeloma that were reported
Across all trials of carfilzomib to date, in which 357 patients
in the ASH/ASCO Joint Symposium by Dr. Jagannath are
have received the drug, the overall rate of grade 3 or 4 neu-
summarized below, followed by a table (see page 5) sum-
ropathy has been less than 2%. Dr. Jagannath concluded
marizing the results of other studies and trials of carfilzomib
that carfilzomib was well tolerated across all phase II trials.
that were reported at ASH. It is anticipated that pivotal trials
Carfilzomib will be tested in a phase III, randomized, inter-
supporting a new drug application (NDA) for this promising
national trial in combination with lenalidomide in 2010.
agent will be completed by the end of 2010. A randomized
international multicenter phase III study will begin enroll-
NPI-0052
ment of 700 patients in early 2010 to compare carfilzomib
Phase I Clinical Trial of the Novel-Structure Protea-
plus lenalidomide and low-dose dexamethasone (CRd) with
some Inhibitor NPI-0052 in Patients with Relapsed and
lenalidomide plus low dose dexamethasone (Rd).
Relapsed/Refractory Multiple Myeloma (MM) (Abstract
431) was presented by Paul Richardson, Dana-Farber Can-
Final Results of PX-171-003-A0, Part 1 of an Open-Label,
cer Institute, Boston, Massachusetts. NPI-0052 is a novel
Single-Arm, Phase II Study of Carfilzomib (CFZ) in
second-generation proteasome inhibitor that is not pep-
Patients (pts) with Relapsed and Refractory Multiple
tide-based and thus differs from bortezomib and carfilzo-
Myeloma (MM) was presented by Sundar Jagannath, St.
mib. It exhibits fast, marked, prolonged inhibition of all
Vincent's Catholic Medical Center, New York, NY. Dr. Jag-
3 proteolytic activities of the proteasome (chymotrypsin,
annath reviewed carfilzomib and preclinical data showing
trypsin, and caspase-like activities), with a unique toxicity
this proteasome inhibitor was active against bortezomib-
profile that is different than that reported with bortezomib.
resistant solid tumor cells. In the first part of the PX-171-
There are two formulations of NPI-0052, an old liquid for-
003-A0 trial in patients with relapsed, refractory myeloma,
mulation and a new lyophile formulation to which studies
46 patients received 20 mg/m2 of carfilzomib by I.V. push
are being transitioned. NPI-0052-101 is a phase I study in
on two consecutive days a week. Patients had received at
patients with relapsed and relapsed/refractory myeloma for
least two prior lines of therapy that included bortezomib
which no other approved treatment is available. To date 32
and immunomodulatory drugs (IMiDs); 80% had received
patients are enrolled with a median of 5 prior regimens:
at least 4 prior lines of therapy. The primary endpoint
66% prior bortezomib, 34% refractory to bortezomib, 62%
was overall response [ORR: complete response (CR) +
prior SCT. The study started at low doses of the liquid for-
partial response (PR)] by International Myeloma Working
mulation from 0.025 mg/m2 escalating to 0.7 mg/m2 and also
Group (IMWG) response criteria. The secondary endpoints
to 0.7 mg/m2 of the lyophile formulation. NPI-0052 is well
included clinical benefit response [(CBR): CR + PR +
tolerated, with few grade 3 or 4 toxicities, most only at high-
minimal response (MR)], time to progression (TTP), and
est dose, that are manageable with supportive measures.
duration of response (DOR), but not overall survival (OS).
Fatigue, significant neuropathy, and myelosuppression
Results for 39 patients were evaluable. Of these, 26% had
were not seen. Some excipient-related AEs with the liquid
CBR, which included 18% PR and 8% MR. In patients with
formulation were not seen with the lyophile formulation.
disease refractory to bortezomib, 22% had CBR. Median
Responses were evaluable in 31 patients with best response
TTP was 5.1 months, DOR for the 10 patients with PR or MR
of SD of 58%. Of these, 9 patients (28%) maintained SD
was 7.4 months. The adverse events (AEs) were primarily
for over 6 months. More trials are planned. Dr. Richardson
hematologic, and grade 3 and 4 neutropenia was <10%. Dr.
thinks the future of NPI-0052 is in combination therapy.
Jagannath concluded that single-agent carfilzomib is active
in heavily treated patients including those with bortezomib-
HDAC Inhibitors
refractory myeloma. The A0 part 1 portion of this trial was
expanded to PX-171-003-A1, a pivotal, dose-escalation trial,
Vorinostat (SAHA, suberoylanilide hydroxamic acid)
increasing the dose of carfilzomib after the first cycle to 27
Combined Vorinostat, Lenalidomide and Dexametha-
mg/m2. Prophylaxis against tumor lysis syndrome was insti-
sone Therapy in Patients with Relapsed or Refractory
tuted. OS was the endpoint. This trial enrolled 269 patients
Multiple Myeloma: A Phase I Study (Abstract 305), was
4
presented by David Siegel, Hackensack University Medical
once a week. In 31 patients with heavily pretreated lenalid-
Center Hackensack, New Jersey. The rationale for this study
omide-refractory myeloma, there was one DLT of diarrhea
was the observed preclinical synergy of vorinostat with
at the highest dose in the dose-finding trial, and no further
IMiDs. The primary objective was to determine MTD, which
DLTs when more patients were treated, so an expansion
was not met. Secondary objectives included safety and
cohort was treated. Most patients experienced adverse reac-
response. Vorinostat was administered one week on, one
tions, commonly diarrhea and fatigue, and also cytopenias.
week off in 28 day cycles, with lenalidomide administered
Serious AEs included increased QTc interval associated with
for 21 days of the cycle, and dexamethasone administered
vorinostat. Thirteen of 28 patients (46%) had a PR or better,
(continues on next page)
Abstract/Phase
Population/Regimen
AEs
Responses
Conclusions
Updated Results of Bortezomib-Naïve Patients in PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in
Patients with Relapsed or Refractory Myeloma (MM), resented by Luhua Wang, MD Anderson Cancer Center, Houston, Texas
Abstract 302
Relapsed/refractory, 1 to 3 prior
Most common: fatigue,
Cohort 1: n=54, ORR
Single agent carfilzomib significant
therapies, bortezomib-naïve
nausea, dyspnea, cough,
46%, disease control
activity in relapsed refractory
Phase II (004 trial)
patients, n=115
anemia, diarrhea, fever;
83%, VGPR or better 11%.
myeloma. AEs generally mild and
Single agent
grade 3 or higher: fatigue,
DOR 8.4 months if PR or
manageable.
myelosuppression; 1
better, 8.8 months if MR
Trial is ongoing.
death due to tumor lysis
or better (not statistically
syndrome led to use of
significant). TTP 7.6
prophylaxis, hydration,
months at median follow-
pretreatment drugs for
up of 9.2 months.
further patients and in
Cohort 2: ORR 53%,
other trials.
disease control 84%, but
small sample size.
PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM);
Updated Results From the Bortezomib-Treated Cohort, presented by David Siegel, Hackensack University Medical Center, Hackensack, New Jersey
Abstract 303
Relapsed/refractory, 1 to 3 prior
Similar to previous trial
ORR 18%, CBR 30%,
Single-agent carfilzomib is tolerable,
therapies, bortezomib treated
(this is a subpopulation).
disease control 70%.
with durable response and disease
Phase II
patients, n=35
DOR if at least PR: 10.6
control, lacks significant toxicity,
Single agent
months, if MR or better:
suggesting it is good for combination
9 months; median TTP
therapy.
5.3 months
Phase Ib Multicenter Dose-Escalation Study of Carfilzomib Plus Lenalidomide and Low-Dose Dexamethasone (CRd) in Relapsed and Refractory
Multiple Myeloma (MM), presented by Ruben Niesvizky, Weill Cornell Medical College, New York, New York
Abstract 304
Relapsed/refractory, 1 to 3 prior
Fatigue most frequent,
In 29 evaluable patients,
Combination is well tolerated in pts
lines of therapy, n=32.
some GI toxicities, low-
ORR 59%, at least SD
heavily pretreated with bortezomib
Phase Ib (006 trial)
Combination with lenalidomide
level myelosuppression,
93%. Median DOR not
and IMiDs. MTD not reached, no DLTs.
and dexamethasone.
rash. No PN, grade
reached. Responses
Expansion cohort is enrolling n=30.
3 fatigue, or venous
improve with prolonged
Prolonged administration is possible
thrombotic events. Serious
treatment.
for >16 months.
adverse events: infections,
fevers, one GI toxicity.
Carfilzomib (CFZ), a Novel Proteasome Inhibitor for Relapsed or Refractory Multiple Myeloma, Is Associated with Minimal Peripheral
Neuropathic Effects, presented by Ravi Vij, Washington University School of Medicine, St. Louis, Missouri
Abstract 430
n=135 combined analysis: 76%
16% PN overall; 10%
For patients with PR
No trend for worsening of neuropathy,
prior thalidomide, 60% prior
treatment related, mostly
or better, neuropathy
36% patients received more than
Phase II
bortezomib, 61% lenalidomide,
grade 1 and 2, one dose
score improved. This
6 cycles of carfilzomib; PN not a
(combined analysis
16% cisplatin; 81% prior
reduction for neuropathy;
may or may not hold up
clinically significant side effect of
003 and 004)
neuropathy at baseline
2.2% grade 3 no grade 4.
multivariate analysis.
carfilzomib.
Phase I Study of Carfilzomib in Patients with Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Insufficiency: Interim
Pharmacokinetics and Safety Analysis, presented by Ashraf Badros, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
Abstract 3877
Relapsed, refractory after at
Manageable and
PK parameters similar in
No dose adjustment of carfilzomib
least 2 therapies; normal renal
comparable to AEs in
all groups. No significant
needed in patients with renal
Phase I
function and mild insufficiency
other studies of single-
accumulation of drug
impairment. CBR 37%. Disease
n=10; moderate and severe renal
agent carfilzomib. No
observed. Proteasome
stabilization for at least 6 months in
insufficiency n=10; dialysis n=2.
exacerbation of pre-existing
inhibition independent
many patients; may reduce frequency
Single-agent carfilzomib
neuropathy; no severe
of renal function.
of hemodialysis in some.
myelosuppression
Additional abbreviations used in the summary table:
DLT: dose-limiting toxicity; GI: gastrointestinal; MTD: maximum tolerated dose;
PN: peripheral neuropathy; VGPR: very good partial response
5
including possible activity in patients who had received
is ongoing, and the dosing schedule may require modifica-
prior lenalidomide. In light of not reaching the MTD, phase
tion to allow better management of thrombocytopenia.
II accrual will continue.
Low-dose panobinostat has also been tested in a phase I/II
Vorinostat in Combination with Peg ylated Liposo-
dose-escalation study in combination with oral melphalan
mal Doxorubicin and Bortezomib for Patients with
in relapsed/refractory myeloma (Abstract 1855, James
Relapsed/Refractory Multiple Myeloma: Results of a
Berenson, Oncotherapeutics, Los Angeles, California). The
Phase I Study (Abstract 306) was presented by Peter M.
most common grade 3 and 4 AEs were reversible neutrope-
Voorhees, Lineberger Comprehensive Cancer Center, Cha-
nia and thrombocytopenia. Once the MTD has been deter-
pel Hill, North Carolina. Although single-agent vorinostat
mined and the dose and schedule optimized, an expanded
is tolerable, treatment resulted in no responses. There is a
phase II trial will be conducted.
strong rationale to combine vorinostat with other agents:
preclinical studies showed a high degree of synergism of
Heat shock protein 90 (Hsp90)
vorinostat plus bortezomib and anthracyclines. In this
disrupter
study, bortezomib was combined with standard pegylated,
liposomal doxorubicin (PLD) 30 mg/m2 on day 4 and dose
Tanespimycin (17-AAG)
escalation of vorinostat from 200 mg to 400 mg daily on
Tanespimycin (17-AAG) disrupts heat shock protein 90
days 4 to 11 of a 3-week cycle. There are not many patients
(Hsp90), and is being studied in several settings. Ashraf Z.
currently enrolling at the highest dose levels. Non-hema-
Badros, University of Maryland Medical Center, Baltimore,
tologic toxicities are common. There were no grade 3 or
Maryland, presented the poster, Tanespimycin + Bort-
4 constitutional or hematologic toxicities, but lower-grade
ezomib in Relapsed/Refractory Myeloma Patients: Results
hematologic toxicities may require careful dose adjustment.
From the Time-2 Study (Abstract 1871). Paul G. Richard-
There were incidences of PN and hand-foot syndrome, one
son, Dana-Farber Cancer Institute, Boston, Massachusetts,
hypersensitivity reaction to PLD, and two patients with car-
presented the poster Tanespimycin + Bortezomib Dem-
diac toxicities (atrial flutter and diastolic dysfunction). ORR
onstrates Safety, Activity, and Effective Target Inhibition in
was 87% (7 of 8 evaluable patients), but this is a small sam-
Relapsed/Refractory Myeloma Patients: Updated Results of
ple size. The study had a potential selection bias, requiring
a Phase I/II Study (Abstract 2890). These studies reported
platelet counts of 100 × 109 or higher, which may result
similar findings, concluding that sufficient tolerability and
in selection of patients with less severe disease. The MTD
activity were seen to support a phase III study of the combi-
remains to be determined. Alternate dosing schedules for
nation of tanespimycin plus bortezomib. The clinical studies
the next levels are being explored. It is not known if vorino-
suggested that tanespimycin protects from bortezomib-
stat exacerbates bortezomib-induced PN.
mediated PN. A preclinical study, Tanespimycin Prevents
Bortezomib Toxicity and Preserves Neuronal Morphology
Vorinostat in combination with bortezomib in relapsed or
in Primary Rat Dorsal Root Ganglion Cultures (Abstract
refractory myeloma was also the subject of two posters,
2847) presented as a poster by Oliver P. Flint, Research and
Abstract 3886 by Sundar Jagannath, St. Vincent's Compre-
Development, Discovery Toxicology, Bristol-Myers Squibb,
hensive Cancer Center, New York, and Abstract 3890, by
Princeton, New Jersey, showed that protection from bort-
David Siegel, Hackensack University Medical Center, Hack-
ezomib neuropathy by tanespimycin was dose-dependent,
ensack, New Jersey. In one study, MTD was not reached and
and appeared to be related to interruption of bortezomib-
doses were recommended for future study. The combina-
mediated aggresome formation.
tion of oral vorinostat and bortezomib was described as
showing promising clinical activity with acceptable toxicity.
Monoclonal Antibodies (mAbs)
The second study, a phase IIb open-label trial (Vantage 095)
is ongoing, and to date shows acceptable tolerability of the
Elotuzumab (HuLuc63, anti-CD1 mAb)
combination. Responses will be evaluated in early 2010.
Phase I/II Study of Elotuzumab in Combination with
Lenalidomide and Low-Dose Dexamethasone in
Panobinostat (LBH589)
Relapsed or Refractory Multiple Myeloma: Interim
Oral panobinostat (LBH589) has been tested in a phase Ib
Results (Abstract 432) was presented by Sagar Lonial,
study in combination with bortezomib in relapsed myeloma
Winship Cancer Institute, Emory University, Atlanta, Geor-
(Abstract 3852, Jesús F. San Miguel, Hospital Universitario
gia. Elotuzumab is a human monoclonal antibody (mAb) of
de Salamanca, Salamanca, Spain). The dose-escalation study
the IgG1 type targeting CS1, a cell surface glycoprotein. CS1
6
is highly and uniformly expressed on myeloma cells, with
plus standard dexamethasone without the antibody
restricted expression on natural killer (NK) cells, and little
(Abstract 2870, Edward Agura, Baylor Sammons Cancer
to no expression on other normal tissues. The mechanism
Center, Dallas, Texas).
of action of elotuzumab was shown in preclinical studies
to be NK-mediated antibody-dependent cell-mediated cyto-
Immunomodulatory Drugs (IMiDs)
toxicity (ADCC). The anti-tumor activity of elotuzumab was
Pomalidomide
enhanced by lenalidomide in a myeloma xenograft mouse
model. In this phase I/II clinical trial, 28 patients received a
A Phase I/II Multi-Center, Randomized, Open Label
fixed 25 mg dose of lenalidomide, low-dexamethasone, and
Dose Escalation Study to Determine the Maximum
escalating doses of elotuzumab weekly, then twice weekly
Tolerated Dose, Safety, and Efficacy of Pomalidomide
at 5, 10, or 20 mg/kg, until they had progressive disease
Alone or in Combination with Low-Dose Dexametha-
(PD). This report is an early look at results. Neutropenia
sone in Patients with Relapsed and Refractory Multiple
and thrombocytopenia were the most common grade 3 to
Myeloma Who Have Received Prior Treatment That
4 toxicities as expected for lenalidomide plus dexametha-
Includes Lenalidomide and Bortezomib (Abstract 301)
sone; there was one anaphylactic reaction, one infusion
was presented by Paul Richardson, Dana-Farber Cancer
reaction with stridor; and some fever and chills, especially
Institute, Boston, Massachusetts. Pomalidomide is a novel,
during cycle 1, ameliorated by pre-infusion treatment. Phar-
third-generation IMiD, structurally similar to thalidomide
macokinetic studies show 70 µg/mL is the minimum con-
and lenalidomide, showing increased potency in preclinical
centration of antibody needed preclinically for efficacy; for
studies and different clinical efficacy and safety profiles. In
the 10 mg/kg and 20 mg/kg human dose, concentrations are
this study, pomalidomide was administered for 21 days of
well above the therapeutic level, which can be achieved with
28-day cycles alone and with low-dose dexamethasone in
biweekly dosing. The CS1 target is saturated at the 5 mg/
patients with relapsed/refractory myeloma and prior therapy
kg and 10 mg/kg doses, and the 20 mg/kg dose cohort is
with at least 2 cycles of lenalidomide and bortezomib. Phase
being evaluated. Of the 28 evaluable patients, ORR ranges
I (n=32) determined the MTD; phase II was a randomized
from 75% to at least 95% depending upon the type of prior
study of pomalidomide with and without low-dose dexa-
therapy. Median follow-up is 4.5 months and the median
methasone, with G-CSF administered after the first cycle.
TTP has not be reached but "looks promising." Further stud-
Myelosuppression was the dominant toxicity, with 31%
ies are planned, including determining if 10 mg/kg or 20
experiencing neutropenia, and 31% experiencing fatigue.
mg/kg is the best dose, and whether after weekly dosing the
Venous thromboembolism (VTE) occurred in 2 patients.
first weeks with the higher dose, treatment could be given
Significant PN occurred in 1 patient. Dexamethasone was
every other week.
added at a median of 3 cycles in 47% of patients. Best
response was evaluable in 25 patients with 28% having at
A poster, Phase I/II Study of Elotuzumab in Combination
least PR, and 52% having at least MR. Added dexamethasone
with Bortezomib in Patients with Multiple Myeloma Fol-
improved the response in about half of the patients, and
lowing 1 to 3 Prior Therapies: Interim Results (Abstract
DOR also improved, although there are not a lot of data yet
3876) was presented by Andrzej Jakubowiak, University of
available. Phase II is ongoing, with completion anticipated
Michigan Comprehensive Cancer Center, Ann Arbor, Michi-
in the last quarter of 2010 for n=200, and will include an
gan. This was a dose-escalation study of elotuzumab plus
analysis of gene expression profiling (GEP).
standard bortezomib. The interim data from 26 patients
showed manageable toxicities, with two serious adverse
Pomalidomide (CC4047) Plus Low-Dose Dexametha-
events (SAEs) in one patient but no DLTs, and MTD was not
sone (Pom/dex) Is Active and Well Tolerated in Lenalid-
reached. The response rate of PR or better was 40%, with
omide-Refractory Multiple Myeloma (MM) (Abstract
median TTP of 9.6 months. Enrollment into the 20 mg/kg
429) was presented by Martha Q. Lacy, Mayo Clinic,
elotuzumab cohort is ongoing.
Rochester, Minnesota. Results for 60 patients on this trial
have been presented. An additional 34 patients have been
Other mAbs
enrolled to further determine response rate and toxicity.
There were reports of the use of other mAbs, but none look
Patients received 2 mg daily of continuous pomalidomide
as promising as elotuzumab. Dacetuzumab (SGN-40), an
(which could be increased to 4 mg at physician discretion)
anti-CD40 mAb, in combination with lenalidomide and
and 40 mg dexamethasone weekly, with aspirin prophylaxis
weekly dexamethasone in relapsed/refractory myeloma
(full dose anticoagulant could be substituted at physician
showed an ORR comparable to that of lenalidomide
discretion). All patients had to have had prior lenalidomide,
7
and over half had prior thalidomide, bortezomib, or stem
patient with myeloma (younger than age 65 to 70 years),
cell transplant (SCT). Overall, 41% of patients were defined
was discussed by Jesús F. San Miguel, Hospital Clinico Uni-
as having high-risk myeloma by mSMART (the Mayo Clinic
versitario de Salamanca, Salamanca, Spain, at the Multiple
risk-stratification algorithm). The combination was gener-
Myeloma Education Session. Dr. San Miguel addressed this
ally well tolerated. The major hematologic toxicity was neu-
topic in depth in a paper published in Hematology 2009,
tropenia in 26% of patients; 23% had PN, and there were
which is available from ASH. This paper summaries all
no VTE. The confirmed rate pf PR or better was 32%. and
relevant studies to date. Therefore, only the main points
ORR was 50%. Dr. Lacy concluded that pomalidomide plus
are summarized here. For a young patient with high risk
dexamethasone had significant activity in heavily pre-treated
disease, novel drugs, especially bortezomib, seem to over-
myeloma refractory to lenalidomide with manageable tox-
come a high-risk prognosis, but the number of patients is
icity. ORR and DOR appear similar to those obtained with
limited and follow-up is short. It is premature to mandate
novel therapy combinations, but pomalidomide combina-
specific therapy based on cytogenetics. Large clinical trials
tions need further investigation.
need to enroll both standard and high-risk patients and col-
lect data. Experimental pilot studies are a potential option
Other New Drugs
for those with high-risk cytogenetics, e.g., targeted therapy
Perifosine, an oral drug that modulates signal transduc-
for t(4;14), FGFR kinase inhibition, or combinations of
tion, is in a phase I/II trial in combination with bortezomib
therapies with complementary mechanisms of action. Out-
in patients with relapsed/refractory myeloma previously
side of clinical trials, one option is induction with a novel
treated with bortezomib (Abstract 1869, Paul Richardson,
agent or combination, followed by autologous SCT (ASCT)
Dana-Farber Cancer Institute, Boston, Massachusetts). The
with high-dose melphalan (MEL); then if the patient is in
combination showed activity (ORR 41%), durable responses,
CR, maintenance with lenalidomide, and if the patient is
a median OS of 25 months, and good tolerability. These
not in CR, consolidation with a novel agent combination.
results form the basis of a phase III trial that is expected
An alternative option is to postpone transplant and treat
to begin soon comparing perifosine, bortezomib, and dexa-
with novel combination therapy, although because there is
methasone to bortezomib plus dexamethasone Other new
always a significant increase in CR rate after ASCT, induc-
drugs are in early stages of development as single agents or
tion with novel therapies and ASCT are complementary.
in combination therapy, including PD 0332991, a cyclin-
The efficacy of conditioning regimens, with MEL 200 as the
dependent kinase 4/6-specific inhibitor, and enzastaurin,
standard, could be improved with the addition of Busulfan
an oral serine/threonine kinase inhibitor targeting the PKC
or bortezomib. Young patients at the beginning of therapy
and PI3K/AKT pathways. Several conjugate drugs are also
are more fit and may tolerate intensive treatment and SCT
being developed to target and kill myeloma cells specifi-
better. This is associated with long event-free survival (EFS)
cally, leaving other cells untouched. These are based on
and good quality of life (QoL). A relapse after MEL 200 will
combining a molecule such as a mAb or ligand that targets a
still respond to novel agents but it isn't known what will
cell-surface component on myeloma cells with a therapeutic
happen after relapse post-treatment with novel agents. Dr.
moiety such as a chemotherapeutic or toxic agent.
San Miguel pointed out that early vs. delayed transplant is
still being investigated, and the joint randomized IFM/DFCI
trial may provide an answer. Dr. San Miguel believes that
allogeneic transplants for patients with myeloma should be
Newly Diagnosed Myeloma
considered investigational and preferably be performed in
Transplant-Eligible Patients
the context of clinical trials. Although allogeneic transplants
have the potential to cure myeloma, they are associated with
Several important issues for transplant-eligible patients con-
a high treatment-related mortality (TRM), and donor avail-
tinue to be investigated, including whether there is a differ-
ability is limited. His group's policy is not to use allogeneic
ence in early vs. delayed transplantation in the era of novel
transplant for initial therapy, but to consider it at relapse for
agents, if patients can be considered to be cured, what the
high-risk patients, including those with early relapses after
best combination of drugs is, and how many drugs a combi-
ASCT, provided their myeloma is under control at the time
nation should include.
of the allogeneic transplant. The role of maintenance in CR,
duration of maintenance, and outcome after relapse need
How to Treat a Young Patient, focusing on the role, advan-
to be investigated further, as does which novel therapies can
tages, and disadvantages of some of the many proposed
overcome which particular high-risk factors. Dr. San Miguel
therapeutic approaches for the newly diagnosed, younger
observed that progress in the last decade has only been
8
possible because of the participation of patients and doc-
choices. There appeared to be a consensus that VGPR and
tors in clinical trials. There are now a large number of drugs
CR after ASCT resulted in similar survival curves, but PR
looking for a place in treatment, e.g., HDAC inhibitors, Akt
after ASCT warranted a second ASCT, and with no further
inhibitors, and others.
improvement, more therapy. It was pointed out that the
percentage of eligible patients who receive transplants var-
Updates in therapeutic approaches for transplanta-
ies by country, and the eligible age cutoff varies as well.
tion-eligible patients was presented by Philippe Moreau,
University Hospital Hôtel-Dieu, Nantes, France, as part of
Timing of Transplant
the IMF Symposium. He (and the audience) believes that
Novel Agents for Initial Therapy of Multiple Myeloma:
ASCT remains the standard of care for eligible patients.
Comparable Results with Continued Initial Therapy and
The preferred induction regimen prior to ASCT is currently
Delayed Transplantation at Relapse Versus Early Trans-
bortezomib plus dexamethasone, but a bortezomib plus
plantation (Abstract 956) was presented by Shaji Kumar,
dexamethasone plus an IMiD may soon replace it, because
Mayo Clinic, Rochester, Minnesota. This retrospective study
this combination triggers two different apoptotic pathways
analyzed results for approximately 290 transplant-eligible,
in malignant plasma cells. The audience agreed with Dr.
newly diagnosed patients treated with an IMiD at the Mayo
Moreau that achievement of CR or VGPR prior to ASCT
Clinic from 2001 to 2008 to see if there was a difference
should be the primary goal of induction therapy. Although
in response or survival between those who received early
a majority of the audience believed that consolidation is
vs. delayed SCT. There did not appear to be a difference
needed after ASCT, Dr. Moreau pointed out that there are
in response rates, TTP following SCT, or OS. Because the
no reliable data showing the need for consolidation, which
study is retrospective, it was not possible to determine what
is the subject of investigation. There are data that show the
influenced the decision to transplant early vs. late. Some-
importance of maintenance, something much of the audi-
one commented that patients with a better prognosis could
ence was aware of. The benefit of thalidomide maintenance
have been selected for later SCT. There were no QoL mea-
has been shown; more data are needed to support the use
surements. Time to next therapy (TTNT) data were also not
of lenalidomide, and studies are ongoing to answer that
available. Dr. Kumar noted that a lot of patients received
question. A topic addressed in Dr. Moreau's presentation
IMiD-based therapy until the time of relapse, and that it
was one that was discussed in other presentations at this
would be important to collect data, including the decision-
meeting, namely whether combination therapies incorpo-
making process, specific therapy before and after SCT, and
rating novel agents without ASCT are superior to ASCT.
QoL in a prospective trial.
Most of the audience thought novel combinations were not
more effective than ASCT, and Dr. Moreau pointed out that
Cure Rate with Total Therapy (TT)
there are no data. The joint IFM/DFCI 2009 study in newly
Modeling for Cure with Total Therapy (TT) Trials for
diagnosed patients who are SCT candidates will answer
Newly Diagnosed Multiple Myeloma (MM): Let the Math
this question. Patients will be randomly assigned to either
Speak (Abstract 744) was presented by Bart Barlogie, Uni-
lenalidomide plus bortezomib plus dexamethasone (RVD)
versity of Arkansas for Medical Sciences, Little Rock, Arkan-
induction, stem cell (SC) mobilization and collection, MEL
sas. Dr. Barlogie reviewed the results of the Total Therapy
200 and ASCT, then RVD consolidation, followed by lenalid-
(TT) 1, 2, and 3 trials in the context of modeling for cure
omide maintenance; or to RVD induction, SC mobilization
in these trials. The model takes into account EFS, includ-
and collection, then RVD consolidation, and lenalidomide
ing reversion to an MGUS-like state and complete response
maintenance with the option of SCT at relapse.
duration, to predict cure fractions (CF) from the pres-
ence of a plateau in Kaplan-Meier plots. Relative survival
A discussion among the panelists raised several unresolved
ratios were computed by comparing patient survival with
issues, including the necessity of conducting a phase III
expected survival of comparable individuals in the general
trial if early-phase trial results are striking, the effect on
population. The amount of time it takes for the relative
trial enrollment when drugs are available in some countries
survival ratios to reach unity are 17 years for TT1, 10 years
but not others, which combinations should be considered
for TT2, and 5 years for TT3. Dr. Barlogie concluded that,
a standard of care for patients with standard-risk disease,
particularly with more recent regimens, cure is a realistic
the true efficacy and risks of the novel agents, particularly
goal of myeloma therapy. The high CF value in TT3 (55%)
for long-term maintenance, and how best to manage newly
for patients with low-risk myeloma is evidence that inclu-
diagnosed patients, e.g., should all or most patients be
sion of both bortezomib and thalidomide increases efficacy.
enrolled into clinical trials or should patients have more
9
However, more effective therapy is still needed to improve
regimen or maintenance therapy.
outcomes for high-risk disease, which still has a relatively
low median survival. Dr. Barlogie suggested that improve-
Velcade, Intravenous Cyclophosphamide and Dexa-
ments in GEP might permit distinction of curable from cur-
methasone ( VCD) Induction for Previously Untreated
rently incurable myeloma. Trials that will incorporate GEP
Multiple Myeloma (German DSMM XIa Trial) (Abstract
data are the joint Dana-Farber/IFM trial (although not for
131) was presented by Hermann Einsele, University of
assigning therapy), and the Arkansas trials, TT4 for low-risk
Wurzburg, Wurzburg, Germany. The aim of this study was to
myeloma and TT5 for high-risk myeloma, where treatment
improve CR rates before and after transplant by using novel
assignment is based on GEP data. Dr. Shaughnessy com-
agents as part of the induction regimen on the assumption
mented that genes over-expressed in patient tumors show-
that improving CR + VGPR rates could result in further
ing the cure fraction appear predominantly on chromosome
improved long-term outcomes. Of 399 patients treated, 395
5, which accords with Dr. Avet-Loiseau's data that patients
were evaluable for evaluation, of whom 26% experienced
with chromosome 5 gains have the best outcome. Notably,
treatment emergent SAEs. There were 5 deaths, 3 of which
the glucocorticoid receptor maps to chromosome 5, which
were treatment-related. Toxicities included infections, with
would explain the efficacy of dexamethasone therapy. Dr.
an 8% incidence of herpes zoster even with prophylaxis
Shaughnessy also speculated that the 14% of patients with
recommended, although 97% of cases of zoster occurred in
high-risk disease who are cured will turn out to be those
patients not taking prophylaxis at the time. The incidence
without chromosome 1 abnormalities.
of all grades of polyneuropathy was 39%. In the modified
intent to treat (ITT) population (n=391) before SCT, ORR
Three-Drug Combinations
was 85.4% with CR/nCR of 14.6%. Patients with high-risk
A Phase II Trial Comparison of Once- Versus Twice-
cytogenetics such as t(4;14) tended to do as well, and those
Weekly Bortezomib in CyBorD Chemotherapy for
with 17 del had lower but not statistically significantly
Newly Diagnosed Myeloma: Identical High Response
lower responses. Patients with lower International Stag-
Rates and Less Toxicity (Abstract 616) was presented by
ing System (ISS) scores or beta-2-microglobulin (beta-2-M)
Craig B. Reeder, MD, Mayo Clinic, Scottsdale. Arizona. This
levels also had better responses. If polyneuropathy was
was a phase II single-arm trial investigating the role of novel
present, there was a statistically significant higher chance
agents plus alkylating agents. The three-drug combination
of responding to therapy. Dr. Einsele concluded that 3
CyBorD (cyclophosphamide, bortezomib, dexamethasone)
cycles of bortezomib cyclophosphamide dexamethasone
was previously shown to be safe and well tolerated in the
(VCD) for induction therapy is among one of most active
relapsed refractory setting. The goal of this study was a
regimens, and overcomes traditionally poor-risk cytoge-
high-depth, fast response prior to SCT. Some results have
netics for response, although data are not yet available for
been published showing rapid response and ability to col-
progression-free survival (PFS) or OS. This regimen has a
lect stem cells. However, dose reductions were needed for
good safety profile, with a treatment-related mortality of less
all drugs due to toxicity. A new cohort received a modi-
than 1%. With an acceptable rate of mild to moderate poly-
fied CyBorD regimen, with bortezomib 1.5 mg/m2 weekly,
neuropathy and low risk of thromboembolism (TE), use of
weekly cyclophosphamide, and dose-reduced dexametha-
VCD is feasible in an outpatient setting. Final results will
sone after the first 4 weeks. This resulted in reduced toxic-
be available at the 2010 ASH Meeting. This study is form-
ity, with lower rates of grades 3 and 4 AEs overall, and no
ing the basis for a larger intergroup study. In response to
grade 3 PN, although the rate of grades 1 and 2 PN were
a question, Dr. Einsele explained that in Germany patients
similar between the original CyBorD cohort and the modi-
are only eligible for high-dose therapy and ASCT up to age
fied CyBorD cohort. Rates of CR/near (n)CR, VGPR, and
60 years. For patients age 60 to 70 years there is a different
ORR were similar between the groups. The combined ORR
high-dose (HD) melphalan 140 SCT protocol, so it is dif-
for both cohorts (n=63) was 90%, and for the 54 patients
ficult to compare across trials. One rationale for the intrave-
receiving 4 cycles was 94%, with 46% CR/nCR. The modi-
nous regimen was to ensure that newly diagnosed patients
fied regimen resulted in less toxicity, so there were fewer
are seen weekly and receive treatment for infections and
dose reductions and higher overall doses could be given;
other supportive care if necessary.
it was more convenient, and it allowed for successful stem
cell harvest. Dr. Reeder said that this regimen doesn't pro-
Three- and Four-Drug Combinations
tect patients with high-risk myeloma from relapse, and that
Novel Three- and Four-Drug Combinations of Bort-
although the initial response was good for both regimens,
ezomib,
Dexamethasone,
Cyclophosphamide,
high-risk patients need either a different conditioning
and Lenalidomide, for Newly Diagnosed Multiple
Myeloma: Encouraging Results From the Multi-Center,
10
Randomized, Phase II EVOLUTION Study (Abstract 127)
3-drug combination VMP (bortezomib, melphalan, predni-
was presented by Shaji Kumar, Mayo Clinic, Rochester, Min-
sone) for this population. VMPT was followed by VT mainte-
nesota. Because three-drug combinations of bortezomib
nance. The trial included 511 patients (VMP n=257, VMPT
with dexamethasone, cyclophosphamide, or lenalidomide
to VT n=254). Bortezomib was initially given twice weekly,
have shown significant activity in untreated myeloma, this
then reduced to once weekly. Responses were better with
study looked at all 4 classes together. The results of the
VMPT vs. VMP, including CR: 38% vs. 24%; VGPR or bet-
phase I portion, during which the MTD was determined,
ter: 59% vs. 50%. Some differences between arms devel-
have already been presented elsewhere. The safety and effi-
oped later during maintenance. The time to next therapy
cacy of the phase II portion, which was intended to increase
(TTNT) was statistically significantly longer for the VMPT
the CR rate and determine the best phase III trial design,
arm, with 75% estimated for TTNT of 3 years at a median
were reported at this meeting. Four treatment arms were
follow-up of nearly 2 years vs. 60% for VMP. PFS at 3 years
compared: VDCR (bortezomib, dexamethasone, cyclo-
was also statistically significantly longer for the VMPT arm
phosphamide, lenalidomide, n=48); VDR (bortezomib,
at 60% vs. 42% for the VMP arm. The projected 3 year OS
dexamethasone, lenalidomide, n=42); VDC (bortezomib,
was nearly 90% for both arms. Grade 3 and 4 hematologic
dexamethasone, cyclophosphamide, n=33); and VDC mod-
toxicity was as expected, primarily neutropenia, slightly but
ified to include an extra dose of cyclophosphamide on day
significantly increased with thalidomide. VMPT was associ-
15 because the response seen with VDC seemed lower than
ated with a higher rate of neuropathy and infections, and
expected from published results (n=15). After a median fol-
significantly higher cardiologic events. The discontinuation
low-up of 7.3 months, the rates of at least VGPR were 59%,
rate due to neuropathy was similar for both arms (6%). The
55%, 47%, and 60%, respectively, for these groups. The best
efficacy, including CR rate and PFS, and toxicity for weekly
response rates are similar in the VDCR and VDR arms, and the
vs. twice-weekly bortezomib were almost the same, partly
nCR/CR responses require marrow assessments for confir-
because patients stay on therapy longer with the less-fre-
mation. About a third of patients in each arm have had stem
quent bortezomib dose. Weekly dosing was associated with
cells harvested, with 2 or 3 failures to collect in the VDCR
the incidence of any grade PN reduced by half, grade 3 and
and VDR arms. This did not occur in the VDC arms. Nearly
4 PN reduced from 14% to 2%, and discontinuation due to
all of the 138 patients have had had at least one AE, with the
PN reduced from 16% to 4%. The total planned dose was
most common non-hematologic and hematologic toxicities
lower for once-weekly bortezomib, but the total dose deliv-
similar across arms, but more grade 3 and 4 neutropenia in
ered was almost identical for both schedules. Thus the total
the cyclophosphamide arms. In a minimum residual disease
planned dose was closer to the actual dose for once-weekly
(MRD) assay feasibility study using flow cytometry-based
bortezomib. PFS was better for patients with CR, but if they
assessment on marrow aspirates collected at screening and
had high-risk cytogenetics, such as t(4;14), t(14;16), or del
at time of suspected CR, samples were examined in the cen-
17, PFS was similar for both arms. Dr. Palumbo concluded
tral lab within 48 hours. During the discussion, Dr. Kumar
that VT maintenance improves PFS, and longer follow-up is
pointed out that more follow-up was needed to determine
needed to assess OS.
if the 4-drug combination would results in longer PFS, and
if it was better to use bortezomib plus an IMiD together or
Thalidomide / Dexamethasone (TD) Vs. Bortezomib
sequentially. He said that if the use of the 4 drugs resulted
( Velcade) /Thalidomide / Dexamethasone ( VTD) Vs.
in a deep response and changed the natural history of the
VBMCP/VBAD/Velcade® as Induction Regimens Prior to
disease to get to the lowest MRD status, then it might be
Autologous Stem Cell Transplantation (ASCT) in Mul-
possible to use all 4 drugs again later at relapse.
tiple Myeloma (MM): Results of a Phase III PETHEMA/
GEM Trial (Abstract 130) was presented by Laura Rosiñol,
Bortezomib, Melphalan, Prednisone and Thalidomide
Barcelona, Spain. There were 306 patients in this study
( VMPT) Followed by Maintenance with Bortezomib and
randomized to one of 3 arms: VBMCP/VBAD (n=100), TD
Thalidomide for Initial Treatment of Elderly Multiple
(n=104), or VTD (n=102). Patients in the VTD arm had
Myeloma Patients (Abstract 128) was presented by Anto-
the highest response rates. Patients with higher-risk disease
nio Palumbo, University of Turin, Turin, Italy. The aim of
based on cytogenetics (about 20% to 25% of patients) had
this study was to compare the best experimental treatment
better responses to bortezomib-containing regimens. Grade
to the standard of care for the newly diagnosed, elderly
3 and 4 AEs, discontinuations, and deaths were similar
myeloma patient population. In Dr. Palumbo's opinion, the
among the arms, although TD was associated with a higher
best 4-drug combination is VMPT (bortezomib, melphalan,
incidence of thrombotic events, and VTD was associated
prednisone, thalidomide), and the standard of care is the
with a higher rate of PN. The CR rates increased after ASCT
11
for each arm: from 23% to 49% for VBMCP/VBAD, from
Bortezomib in Combination with Pegylated Liposomal
14% to 37% for TD, and from 31% to 52% for VTD. Patients
Doxorubicin and Thalidomide (VDT), An Effective Steroid-
receiving TD had significantly shorter TTP and PFS. About
Independent Regimen for Previously Untreated Multiple
15% to 20% of patients had extramedullary plasmacytomas,
Myeloma Patients: Final Result of a Phase II Study (Abstract
and these patients had better responses to VTD, although
618) was presented by Taimur Sher, Roswell Park Cancer
they had a higher rate of progressive disease and shorter
Center, Buffalo, New York. In this study in 40 patients, the
TTP than other patients. There is no difference among treat-
steroid-free regimen of bortezomib (every other week sched-
ments for OS at the current follow-up time.
ule) plus PLD plus thalidomide resulted in a rate of PR or
better of 78%, with CR/nCR of 35%, and CR immunofixation
Lenalidomide, Bortezomib, Peg ylated Liposomal
(IF)-negative of 23%. Median TTP was 29.5 months. There
Doxorubicin, and Dexamethasone in Newly Diag-
were significant toxicities, including hand-foot syndrome,
nosed Multiple Myeloma: Updated Results of Phase I/
infections, neuropathy, and some thromboembolic events.
II MMRC Trial (Abstract 132) was presented by Andrzej J.
Dr. Sher concluded that this regimen would be an accept-
Jakubowiak, University of Michigan, Ann Arbor. The MTD of
able for alternative for patients who can't tolerate steroids.
the 4 drug combination RVDD (lenalidomide, bortezomib,
pegylated liposomal doxorubicin, and dexamethasone),
Transplant-Ineligible Patients
was determined to be lenalidomide 25 mg, bortezomib 1.3
mg/m2, PLD 30 mg/m2, and dexamethasone 20 mg. A total
Dr. Mateos' presentation during the Plenary Session was
of 72 patients were treated in both phases. Toxicities have
introduced by Donna Weber, MD Anderson Cancer Center,
been manageable and include some grade 3 and 4 cytope-
Houston, Texas, who reviewed randomized trials in elderly
nias and grade 3 neuropathy. About a third of the patients
patients who are not transplant candidates. Dr. Weber noted
have gone on to at least one planned ASCT. Median TTP,
that there are more questions than answers as the number
PFS, and OS have not been reached with a median follow-up
of possible combinations of novel and conventional chemo-
of 8 months. There was a question as to whether this com-
therapy agents increases. Although there have been improve-
bination would be an improvement over the combination
ments in response rates and PFS, these don't necessarily
of lenalidomide plus bortezomib plus dexamethasone, that
translate into improved OS. Questions remain about the
is, what contribution the inclusion of PLD makes. More data
role of consolidation therapy for elderly patients who may
on both combinations will be needed to address that issue.
go on to SCT. The study presented by Dr. Mateos is the first
time a combination including a novel agent has been used
Phase I Study of Bortezomib(Bz), Peg ylated
as the comparator arm for another novel agent-containing
Doxorubicin(DOX) and Dexamethasone(dex); ( VDD)
regimen. A review of trials of maintenance therapy after
with Escalating Doses of Cyclophosphamide(Cy) in
ASCT has shown various results from deleterious effects to
Patients with Newly Diagnosed Myeloma (Abstract 617)
no effect to improved results. Novel agents for induction
was presented by Melissa Alsina, MD, Lee Moffitt Cancer
therapy in cytogenetic high-risk myeloma, e.g., bortezomib
Center, Tampa, Florida. Phase I enrolled 31 transplant-eligi-
in TT2, may lead to improved survival, but the use of novel
ble patients and is complete with dose escalation to the max-
agents, e.g., lenalidomide, in maintenance therapy, needs
imum planned dose level; phase II enrollment is ongoing.
further study.
Toxicities in phase I were manageable, and stem cells could
be collected with growth factors in all patients attempted
Plenary Session
to date. Encouraging response rates support plans to fin-
A Prospective, Multicenter, Randomized, Trial of Bort-
ish phase II accrual, which will stratify patients for high vs.
ezomib/Melphalan/Prednisone ( VMP) Versus Bort-
standard risk. It was asked if newly diagnosed patients really
ezomib/Thalidomide/Prednisone ( VTP) as Induction
need 4 drugs, given the high rate of dose reductions for the
Therapy Followed by Maintenance Treatment with Bort-
modest increase in responses, and if one drug had to be
ezomib/Thalidomide ( VT) Versus Bortezomib/Predni-
spared, which would it be? Dr. Alsina responded that studies
sone ( VP) in Elderly Untreated Patients with Multiple
do show robust response rates with 3-drug combinations,
Myeloma Older Than 65 Years (Abstract 3) was pre-
and they are using a 4-drug combination to increase the
sented by María Victoria Mateos, University of Salamanca,
depth or quality of response. The response rate is good for
Salamanca, Spain, during the Plenary Session. This study
3-drug combinations, but they want to contribute to OS. A
randomly assigned 260 patients to 6 cycles of VMP vs. VTP
randomized trial is needed to compare all the regimens.
as induction therapy followed by maintenance with VT vs.
VP for up to three years. Therefore, there are 4 treatment
12
cohorts, VMP-VT, VMP-VP, VTP-VT, and VTP-VP. Study goals
thalidomide and lenalidomide treatment should include
included determining the best agents to add to bortezomib
prophylaxis for VTE, and previous VTE, infection, immobi-
therapy, decreasing toxicity by reducing doses of bortezo-
lization, conventional chemotherapy, or doxorubicin add
mib, and adding maintenance therapy to maintain efficacy.
to the risk. The best agent for deep vein thrombosis (DVT)
ORR was 80% vs. 81% and IF-negative CR rate was 20% vs.
prophylaxis remains a question; however, low molecular
27% for VMP vs. VTP, which is not statistically significant.
weight heparin (LMWH), which has been tested vs. aspi-
The hematologic and non-hematologic toxicities were gen-
rin and warfarin, may be best for patients at highest risk
erally higher in the VMP group, but there were more SAEs
for VTE, and aspirin, which has potential cardioprotective
and more discontinuations in the VTP group, and VTP,
effects, may be best for standard-risk patients. VMP is also
which contains two neurotoxic drugs, had a higher rate of
a current standard of care, with PN as a major side effect.
grade 3 and 4 PN (9%) vs. VMP (5%). There are 91 patients
Reduction of bortezomib from twice weekly to once weekly
on VT maintenance therapy and 87 patients on VP mainte-
may reduce both the risk of neuropathy and the discontinu-
nance who are evaluable. The IF-negative CR rate increased
ation rate. MPR also has the potential to become a standard
from 23% overall after induction up to 42% after mainte-
of care. Dr. Palumbo currently suggests MPT (if cytopenia
nance therapy. Median TTP after a follow-up of 24 months
is a concern) or MPR (if neuropathy is a concern) for older
was not reached. Median PFS was 33 months, with an OS
patients at standard risk and VMP (if DVT and/or renal insuf-
of 75% of patients alive at 3 years. Median PFS with VMP is
ficiency are concerns) for high-risk younger patients. Future
34 months and with VTP is 23 months, which is not statisti-
options include moving to combination therapy with 4
cally significant. Median follow-up for maintenance therapy
drugs, e.g., VMPT, to increase response, and adding mainte-
is 15 months. Median PFS was not reached with VMP-VT
nance, e.g., with bortezomib, thalidomide, or lenalidomide
or VTP-VT. With VMP-VP median PFS was 32 months, and
plus low-dose dexamethasone, to improve remission dura-
with VTP-VP it was 26.5 months. There was a small cohort of
tion. Alternative options include using single agents in a
patients with high-risk cytogenetics, so their outcomes were
sequential "friendly" approach, with 1 or 2 drugs up front,
pooled for responses after induction and maintenance,
and a different drug at relapse. Dr. Palumbo recommends
which were almost identical, and were identical compared
adjusting therapy to the patient, with full-dose therapy for
with responses for patients with standard-risk cytogenetics.
those age 65 to 75 years if they have normal cardiac, pulmo-
nary, liver, and renal function. If they are younger than age
Dr. Mateos concluded that alkylating agents should remain
65 years they can probably tolerate full-dose therapy even if
important drugs for the treatment of elderly untreated
some organ functions are abnormal. Reduced-dose chemo-
patients. The weekly schedule of bortezomib significantly
therapy is recommended for those with normal organ func-
reduced PN. Maintenance therapy increased the CR rate
tion if they are older than age 75 years. Melphalan especially
with a low toxicity profile. VT maintenance showed supe-
requires adjustment for patient age and hematologic AEs,
rior time to events, but lenalidomide should be explored
but so do lenalidomide, thalidomide, and bortezomib, e.g.,
as maintenance therapy. Currently, the combination of VMP
twice- to once-a-week bortezomib to reduce neurotoxicity.
followed by VT is significantly superior to VTP followed by
In response to a question, Dr. Palumbo said that there is no
VP in this patient population. Notably, high-risk cytogenet-
reliable marker (such as factor V Leiden) for risk of IMiD-
ics are overcome by either regimen.
associated thrombosis.
How to Treat an Elderly Patient: Combination Therapy
Practical recommendations for myeloma patients ineli-
or Sequencing was presented by Antonio Palumbo, MD,
gible for transplantation was presented by Mario Boc-
University of Torino, Torino, Italy, as part of the Multiple
cadoro, University of Torino, Torino, Italy, as part of the
Myeloma Education Session. This topic is presented in
IMF Symposium. He reviewed published results of phase
depth in a paper, co-authored by Dr. Palumbo and Franc-
III trials in the non-transplant eligible, newly diagnosed
esca Gay, published in Hematology 2009, which is available
population. Results show equivalence of TD and MP, supe-
through ASH. This paper reviews diagnosis and treatment
riority of MPT and MPV over MP. Trials of MRP vs. MP and
of myeloma in general, and historically for elderly patients,
VMPT vs. VMP presented at this ASH meeting are described
summarizes current treatment options, including the effi-
elsewhere in this summary. Cyclophosphamide plus TD,
cacy of regimens used for front-line treatment of this patient
and lenalidomide plus reduced-dose dexamethasone are
population, the role of maintenance therapy, and manage-
also being tested. Dr. Boccadoro discussed the increasing
ment of AEs. Dr. Palumbo believes that MPT should be con-
incidence of frail patients in the population of age 75 to
sidered a major standard of care in elderly patients. Both
101 years at diagnosis, which he believes is the result of an
13
increase in the older population rather than an increase in
lenalidomide followed by continuous lenalidomide main-
the incidence of myeloma. This frail population is at risk of
tenance; n=152), MPR (n=153), or MP (n=154) for 9
early discontinuation from treatment as a result of toxicity,
cycles. All patients could receive lenalidomide 25 mg/day
so regimens must be modified by dose reductions. Dr. Boc-
plus or minus dexamethasone if their disease progressed.
cadoro presented a scheme for dose reductions for patients
The patient population had a higher than usual percentage
over age 75 years that could be further modified if necessary
of patients with ISS stage III disease. At the first indepen-
for frail elderly patients to keep them on therapy longer. It
dent interim analysis at the short follow-up of 9.4 months,
was pointed out that although in some settings, thalidomide
the data monitoring committee recommended unblind-
maintenance after SCT is well established, it is not used in
ing the study because there was a statistically significant
France. Dr. Orlowski observed that it is difficult to compare
difference between the MPR and MP arms. The best ORR
the non-transplant population in the US to that in Europe
for MPR-R vs. MPR vs. MP was 77% vs. 67% vs. 49%, which
because the US population is older and therefore probably
was statistically significantly different for the MPR combina-
has more comorbidities.
tions vs. MP. The VGPR or higher rates were 32% vs. 33%
vs. 11%, respectively, and the unconfirmed CR rates were
Phase IIIb UPFRONT Study: Interim Results From a
18% vs. 13% vs. 5%, respectively. The median time to first
Community Practice-Based Prospective Randomized
response was significantly shorter with the 3-drug combina-
Trial Evaluating Three Bortezomib-Based Regimens in
tion. Median PFS for MPR-R has not been reached, for MPR
Elderly, Newly Diagnosed Multiple Myeloma Patients
it is 13.2 months, and for MP it is 13.0 months. Grade 3 and
(Abstract 129) was presented by Ruben Niesvizky, Cor-
4 hematologic toxicities were as expected; 49% of patients
nell/New York Presbyterian Hospital, New York. This study
on MPR-R received granulocyte colony stimulating factor
is ongoing and still recruiting patients. In this open-label,
(G-CSF) vs. 29% of patients on MP. Overall discontinuations
community-based trial, patients were randomized to one of
due to AEs were 16% for MPR-R vs. 7% for MP. Dr. Palumbo
three bortezomib-based regimens: VTD (bortezomib, thalid-
concluded that continuous lenalidomide (MPR-R) was supe-
omide, dexamethasone), VD (bortezomib, dexamethasone),
rior to regimens of more limited duration because it led to
or VMP (bortezomib, melphalan, prednisone) for 8 cycles (3
higher and more rapid responses and a 50% reduced risk of
weeks each), followed by 5 cycles (5 weeks each) of mainte-
progression. No grade 3 or 4 PN occurred. Dr. Palumbo, in
nance with 1.6 mg/m2 of bortezomib weekly in 4 of every 5
response to a question, said that there are no survival data
weeks. Patients on the VTD arm received prophylactic aspi-
to determine whether bortezomib plus MP (MPV) or MPR
rin, full-dose warfarin, or LMWH unless contraindicated.
or MPT would be the better regimen in this patient popula-
Patients also received prophylaxis for herpes zoster. Results
tion. He thought an IMiD plus MP might be more suitable
of the specified interim analysis for the first 70 patients per
for frail patients or those at standard risk, whereas the bort-
arm who had received 4 cycles were presented. The highest
ezomib MP combination could be recommended for more
rate of PN occurred in patients receiving VTD, although the
fit patients or those with aggressive disease.
discontinuation rate was similar across arms. Hematologic
AEs were highest in the VMP arm. There were more deaths
Melphalan and Prednisone (MP) Versus Melphalan,
and pneumonia in patients receiving VD. In general the AE
Prednisone and Thalidomide (MPT) as Initial Therapy
rates were similar, and responses were good, but more fol-
for Previously Untreated Elderly and/or Transplant-Inel-
low-up is needed. In a QoL assessment, improvement was
igible Patients with Multiple Myeloma: A Meta-Analysis
seen in all arms, but patients in the VTD arm reported infe-
of Randomized Controlled Trials (Abstract 615) was
rior physical and role functions, that is, interference with
presented by Prashant Kapoor, Mayo Clinic, Rochester,
activities, including their usual daily activities. The Indepen-
Minnesota. This study was a retrospective literature review
dent Data Monitoring Committee concluded that the study
using a random effects model, testing heterogeneity with
should continue with accrual to all three arms.
Cochrane Q. The authors did not have access to original
patient data, but are now reviewing those data. This analysis
A Phase III Study to Determine the Efficacy and Safety
shows the addition of thalidomide to MP improves response
of Lenalidomide in Combination with Melphalan and
rates and PFS at a cost of additional toxicity, but does not
Prednisone (MPR) in Elderly Patients with Newly Diag-
currently support the use of MPT over MP for improved
nosed Multiple Myeloma (Abstract 613) was presented by
OS. However, Dr. Kapoor thinks that once their analysis is
Antonio Palumbo, University of Torino, Torino, Italy. In this
updated with HOVON study results, it will show significant
study, patients age 65 to 75 years were randomly assigned
increased OS for MPT vs. MP, but at the cost of additional
to one of 3 treatment arms: MPR-R (melphalan, prednisone,
toxicity. He pointed out that alternative effective regimens
14
in elderly patients include MPR and VMP, which need to be
escalation study is continuing and the authors conclude
analyzed vs. MP, and concluded that MPT can be considered
that the combination warrants further study in the relapsed/
an appropriate front-line regimen in newly diagnosed trans-
refractory setting, and possibly in newly diagnosed patients.
plant-ineligible elderly patients. The role of maintenance
therapy has not been analyzed.
Thalidomide Monotherapy
OPTIMUM Dose of Thalidomide for Relapsed Multiple
Myeloma (Abstract 959) was scheduled to be presented
Relapsed/Refractory Myeloma
by first author Martin Kropff, University of Muenster, Muen-
ster, Germany, but was presented by another member of his
New approaches for patients with relapsed or refractory dis-
group. This trial was designed in 2005 to test thalidomide
ease was presented by Robert Z. Orlowski, MD Anderson
monotherapy after being requested by European regulatory
Cancer Center, Houston, Texas, as part of the IMF Sympo-
authorities at that time. There were 499 patients randomized
sium. He observed that despite therapeutic improvements
to one of 4 arms: full-dose dexamethasone that was later
for both transplant eligible and non-eligible patients, most
reduced, 100 mg thalidomide, 200 mg thalidomide, or 400
patients will eventually have relapsed disease. He reviewed
mg thalidomide, Patients were stratified by prior treatments,
the 2009 NCCN guidelines by quality of evidence for avail-
prior ASCT, and ISS stage. Patients were young (median age
able treatments, as well as what is currently known about
63 to 65 years), with a median of 1.3 prior therapies, and
active combinations and single agents, and mentioned many
could not have received prior IMiDs. After 12 cycles, the
of the studies of new agents being reported at this ASH
investigator could decide whether patients could continue
meeting. He pointed out that although mAbs have made
their treatment. The objective was to select the optimum
a big difference in the treatment of lymphomas and leuke-
thalidomide dose. The primary endpoint was TTP, and sec-
mias, they have not played a major role in the treatment
ondary endpoints included response, duration of therapy,
of myeloma. He speculated that CNTO 328, an anti-inter-
PFS, and OS. There was no difference between arms for TTP
leukin-6 mAb, particularly in combination with bortezomib,
in the ITT population. For patients who had 2 to 3 (but not
may prove useful in the treatment of myeloma, but the
1) prior therapies, all thalidomide arms were superior to the
results of a current randomized study will not be available
dexamethasone arm for TTP. There was no significant dif-
until later in 2010. He presented the case of a patient whose
ference in best response rate between the dexamethasone
disease relapsed repeatedly. He pointed out that if a therapy
and thalidomide groups. DOR was almost double for the
worked once, it could be repeated or "tweaked" and could
increasing thalidomide doses (12.7, 13.1, and 11.6 months,
continue to provide benefit as long as the patient had the
respectively) compared with dexamethasone (6.5 months).
relapse off therapy, had at least a year of benefit, and toler-
Crossover was allowed after progression, so most patients
ated the therapy. Otherwise, a regimen containing a class
on dexamethasone crossed to a thalidomide arm. For the
of agent the patient had not previously received would be
highest (400 mg) dose of thalidomide, patients didn't get all
a better choice. Dr. Orlowski stated that in the relapsed/
of the drug planned due to dose reductions; therefore the
refractory setting, lenalidomide plus dexamethasone or
average daily dose was not much more than that received by
bortezomib plus PLD are standards of care. Carfilzomib and
patients on the 200 mg dose. The speaker concluded that it
pomalidomide as single agents and new combinations are
doesn't make sense to give thalidomide at a dose of 400 mg.
showing promise, including combinations of bortezomib
Hematologic toxicities were manageable. Non-hematologic
with HDAC inhibitors and other new classes of agents. He
toxicities were similar but higher in the 400 mg thalido-
concluded that patients with relapsed/refractory myeloma
mide group. PN was similar across arms. There was a higher
are now doing better than at any other time in the past.
incidence of grade 2 or higher neuropathy in the 200 mg
and 400 mg thalidomide arms, with onset related to cumu-
Combination Therapy
lative dose. Some patients are more sensitive and develop
A Phase I Study of Bendamustine Combined with
PN early. This is the first randomized, controlled trial to
Lenalidomide and Dexamethasone in Patients with
evaluate the single-agent activity of thalidomide and dose-
Refractory or Relapsed Multiple Myeloma (Abstract
dependent safety. As a salvage therapy, thalidomide mono-
1856) was presented as a poster by Suzanne Lentzsch, Uni-
therapy at all dose levels significantly improved TTP after 2
versity of Pittsburgh School of Medicine and Cancer Insti-
and 3 prior lines compared with dexamethasone. However,
tute, Pittsburgh, Pennsylvania. This combination, in a phase
the presenter said he recognized that combination thera-
I dose-escalation trial, was well tolerated, with a prelimi-
pies are more effective. He noted in response to a question
nary overall response rate of 70% in 10 patients. The dose
that he felt that either 200 mg or 100 mg of thalidomide
15
would be an appropriate starting dose, but that 100 mg was
associated with primary cytogenetic abnormalities such as
also effective and may be safer; they are using 100 mg in
IgH translocation and hyperdiploidy. The second hit result-
combinations. He pointed out that for patients on the 400
ing in progression of MGUS to multiple myeloma includes
mg dose, the average dose received was 256 mg, whereas
mutations in the oncogenes ras and myc, secondary trans-
patients assigned to the 200 mg dose actually received an
locations, increased angiogenesis, and other abnormalities.
average dose of 198 mg.
Currently there is no way to prevent this progression.
MGUS and SMM
Diagnosis, Risk Stratification,
High-Risk SMM
and Staging
Open-Label, Phase III Trial of Lenalidomide-Dexameth-
asone (Len/dex) Vs Therapeutic Abstention in Smolder-
The evolving role of diagnostic testing and response criteria
ing Multiple Myeloma at High Risk of Progression to
was presented by Dr. S. Vincent Rajkumar, MD, Mayo Clinic,
Symptomatic MM: Results of the First Interim Analysis
Rochester, MN, as part of the IMF Symposium. He presented
(Abstract 614), was presented by María Victoria Mateos,
a case study of a man diagnosed with MGUS as a result of
University of Salamanca, Salamanca, Spain. This was an
routine blood tests. Two years later, this patient developed
interim analysis of a PETHEMA/GEM trial. SMM is defined as
lytic bone lesions and was then diagnosed with multiple
M-protein at least 30 g/L and/or bone marrow clonal plasma
myeloma, ISS stage III and Durie-Salmon stage IIIA. Dr. Raj-
cells at least 10% but no CRAB, i.e., no end organ damage.
kumar reviewed diagnostic tests, including serum protein
Several factors predict the risk of progression over time,
electrophoresis (SPEP), which can show the presence of an
e.g., the type and amount of M-protein, and the percentage
M-spike in the immunoglobulin region; immunofixation
of abnormal plasma cells (PCs) in the bone marrow com-
electrophoresis (IFE), which is used to identify the type of
partment. Standard of care for managing SMM is close fol-
antibody forming the M-spike; and the free light chain (FLC)
low-up and no active therapy. There have been attempts to
assay, which can detect unbound Ig light chains. IFE is the
treat SMM, including a comparison of MP to no treatment.
test of choice to detect residual monoclonal Ig. He recom-
Thalidomide has been shown to cause toxicity, and in one
mended SPEP and a 24-hour urine PEP (UPEP) for screening
trial, led to responses but a shorter time to myeloma ther-
along with serum IFE and FLC. He prefers using both the
apy. This trial included patients at high risk for progression,
Durie-Salmon and ISS staging systems because the Durie-
with 94 of a planned 120 patients enrolled. The treatment
Salmon system measures disease burden. Once a patient
received was 25 mg lenalidomide plus dexamethasone for
is diagnosed, the ISS can be used. Criteria in the mSMART
9 cycles of induction, then lenalidomide maintenance at 10
classification of high- vs. standard-risk active myeloma need
mg. The control arm was no therapy. The primary objective
to be re-examined in the age of the novel and even newer
was TTP to symptomatic myeloma. The secondary objec-
therapies. Both PET and MRI are useful imaging modalities.
tives included response rates and safety. The biological
Reading the discussion of imaging in the IMWG paper in
objective was to conduct phenotype and functional studies
Leukemia was recommended.
of patients' T and NK cells, and to perform GEP and other
appropriate studies. An external data monitoring commit-
Dr. Rajkumar reviewed the definitions of MGUS, SMM (smol-
tee validated the inclusion criteria and the TTP to myeloma.
dering MM or asymptomatic MM-AMM), and MM. In both
There are 40 patients evaluable who have completed the
MGUS and SMM there is neither anemia nor bone lesions,
first cycle, with a median number of 4 cycles. ORR=81%,
and calcium and kidney function are normal. MGUS and
at least VGPR=30%. For the 23 patients who have com-
SMM are distinguished by the amount of M protein and per-
pleted 9 induction cycles the ORR increased to 91%, includ-
centage of plasma cells (PC), and should not be treated. MM
ing quality responses increasing with treatment cycle to at
is distinguished by the presence of anemia, bone lesions,
least a VGPR of 38%. Median follow-up is 14 months in 94
high calcium, and/or abnormal kidney function related to
patients. Median TTP for those patients on the control arm
the PC and M-spike. The diagnosis of MM should be based
(not treated) is 19.3 months, with 16 PD, most having lytic
on clinical factors not just laboratory test results. The risk
lesions with or without anemia or anemia alone, and renal
of MGUS progressing to MM over time is related to M-spike
dysfunction in one patient. For those on the lenalidomide
size and type and FLC. SMM is more likely to progress to
plus dexamethasone treatment arm, there was 1 PD after
MM than MGUS over time. Progression of MGUS to MM may
leaving the trial; another patient left the trial after the 8th
involve a two-hit model similar to that seen in other can-
cycle. There were no grade 4 AEs. Grade 3 AEs were low,
cers. The first hit resulting in the development of MGUS is
16
and included constipation. Grade 1 to 2 AEs included neu-
Induction with Velcade®/Dexamethasone Partially
tropenia, diarrhea, rash, and deep vein thrombosis (DVT; 1
Overcomes the Poor Prognosis of t(4;14), but Not That
patient not taking prophylaxis, 1 taking aspirin, 1 with a low
of Del(17p), in Young Patients with Multiple Myeloma
INR; prophylaxis was not mandated at the beginning of the
(Abstract 957) was presented by Hervé Avet-Loiseau. This
trial). There were several SAEs, and dose reductions were
study analyzed 426 patients treated in the IFM-2005-01
required for some patients.
trial, arm B: induction with 4 cycles of bortezomib plus
dexamethasone (VD), followed by one or two courses of
Dr. Mateos concluded that the efficacy results are promis-
MEL 200. Dr. Avet-Loiseau concluded that t(4;14) and del
ing and the toxicity profile is acceptable. Dr. Dimopolous
17p remain prognostic factors with VD and that VD was not
observed that to change treatment practice, a survival
superior to VAD for del 17 but is superior for t(4;14). One
advantage has to be demonstrated. Dr. Mateos responded
difference between this study and the VISTA study and Uni-
that it was notable that most of the patients with PD in the
versity of Arkansas for Medical Sciences studies (Total Ther-
non-treatment arm had bone lesions which are irreversible
apy) is that the duration of bortezomib induction is longer,
in myeloma, although only a few patients had bone surveys
so longer treatment with bortezomib or possibly lenalido-
other than the basic skeletal survey at baseline unless they
mide may improve the prognosis for patients with t(4;14),
were symptomatic. They have not observed cytogenetic dif-
but might not for those with del 17p, for which there is no
ferences between the two treatment groups. Longer follow-
good treatment so far.
up is needed, and it is possible that the interim analysis
may indicate whether treatment is warranted for patients
Treatment of Patients with Relapsed/Refractory Multiple
with high-risk SMM. Dr. Durie commented that these were
Myeloma (MM) with Lenalidomide and Dexamethasone
interesting results, but that it was not yet time to change
with or without Bortezomib: Prospective Evaluation of
treatment recommendations from observation to active
the Impact of Cytogenetic Abnormalities (Abstract 958)
treatment for patients with SMM.
was presented by Meletios A. Dimopoulos, University of
Athens School of Medicine, Athens, Greece, who also con-
Active Myeloma
cluded that the addition of bortezomib could overcome the
Cytogenetic Prognostic Factors
negative effects of t(4;14), 1q21, and del 13q, but not del
17p.
Impact of FISH and Cytogenetics On Overall and Event-
Free Survival in Myeloma: An IMWG Analysis of 9,897
Myeloma Biology
Patients (Abstract 743) was presented by Hervé Avet-
Loiseau, University Hospital of Nantes, Nantes, France,
Natural History of Multiple Myeloma Relapsing After
on behalf of the International Myeloma Working Group
Therapy with IMiDs and Bortezomib: A Multicenter
(IMWG). Data from 9,897 patients available to members of
International Myeloma Working Group Study (2878),
the IMWG at 14 sites were analyzed. Of these 2,295 patients
was presented by Shaji Kumar, on behalf of the IMWG. This
had at least one cytogenetic or FISH abnormality, includ-
was a retrospective case study of 270 patients to determine
ing hypodiploidy; hyperdiploidy; del 13; del p17; t(11:14);
the OS of patients with myeloma that was refractory to bort-
t(4;14); and/or t(4;16). Available data included prognostic
ezomib and at least one of the IMiDs. Median time from diag-
factors, ISS stage, PFS, and OS. Univariate and multivari-
nosis to development of refractory disease was 32 months.
ate analyses were performed, confirming the association
Median OS from development of myeloma refractory to the
between cytogenetic or FISH abnormalities and prognosis.
novel agents is 8 months for all patients in the cohort, and 7
These abnormalities provide the best predictive capability
months for those without a first SCT. In a multivariate analy-
when combined with ISS stage. The presence of any cyto-
sis, at the time of development of refractory disease, age
genetic abnormality, t(4;14), del 17p, hypodiploidy, and/or
less than 60 years and at least one SCT were predictive of a
cytogenetic del 13q contribute to poorer outcomes by ISS
response of at least PR, and normal creatinine and albumin
stage. Hyperdiploidy and/or t(11;14) are predictive of better
best predicted better OS. A beta-2-M of less than 3.5 mg/dL
prognosis. Future correlative studies will include looking at
at diagnosis was associated with better EFS at the time of
the role of transplant vs. no transplant. Dr. Shaughnessy
development of refractory disease. Therefore, conventional
suggested looking at the role of t(4;16) and t(14;20). Dr.
prognostic factors are still important for survival outcome
Avet-Loiseau agreed this might be useful, but these trans-
for patients with myeloma resistant to novel agents.
locations are rare and this data set did not include enough
information.
17
Ad Hoc Scientific Committee on Plasma
Extramedullary Myeloma was discussed by Joan Bladé,
Cell Biology: Scientific Linking of Unusual
Hospital Clinic, Institut d'Investigacions Biomèdiques
Manifestations of Myeloma
August Pi i Sunyer (IDIBAPS), Barcelona, Spain. There are
several patterns in the development of extramedullary
Chair Raymond Powles, Parkside Oncology Clinic, Wimble-
myeloma, including local soft-tissue growth from adjacent
don, United Kingdom, said that although this scientific com-
bone lesions; hematogenous spread resulting in single or
mittee is still ad hoc, they were hoping to get full status as
multiple large subcutaneous plasmacytomas; metastatic-
a scientific committee by 2010. The committee is looking
like nodules in the skin, liver, kidney, breast, lymph nodes,
for suggestions for topics for 2010 and 2011 via the ASH
CNS (e.g., meninges), or other organs or tissue; or local
management, which will see that the committee receives
dissemination triggered by surgical procedures, result-
them. The 2009 session was an attempt to find commonality
ing in plasmacytomas at the sites of catheter insertion or
among the topics of plasma cell leukemia, extramedullary
laparotomy or other surgical wounds, and in the case of
myeloma, and bone-spared myeloma to further understand-
bone surgery, leading to muscular infiltration. Soft-tissue
ing of myeloma in general.
extramedullary plasmacytomas (EMPs) may be present at
diagnosis or develop during the course of the disease, and
Plasma Cell Leukemia (PCL) was discussed by Rafael Fon-
occur in up to one third of patients with myeloma. Factors
seca, Mayo Clinic, Scottsdale, Arizona. Plasma cell leukemia
associated with the development of EMPs appear to include
(PCL) represents an aggressive variant of multiple myeloma
aggressive myeloma, relapsed disease, and independence of
characterized by the presence of a large number of circu-
myeloma cells from the bone marrow microenvironment.
lating PC in the peripheral blood. It is arbitrarily defined
Possible mechanisms of spread include decreased expres-
as more than 20% of leukocytes being PC in the peripheral
sion of adhesion molecules, down-regulation of chemo-
blood or more than 2 × 109 cells/L. PCL may be the pri-
kine receptors, down-regulation of tetraspanin expression,
mary manifestation of a PC neoplasm, which often responds
hypoxia, and decreased adhesion of PCs to bone marrow
to treatment, occasionally with a durable response and OS
stromal cells, leading to egression of myeloma cells from
of 11.2 months. It can also occur as a secondary leukemic
the bone marrow. Tetraspanins are expressed on the cell
transformation of myeloma, with a very poor prognosis
surface and are involved in cellular adhesion, motility, acti-
and OS of 1.3 to 7 months. The rarity of PCL has limited
vation, and metastasis, interacting with integrins and other
the ability to study its genetic features. Dr. Fonseca focused
molecules involved in signaling and immune function.
his discussion on genetic alterations that he believes drive
EMP is associated with shorter EFS and OS. EMPs tend to
the emancipation of PC from the bone marrow, contribute
have immature morphology and plasmablastic features and
to the pathogenesis of PC disorders, and result in aggres-
may acquire genetic abnormalities that are different from
sive clonal proliferation and expansion. IgH translocations,
those in the patient's bone marrow plasma cells (BMPC).
e.g., t(11;14)(q13;q32), are common, as are hypodiploidy,
EMPs may respond to high-dose therapy, alkylating agents,
del 17p13 at the TP53 locus, mutations in myc, and del 13.
and/or radiation therapy, and may be more likely to occur
Deletions of p53 are not common, but are an important
after reduced intensity conditioning allogeneic SCT than
prognostic factor, because OS is 4.2 months for patients
after ASCT. EMP does not respond to thalidomide but
with the deletion vs. 37.8 months for those without. Dele-
does respond to bortezomib. There are no formal studies
tions of p53 are rare in MGUS and SMM, and are seen in
of sensitivity to lenalidomide, but case reports suggest the
increasing frequency over the spectrum from newly diag-
possible efficacy of lenalidomide plus dexamethasone. Dr.
nosed myeloma to first relapse to second relapse to PCL to
Bladé also referred to an entity macrofocal extramedul-
myeloma cell lines capable of independent growth in tis-
lary myeloma, which occurs in young patients (<40 years
sue culture. Therefore, Dr. Fonseca suggests that long-term
old) and is associated with multiple skeletal lesions, 10%
maintenance therapy should address pathways affected by
BMPC, and a favorable prognosis. Dr. Bladé suggested that
p53 deletion, and p53 status could be included in a molecu-
the focus of future research should be on myeloma cell
lar staging scheme that might in the future replace clinical
homing and survival, myeloma stem cell characteristics, cell
staging. The rarity of PCL precludes randomized trials, and
adhesion mechanisms, egression, mobilization, molecu-
there is no defined standard of care; therefore, treatment of
lar genetics, and drug sensitivity and resistance. There are
PCL should mirror that of high-risk myeloma, and include
appropriate animal models of EMP that can be used for
combinations of IMiDs, bortezomib, doxorubicin, and SCT.
preclinical drug testing, including subcutaneous xenograft
Dr. Fonseca predicts that with increasing survival of patients
cell lines, SCID mouse models incorporating bone grafts of
with myeloma, secondary PCL will become an increasingly
human or rabbit myeloma cells, and the Los Angeles (Beren-
common and difficult problem to manage.
son) and 5TMM series models. During the question session,
18
Dr. Bladé noted that there are 2 types of EMPs: 1) those that
Obesity and Melphalan
spread by direct extension from bone, have a less aggressive
microscopic phenotype, and have a better prognosis; and
Effect of Obesity and Renal Insufficiency On Toxicity of
2) those that metastasize to organs such as the liver, have a
High-Dose Melphalan for Multiple Myeloma (Abstract
more aggressive microscopic phenotype, and have a worse
1177) was presented by Dan T. Vogl, Myeloma Program,
prognosis. Dr. Bladé suggested the use of VTD or VRD for
Abramson Cancer Center, University of Pennsylvania, Phila-
young patients with EMD.
delphia, Pennsylvania. This study in 39 patients receiving
high-dose melphalan followed by ASCT investigated the
Bone-Spared Myeloma was discussed by Gregory R. Mundy,
role that obesity and renal insufficiency play in the toxic-
Vanderbilt University, Nashville, Tennessee, who pointed
ity of melphalan. The authors concluded that more obese
out that the bone manifestations of myeloma, even at
patients, as measured by percent body fat, have more severe
the clinical level, let alone the molecular level, are still
oral mucositis after high-dose melphalan, independent of
not well understood. Dr. Mundy reviewed what is known
melphalan dose, body weight, and renal function. Dr. Vogl's
about osteoblast and osteoclast pathways and function
group is in the process of looking at the pharmacokinetics
in myeloma, including the wnt pathway, and the roles of
of melphalan in obese patients. Further study is needed to
DKK1, which blocks osteoblast differentiation, disregulates
determine the role of dose adjustment.
(increases) RANK L production by osteoblasts, and disregu-
lates (decreases) the production of osteoprotegerin. DKK1
has been shown by immunohistochemistry to be produced
by myeloma cells. He speculated that osteoporosis could
Conclusions
be considered a paraneoplastic process because bone for-
The trend of increased survival for patients with myeloma
mation is impaired. As patients live longer, the probability
that began in the era of novel agents (bortezomib, lenalid-
of experiencing cancer-related bone disease increases for
omide, and thalidomide) is continuing. The novel agents
patients with breast and prostate cancer as well as for those
are no longer so novel, as they have been integrated into
with myeloma. Experiments in preclinical models should
new standards of care. Even newer agents are being devel-
be useful for determining if myeloma can be uncoupled
oped with promising results. Many of these may work best
from bone disease, and if that would alter its natural his-
in combination therapies, and because many have unique
tory, including response to therapy. In response to the
mechanisms of action and non-overlapping toxicities, com-
other presentations in the session, Dr. Mundy noted that the
bination therapy attacking myeloma cells at several vulner-
staging of myelomas in remission and at relapse is impor-
able targets should lead to continued improved patient
tant. Research needs to focus on detecting extramedullary
survival and quality of life.
disease in the absence of symptoms. He speculated that
treatment, with bortezomib in particular, might be turning
myeloma cells into metastatic cells.
Of Interest to Patients
Alpha Lipoic Acid and Bortezomib
Alpha Lipoic Acid (ALA) Inhibits the Anti-Myeloma
Effects of Bortezomib (Abstract 3832) was presented
by Eric Sanchez, Institute for Myeloma and Bone Cancer
Research, West Hollywood, California. Alpha lipoic acid
(ALA), an anti-oxidant supplement that is used in the man-
agement of peripheral neuropathy in myeloma, has been
shown to inhibit the anti-myeloma effects of bortezomib in
myeloma cell lines. This phenomenon is being investigated
further in patient myeloma cells and in a xenograft model,
as are possible ways to overcome the inhibitory effects of
alpha lipoic acid on bortezomib while preserving the ben-
eficial effects of the supplement in PN.
19
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