INTERNATIONAL MYELOMA FOUNDATION
ASCO 2010
Highlights
for Physicians

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Compiled by Lynne Lederman, PhD
This publication is sponsored by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

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ASCO 2010: Myeloma Highlights for Physicians
Introduction
versus placebo maintenance therapy following single
autologous stem cell transplant (ASCT) for multiple
The 46th Annual Meeting of the American Society of Clini-
myeloma (MM).
cal Oncology (ASCO) was held from June 4 through June
8, 2010, in Chicago, Illinois. This year's education sessions
There is a need for maintenance therapy because induction
on myeloma addressed management of older patients with
therapy followed by ASCT alone results it cytoreduction, but
lymphoma and myeloma and complications of myeloma
not cure, for most patients with myeloma. CALGB 100104
and myeloma therapies. The clinical science symposium
included patients younger than age 70 years who were
addressed novel therapies for myeloma. The lymphoma and
treated with at least 2 months of induction therapy to which
plasma cell disorders poster discussion addressed person-
they had a response of at least stable disease (SD), were 1
alized therapy and new agents in myeloma, and included
year or less from the start of therapy, and who had adequate
two main themes: 1) improving on the efficacy of lenalid-
numbers of stem cells (SC). Patients received one round of
omide with or without dexamethasone, especially in the
high-dose (HD) melphalan followed by autologous stem
relapsed/refractory setting, and 2) 1q21 amplification as a
sell transplantation (MEL200 ASCT), then were restaged
poor-risk feature.
90 to 100 days after recovery. Those who had a response
of SD or better were randomly assigned to placebo or to
The most encouraging developments presented at this
lenalidomide at 10 mg per day, which could be increased
meeting include the following:
to 15 mg/day or decreased to 5 mg/day as tolerated. Patients
· Lenalidomide maintenance therapy
were stratified by beta 2 microglobulin (B2M) and use of
lenalidomide in induction therapy. The objectives were to
· Progress in the development of new
determine if lenalidomide prolonged time to progression
anti-myeloma agents
(TTP) following ASCT. The study was powered to detect
· The role of transplant in the era of novel agents
prolongation of TTP from 24 months to 33.6 months. Sec-
· Identification of risk factors
ondary objectives included the complete remission (CR)
rate post-ASCT, progression-free survival (PFS), overall sur-
· Anti-myeloma effects of zoledronic acid
vival (OS), and the feasibility of long-term administration
· Identification of erythropoietin receptors
of lenalidomide.
on myeloma cells
The accrual target was to register 538 patients with a goal
Lenalidomide-Based Maintenance
of randomly assigning 462 patients based on an estimated
Therapy
10% dropout rate; however, the actual dropout rate before
randomization was 15%. Enrollment was slow until after the
CALGB 100104 A phase III randomized,
BMT CTN 0102 cooperative group study closed, after which
double-blind study of maintenance
time accrual was more rapid. This demonstrates that hav-
therapy with lenalidomide (CC5013) or
ing two cooperative group studies open at the same time
placebo following autologous stem cell
competing for patients is not ideal. Results were analyzed
transplantation for multiple myeloma.
in November of 2009 for 201 patients randomly assigned
to lenalidomide and 208 randomly assigned to placebo
Dr. Philip L. McCarthy, Roswell Park Cancer Center,
(n=418).
Buffalo, New York, presented Abstract 8017 on behalf
of CALGB, ECOG, and BMT CTN (Blood and Mar-
An analysis of adverse events (AE) for 368 of 418 randomized
row Transplant Clinical Trials Network). The original
patients during the maintenance phase receiving lenalido-
title was Phase III intergroup study of lenalidomide
mide (n=194) vs. placebo (n=174) show significantly
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more grade 3 and 4 hematologic toxicities with lenalido-
corticosteroids is not effective. Thalidomide maintenance
mide, and more grade 3 non-hematologic toxicities, but no
after ASCT increases the CR rate, event-free survival (EFS)
difference in grade 4 and 5 non-hematologic AE. (Note that
or PFS, and OS. In the IFM 99-02 trial, no benefit for tha-
the abstract showed AE from ASCT, and transplant over-
lidomide was seen if deletion 13 (del 13) was present or if
whelmed the AE and the difference between the arms). The
the response was a very good partial response (VGPR) or
most common and significant AE with lenalidomide were
better after ASCT, suggesting that the major role for thalido-
neutropenia, and to a lesser extent thrombocytopenia, and
mide was to reduce residual myeloma that was still pres-
anemia; the only other significantly higher AE in the lenalid-
ent after ASCT rather than to prolong the duration of CR
omide arm was documented infection. Discontinuation due
or VGPR. This result could be explained by the high rate of
to AE was 13% for lenalidomide vs. 2% for placebo, and 12%
peripheral neuropathy (PN) that shortened the duration of
vs. 7% for other reasons.
thalidomide treatment. So the rationale for the IFM 2005-02
phase III randomized trial was to determine if lenalidomide
From day 0 of ASCT, 29 of the 210 patients on lenalidomide
could be safe and effective when administered for a long
and 58 of the 208 patients on placebo experienced disease
time, given its convenience as an oral agent known to be
progression or death (an event), a difference which is statis-
active in patients for whom HD therapy had failed, and its
tically significant. At a median follow-up of 12 months, there
lack of strong association with PN.
was a 58% reduction in TTP with lenalidomide. TTP was not
reached with lenalidomide vs. a TTP of 25.5 months with
IFM 2005-02 enrolled 614 patients younger than age 65
placebo. The follow-up is not long enough to determine a
years with non-progressive disease within 6 months of ASCT
difference in OS. The study was unblinded in December,
as frontline therapy. After stratification according to risk fac-
2009, to allow cross-over with physician support to open-
tors and response, patients received 2 months of consolida-
label lenalidomide. Patients were stratified by B2M and
tion with 25 mg/day of lenalidomide, then were randomly
prior thalidomide and lenalidomide; patients in each strati-
assigned to either placebo or 10 to 15 mg/day lenalidomide
fication who received lenalidomide maintenance fared bet-
(n=307 in each arm). The primary endpoint was PFS; the
ter. For patients who received prior thalidomide, the benefit
secondary endpoints were CR rate, TTP, OS, and feasibil-
of lenalidomide maintenance was not seen early on, but
ity of long-term lenalidomide therapy. Of the 614 patients,
developed over time.
572 received consolidation. The first interim analysis was
in December, 2009, with a median follow-up of 24 months
Dr. McCarthy concluded that maintenance with lenalido-
(34 months post-diagnosis and random assignment), after
mide vs. placebo significantly prolongs TTP. There is no dif-
which the independent data monitoring committee recom-
ference in OS at a median follow-up of 1 year post-ASCT.
mended unblinding of the study. The median age for both
Lenalidomide prolonged TTP within stratification by high
groups was 55 years, and the two arms were comparable in
B2M, and prior thalidomide or lenalidomide induction ther-
all demographic and disease characteristics.
apy. Lenalidomide maintenance therapy produced some
hematologic toxicity but this was not severe, given that the
There was a significant increase in response after lenalido-
discontinuation due to AE was 13%.
mide consolidation in the CR rates (from 13% to 19%) and
VGPR (from 58% to 68%) for the 572 patients. For the intent-
Lenalidomide maintenance after
to-treat (ITT) population, the best response improved
transplantation for myeloma: first interim
for patients receiving lenalidomide maintenance, but the
analysis of a prospective randomized
change was not statistically significant. Lenalidomide main-
study of the Intergroupe Francophone du
tenance did improve the median PFS, which was 24 months
Myelome (IFM 2005-02 trial)
for the placebo arm but was not reached in the lenalidomide
Dr. Michel Attal, Hopital Purpan, Toulouse, France,
arm. Three years post-random assignment (which equals
presented Abstract 8018 on behalf of the IFM.
4 years post-diagnosis), the PFS was 34% in the placebo
arm vs. 68% in the lenalidomide arm, which is statistically
Residual disease is always present after single or double
significant. The benefit of lenalidomide maintenance was
ASCT, and is responsible for relapse. The ideal maintenance
observed in all stratified subgroups of patients, including
regimen is not known, but what is known is that mainte-
pre-consolidation response, whether partial response (PR)
nance with conventional chemotherapy, interferon, or
or SD, or VGPR or better; high or low B2M levels; presence
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or not of del 13; and VAD (vincristine Adriamycin dexameth-
therapies. What do these studies mean for the practic-
asone) vs. VD [bortezomib (VELCADE) dexamethasone]
ing physician?
induction regimen. Two prognostic factors were associated
with longer PFS in a multivariate analysis: lenalidomide
Dr. Giralt said that these are two of the most important prac-
maintenance, and a response of VGPR or better after ASCT
tice-changing presentations in myeloma in the last couple of
or consolidation. Therefore, a response of VGPR or better
years. The question is now what to do in the clinic based on
remains an important prognostic factor even with effective
the data presented at this meeting. The goals of treatment
maintenance therapy.
should be to provide patients with the longest life and best
quality of life (QoL) with a minimum burden of therapy.
Lenalidomide maintenance was well tolerated. The discon-
Maintenance is important in myeloma therapy because
tinuation rates and AE were similar between arms during
induction therapy followed by ASCT alone will cytoreduce
maintenance. Neutropenia was higher with lenalidomide
but not cure most myeloma. He thinks maintenance therapy
but there was no increased risk of febrile neutropenia. The
should be called "post-transplant continuous therapy." Post-
rates of deep vein thrombosis (DVT) and PN were similar
transplant therapy is active treatment, as it implies further
in both arms and were low. The OS at 3 years from random
reduction of disease burden, may involve more effective
assignment (4 years post-diagnosis) was 80% for placebo
drugs, and is not envisioned as long-term treatment; the
vs. 88% for lenalidomide, which is not significant. Dr. Attal
maximum time this treatment can be given should be inves-
said these survival rates are unprecedented compared with
tigated. Post-transplant therapy generally shows a benefit
results from all previous IFM trials.
for thalidomide in PFS and OS, although toxicity is an issue.
Thalidomide maintenance might need to be compared with
Dr. Attal concluded that maintenance with lenalidomide
lenalidomide maintenance, because, at least for areas of the
was well tolerated, resulted in a low discontinuation rate
world where cost is an issue, thalidomide is much cheaper.
due to severe AE, and caused no increased risk of DVT or
PN. Lenalidomide maintenance is highly effective in reduc-
Dr. Giralt noted the similarities of these two studies, which
ing the risk of progression in all stratification subgroups,
involved young patients receiving a single ASCT. In the IFM
with an overall 54% reduced risk, although longer follow-up
study, 10 to 15 mg/day lenalidomide is administered until
is required to appreciate the impact of lenalidomide on OS.
relapse with dose modification for toxicity. He thought the
The final analysis of this trial is expected in August, 2010.
best responses were somewhat disappointing, with CR of
25% in the lenalidomide arm, but 77% of patients had at
Discussion
least VGPR. What is most important in the subset analysis
Post-presentation Q&A
is that the benefit of lenalidomide is seen regardless of the
Dr. Antonio Palumbo, University of Turin, Ospedale Moli-
response to transplant. Lenalidomide maintenance abro-
nette, Turin, Italy, observed that in the CALGB trial, the
gates the effects of del 13. The response after consolidation
grade 3 and 4 neutropenia was 50% and thrombocytopenia
is the most important prognostic factor. The most impor-
was 10%. In the IFM trial, the AE profile was much better,
tant side effect is neutropenia, and it will be interesting to
and he asked why there was a discrepancy. Dr. Attal said
see why this was significantly lower than in the CALGB trial
he didn't know and would have expected neutropenia to
results and to see if they were monitoring more often or if
be higher than in the CALGB trial because of the 2-month
it was due to the pre-ASCT induction regimen. The most
consolidation phase, and neutropenia occurs in the first
important message is that as of today, there is no survival
month of maintenance mainly due to consolidation. He has
benefit for lenalidomide maintenance, and this needs fur-
no explanation for why it is 31% (7% grade 4) in the IFM
ther observation.
trial. The rate of grade 3 and 4 thrombocytopenia is 8% (3%
The CALGB study also showed that the PFS was better with
grade 4).
lenalidomide maintenance, with no benefit for OS. The
Formal Discussion
important subanalysis from this trial showed that the benefit
of lenalidomide is seen regardless of the use for induction
After the presentations, Dr. Sergio Giralt, Memorial
of thalidomide or lenalidomide, which is becoming the stan-
Sloan-Kettering Cancer Center, New York, New York,
dard in the U.S.. Neutropenia was a significant side effect,
discussed these two studies (abstracts 8017 and 8018)
occurring in 42% of patients (grade 3 to 5). Because there
in a presentation entitled: Post-transplant maintenance
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was a significant increase in febrile neutropenia, this ther-
post-transplant therapy is an open question. There are at
apy should be monitored when it is used in the community
least two agents that have been shown to improve PFS, and
to prevent severe toxicities, such as sepsis.
both are IMiDs. Bortezomib data suggest it plays a role in
further reduction of tumor burden and PFS improvement.
If the goal of treatment is to delay progression, patients
A good measure for tumor burden, e.g., PCR (polymerase
should probably receive lenalidomide maintenance whether
chain reaction ­ do we need to clarify this, or will physi-
they are in stringent CR after ASCT, or show residual disease
cians know without explanation?), would be helpful, and
after ASCT, although they may not live longer with mainte-
disease reduction could then be quantified as a threshold
nance. Other important questions to answer include what
to determine rationally whether to administer maintenance
is the role of consolidation post-transplant, given the good
therapy or not.
responses seen after Total Therapy 2 (TT2) and TT3; how
long should maintenance be given; and what is the role of
Someone asked what Dr. Giralt would do in his practice
transplantation in the era of novel therapies?
following this meeting. Dr. Giralt said that when the study
report came out, they had to contact patients on placebo.
The next trial after CALGB 100104 has been planned. BMT
If those patients had low-risk disease and were in CR, he
CTN 0702 StAMINA is a trial of single ASCT with or without
recommended they not go on lenalidomide maintenance.
RVD consolidation vs. tandem transplant and maintenance
If they had high-risk disease and were on placebo and
therapy in 750 patients. It has been designed to answer
their disease had not relapsed, he recommended they go
the questions, "What is the best consolidation regimen for
on lenalidomide maintenance. Most patients are on study,
patients undergoing a single ASCT in the context of lenalid-
so they follow the protocol. For those patients off study,
omide maintenance? Should patients receive a second
if there is any evidence of residual disease post-ASCT, he
ASCT, or nothing at all, or 4 cycles of RVD?" Lenalidomide
recommends they go on lenalidomide maintenance. If the
maintenance is planned for 3 years, and it will be interesting
response was CR but patients have high-risk disease, he
to compare the results to 1 year of maintenance or mainte-
recommends they go on lenalidomide maintenance. For
nance until progression.
the few patients with low tumor mass and low-risk disease,
Dr. Giralt concluded that both studies show that lenalido-
the possibility of maintenance or not can be discussed. For
mide prolongs TTP when compared with placebo, with no
patients on thalidomide maintenance who tolerate it well,
OS benefit, although follow-up is short, and an OS benefit
he wouldn't switch IMiDs.
may not be seen due to cross over. There is a lenalidomide
Additional Discussion of Maintenance Therapy
benefit regardless of B2M, cytogenetics, type of induc-
tion therapy, or response to initial therapy. Neither study
Dr. Jean-Luc Harousseau, MD, Rene Gauducheau
addresses issues of duration of therapy, if there is a ben-
Cancer Center, Nantes, France, discussed the CALGB
efit for patients in CR after ASCT, the effect of early vs. late
and IFM studies during one of the Highlights of the
intervention, or the effect of the depth of CR. It is also not
Day sessions.
possible to determine yet who would and who would not
Four published randomized studies show a benefit for tha-
need maintenance.
lidomide after ASCT, including an increase in CR/VGPR rates
Dr. Andrzej J. Jakubowiak, University of Michigan Compre-
and prolongation of PFS in all four, and prolongation of OS
hensive Cancer Center, Ann Arbor, Michigan suggested two
in three. However, thalidomide maintenance has never been
additional questions: how to view previously published
considered the standard of care because the optimal dose
results of thalidomide maintenance, and how to view bort-
and duration of therapy are not known, nor is the ability
ezomib (VELCADE) plus thalidomide (VT) maintenance
to determine which patients would benefit, and prolonged
vs. maintenance with an immunomodulatory drug (IMiD)
treatment results in toxicity, especially PN.
alone. Dr. Giralt said consideration of thalidomide mainte-
In both the CALGB and IFM trials, lenalidomide maintenance
nance is essential for the global community, because tha-
improves PFS when compared with placebo across different
lidomide is what will be accessible in the developing world.
prognostic subgroups, including beta 2 microglobulin for
The role of VT, which could be a better treatment, should
both; del 13 in the IFM trial, the type of induction therapy
be answered in the context of a randomized trial. The best
(VAD/VD for IFM, prior thalidomide or lenalidomide or not
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for CALGB), and response to induction (CR or VGPR/PR)
Of the 35 patients enrolled, there were 15 patients with
for IFM. There was a significantly prolonged PFS in both
high-risk myeloma by mSMART criteria. The median number
trials across different prognostic subgroups. Except for neu-
of prior treatments was 6 regimens, and all patients had at
tropenia (with very rare incidence of infections) low-dose
least 3 prior regimens, including 100% prior lenalidomide
lenalidomide was well tolerated. Due to the short follow-up
and bortezomib (by definition), and most had received tha-
there is no difference as yet in OS curves between main-
lidomide and ASCT. Dose reductions were both per protocol
tenance therapy and placebo. We also know that low-dose
and for AE, primarily neutropenia. The median follow-up
lenalidomide also prolongs PFS after induction treatment in
was 5 months, at which time 66% of patients experienced
elderly patients, who are not transplant eligible, as shown
no progression.
in the MM015 study presented by Dr. Palumbo at ASH and
also discussed at this meeting by Dr. Raje at the joint ASCO/
Neutropenia was the major grade 3 or 4 hematologic toxic-
ASH session (which is summarized in the section below on
ity in 34% of patients; non-hematologic toxicities were not
therapy for non-transplant eligible patients). He concluded
common, and included one thromboembolic event. Neu-
that lenalidomide maintenance might become a new stan-
ropathy occurred in 5 patients (14%) with 3% grade 1 and
dard of care.
11% grade 2. Four of the five patients had neuropathy at
baseline that worsened with treatment.
New Anti-Myeloma Agents
The RR of confirmed PR or better was 26%, and of mini-
Progress is being made in the development of new therapies
mal response (MR) or better was 54%. Best response by
for myeloma. Some of these are second and third genera-
mSMART was 47% in the high-risk group vs. 54% in the
tions of already approved classes of anti-myeloma agents,
whole cohort, which was not significant. Nine patients
e.g., proteasome inhibitor and IMiD, and others represent
received an increased dose per protocol; of these, one had
classes that may have been approved in other malignancies,
an increased response from SD to MR, and the rest had SD.
e.g., histone deacetylase (HDAC) inhibitors, mTOR (mam-
The median time to response (TTR) was 1 month and dura-
malian target of rapamycin) inhibitors, and monoclonal
tion of response (DOR) and OS have not yet been reached.
antibodies (mAbs).
PFS was 8.0 months, and 58% of patients had a PFS of 6
Pomalidomide
months. The OS at 6 months was 86%.
Dr. Martha Lacy, Mayo Clinic, Rochester, Minnesota,
Dr. Lacy concluded that the pomalidomide plus dexametha-
presented Abstract 8002: Activity of pomalidomide
sone regimen had significant activity in lenalidomide- and
plus dexamethasone (Pom/dex) in dual lenalidomide/
bortezomib-refractory myeloma. Responses were rapid.
bortezomib-refractory multiple myeloma (MM).
Toxicity was manageable and consisted primarily of neutro-
penia. Further studies are ongoing to see if starting with a
Pomalidomide is a novel IMiD derived from thalidomide.
4-mg dose of pomalidomide will result in higher response
Although similar to thalidomide and lenalidomide, pomalid-
rates.
omide has a different clinical efficacy and side effect profile.
Pomalidomide plus dexamethasone has shown activity in
Discussion
patients with relapsed myeloma and lenalidomide-refrac-
Dr. Bart Barlogie, University of Arkansas for Medical Sci-
tory disease.
ences, Little Rock, Arkansas, pointed out that the median
This phase II trial of pomalidomide plus dexamethasone
time to response of 1 month is very rapid, and he wondered
in relapsed myeloma refractory to both lenalidomide and
if Dr. Lacy thought there are enough data to be certain. If the
bortezomib (defined as progression on or within 60 days
response is really so rapid, it would be the best treatment to
of last therapy) assessed response rates (RR) and toxicity.
be given up front. Dr. Lacy said she suspected it would be
Patients received 2 mg pomalidomide continuously every
very effective up front. Dr. Barlogie then commented that
day, 40 mg dexamethasone once a week, and 325 mg aspi-
when his group treats patients with everything available
rin daily, although investigators could administer full-dose
using TT3, the median time to CR is 6 to 8 months, and
anticoagulant at their discretion. If there was no response or
it's gradual, so what Dr. Lacy is seeing in this trial may be
progressive disease after 2 cycles, the dose of pomalidomide
due to small numbers of patients. He wanted to warn about
could be increased to 4 mg.
high- vs. low-risk and incidence of remission. He thinks the
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issue for patients with high-risk disease is not remission
most patients had anemia and neutropenia and nearly half
but rather durability of response. He doesn't think there
had thrombocytopenia and PN. The results are summarized
are data showing that patients with high-risk disease do
in Table 1. ORR = overall response rate; clinical benefit
less well with initial response. Dr. Lacy agreed. DOR with
response (CBR) was defined as at least MR.
high-risk disease is hugely important, but in their experi-
ence, once relapse occurs, it's hard to get the disease into
There was grade 1 to 2 neuropathy at baseline in nearly half
remission. Dr. Lacy said that the median follow-up was not
of the patients. Treatment-emergent neuropathy grade 1
long enough to look at TTP in high- vs. standard-risk dis-
and 2 occurred in 12% to 17% of patients, grade 3 was 0
ease. Dr. Harousseau asked if they looked for deletion 17p.
to 3%, depending on treatment group, and there was no
Dr. Lacy said that they don't have data on that, but in the
grade 4 PN. PN rates were highest in the bortezomib-treated
initial cohort, the response was high, about 70% to 80%.
patients. One of the patients in the bortezomib-treated arm
discontinued due to PN. Fatigue, nausea, dyspnea, and cyto-
Carfilzomib
penias were among the common AE, were mostly grade 1
or 2, and were manageable. There were 5 on-study deaths,
Dr. Ravi Vij, Washington University School of Medicine,
2 due to progressive disease, 2 due to study treatment, and
St. Louis, Missouri, presented Abstract 8000: Results
1 unrelated to treatment. At follow-up about 25% of patients
of an ongoing open-label phase II study of carfilzomib
remain on trial, about 25% have been treated with the full
in patients with relapsed and/or refractory multiple
12 cycles, and 9% (n=14) are on an extension protocol.
myeloma.
Dr. Vij concluded that single-agent carfilzomib shows sig-
Carfilzomib is a novel, selective proteasome inhibitor with
nificant activity in relapsed or refractory myeloma; although
highly selectable and irreversible proteasome binding and
responses were seen in bortezomib-treated patients,
target inhibition and minimal off-target activity. It over-
responses were higher in bortezomib-naïve patients,
comes bortezomib resistance and has not been associated
with durable responses in all three treatment groups.
with nervous tissue damage or neutropenia in pre-clinical
Preliminary data suggest higher response rates with higher
studies.
doses. AE were generally mild and clinically manageable.
PX-171-004 enrolled 155 patients with relapsed or refrac-
Severe PN was rare and does not limit therapy despite pre-
tory myeloma following 1 to 3 prior treatment regimens.
existing symptoms. Carfilzomib was tolerated for at least 12
Cohort 1 received a dose of carfilzomib of 20 mg/m2; this
cycles. The lack of significant toxicities suggests that carfil-
cohort was divided into bortezomib-treated (n=36) vs.
zomib is suitable for use in combination therapy regimens,
naïve (n=59) patients ; cohort 2 (n=60) received a dose of
and combinations are being tested. The trial is ongoing at
20 mg/m2 in cycle 1 that was escalated to 27 mg/m2 in subse-
a dose of 27 mg/m2. In other trials in solid tumors, carfilzo-
quent cycles, and included only bortezomib-naïve patients.
mib has been administered in doses up to 70 mg/m2 using
In all, 140 patients were evaluable for efficacy. At baseline,
slower infusion rates.
Table 1. Results of PX-171-004, single agent carfilzomib
cohort 1
cohort 1
cohort 2
bortezomib-treated
bortezomib-naïve
bortezomib-naïve
(n=34)
(n=53), 20 mg/m2
(n=53) 20/27 mg/m2
ORR
21%
45%
55%
CBR
33%
58%
62%
median TTP
8.1 months
8.3 months
11.2 months
median DOR for patients
8.5 months
8.3 moths
11.5 months
with at least MR
median DOR for patients
11.5 months
10.2 months
11.5 months
with at least PR
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Discussion
Disorders Poster Discussion, discussed this poster. He
A participant pointed out that in bortezomib-resistant dis-
observed that this study enrolled patients with a median of
ease, the responses are lower but the TTP is equal to that
4 prior lines of therapy, so they were further along in the
in bortezomib-responsive disease, and asked why there was
disease process than those in the Mateos study of combi-
a discrepancy. Dr. Vij responded that he can't say why the
nation panobinostat, which is discussed below. Of the 31
response is lower, but the durability of response is encour-
patients, 84% had prior thalidomide and/or lenalidomide,
aging even in this patient population. As a follow-up, a
87% demonstrated at least SD, i.e., clinical benefit, and the
participant asked if the discrepancy was due to definitions
ITT response rate of at least PR in 52% of patients is encour-
responses. Dr. Vij pointed out that the time to next therapy
aging. Responses in lenalidomide-exposed patients and in
(TTNT) is a more valuable endpoint, and the requirement
lenalidomide-refractory disease suggest that vorinostat may
for salvage treatment is prolonged whether the response
help overcome resistance.
was MR or PR. Patients with MR have a survival advantage
Panobinostat
over patients who don't respond at all based on APEX
trial data.
Dr. Kenneth Anderson, Dana-Farber Cancer Institute,
Boston, Massachusetts, presented Abstract 8001 on
Someone asked why, given the mild toxicity profile and the
behalf of Jesus San-Miguel and their colleagues: Phase
escalating responses observed with increasing doses, the
Ib study of oral panobinostat (LBH589) plus intrave-
dose was not increased beyond 27 mg/m2. Dr. Vij said that
nous bortezomib in patients (Pts) with relapsed (Rel)
in phase I trials, two different regimens were tested. What
or Rel and refractory (Ref ) multiple myeloma (MM).
was thought to have been associated renal toxicity could
also have been toxicity associated with tumor lysis syn-
Panobinostat has limited activity as a single agent, so it is
drome, sepsis, myeloma disease, or the drug, so the choice
being tested in combination regimens.
of dose was conservative. Now it is known that patients with
The LBH589B2207 dose escalation study enrolled 47
solid tumors have received 70 mg/m2 via a 30-minute infu-
patients with relapsed or relapsed and refractory myeloma.
sion. Doses of 36 and 45 mg/m2 are tolerable in myeloma
Panobinostat was administered three times a week every
patients. Perhaps higher doses with longer infusion times
week, bortezomib was administered on the "classic" sched-
would result in a toxicity profile that is no different from
ule for 2 weeks on and 1 week off, and dexamethasone was
that associated with lower doses and might improve the
administered on the day of and the day after bortezomib.
response rate.
The MTD was considered to be 20 mg panobinostat 3 times
Vorinostat
a week with 1.3 mg/m2 bortezomib. Cohort 3 (n=8) and an
expansion cohort 6 (n=9) received these doses.
Dr. Paul Richardson, Dana-Farber Cancer Institute, Bos-
ton, Massachusetts, presented the poster, Abstract 8031:
AE included a high rate of grade 3 and 4 thrombocytopenia
Phase I study of combined vorinostat ( V), lenalido-
that was manageable with dose modification and/or platelet
mide (L), and dexamethasone (D) in patients (pts) with
transfusions, and other cytopenias. The non-hematologic
relapsed or refractory multiple myeloma (MM)
AE were primarily GI-related, as well as fatigue and asthenia,
and were mostly grade 1 and 2. The combination was asso-
At this time, all data are preliminary, but they suggest vori-
ciated with minimal grade 3 and 4 PN (4%), and there was
nostat, an HDAC inhibitor, combined with lenalidomide and
no dose-related QT prolongation, which has been reported
dexamethasone may be a convenient, effective, and gener-
with HDACs.
ally well-tolerated oral regimen for patients with relapsed
or relapsed and refractory myeloma, including those who
Responses were seen even at the lowest doses, with a CR
have received prior lenalidomide therapy. There were no
in cohort 2. CBR was seen in 76% of the combined cohort
treatment-related deaths and no maximum tolerated dose
3 and expansion cohort 6. For all 47 patients the ORR was
(MTD) reported. A phase II study is planned.
70%; in bortezomib-refractory disease (n=15) the ORR was
60%. Median duration on study because of HDAC inhibitor
Discussion
side effects for cohort 3 and 6 was an average of 3 months
Dr. Robert Orlowski, University of Texas, MD Anderson
(it was less for all other cohorts), although one patient has
Cancer Center, co-chair of the Lymphoma and Plasma Cell
been on therapy for 1.5 years.
9

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Dr. Anderson concluded that oral panobinostat can be
this combination can overcome bortezomib resistance in a
safely combined with bortezomib and dexamethasone, and
population with an unmet medical need.
that this is among the most active combinations in bortezo-
mib-resistant myeloma. Future directions include a large,
Elotuzumab
international, randomized phase III trial of bortezomib plus
Dr. Sagar Lonial, Emory University School of Medicine,
panobinostat vs. bortezomib (PANORAMA 1) in relapsed
Atlanta, Georgia, presented Abstract 8020, Elotuzumab
myeloma that is ongoing, and in the US a phase II trial of
in combination with lenalidomide and low-dose dexa-
bortezomib plus panobinostat at the MTD (PANORAMA 2) in
methasone in relapsed or refractory multiple myeloma:
patients with relapsed and bortezomib-refractory myeloma.
a phase I/II study.
Dr. María Victoria Mateos, Hospital Universitario de
The presentation was an update of data presented at ASH,
Salamanca, Salamanca, Spain presented poster Abstract
2009. Elotuzumab is a humanized IgG1 mAb targeting CS1,
8030: Phase Ib study of oral panobinostat (LBH589)
a cell surface glycoprotein that is highly and uniformly
+ lenalidomide (LEN) + dexamethasone (DEX) in
expressed on myeloma cells, with restricted expression on
patients (Pts) with relapsed (Rel) or Rel and refractory
natural killer (NK) cells, and little or no expression on nor-
(Ref ) multiple myeloma (MM).
mal tissues. Preclinical data suggest the mechanism of action
(MOA) is mainly through NK-mediated antibody-dependent
Dr. Robert Orlowski, co-chair of the Lymphoma and Plasma
cell-mediated cytotoxicity. As a single agent it has a safety
Cell Disorders Poster Discussion, Personalized Therapy and
profile not dissimilar to that of other mAbs, with AE being
New Agents in myeloma, discussed this poster.
primarily infusion-related reactions, and with responses
High-dose dexamethasone plus lenalidomide and oral pan-
mostly SD. Preclinical combination studies showed syner-
obinostat was administered on an every-other-day schedule
gism with lenalidomide.
to the 46 patients enrolled. Patients with primary refractory
The study objectives for the phase Ib portion were to deter-
myeloma were excluded, although 54% of patients were
mine the MTD of elotuzumab in combination with lenalido-
refractory to last line of therapy; only 17% of them had
mide and low-dose dexamethasone. The phase II primary
prior lenalidomide. There was a 48% response of at least
objective was to evaluate the safety and efficacy of two doses
MR, which includes 7 VGPR, 2 CR, and 1 sCR, but none of
of elotuzumab, either 10 or 20 mg/kg, and to optimize
these were in patients in the lenalidomide-refractory group.
the premedication regimen in 60 additional patients with
Hematologic AE were commonly observed, with about
advanced disease; those with prior lenalidomide treatment
half of patients experiencing grade 3 or 4 neutropenia and
were excluded. In phase Ib, doses of elotuzumab were 5,
thrombocytopenia. There were 7 deaths, three of which
10, and 20 mg/kg in combination with 25 mg lenalidomide
were suspected of being treatment-related; 10 patients dis-
and low-dose dexamethasone. For the first 2 weeks, elotu-
continued due to AE. Dr. Orlowski thinks this is a high rate
zumab was dosed weekly; subsequently it was dosed every
of deaths, comparable to those seen in the study combining
other week until progression. The phase I portion of the
lenalidomide with high-dose dexamethasone. Future stud-
study was originally supposed to end after 6 months, but
ies will use a lower dose of dexamethasone and less fre-
based on favorable responses, it was amended to continue
quent administration of panobinostat.
to progressive disease (PD).
Dr. Melissa Alsina, H. Lee Moffitt Cancer Center and
In the phase Ib portion, 28 patients were treated, and 12
Research Institute, Tampa, Florida, presented poster
are still on study. There were no dose-limiting toxicities
Abstract TPS308 (Trials In Progress Session), PAN-
(DLT). The AE were similar to those seen in lenalidomide
ORAMA 2: A phase II study of panobinostat (LBH589)
trials except for infusion reactions thought to be attribut-
in combination with bortezomib (BTZ) and dexametha-
able to elotuzumab, which occurred in 2 patients. The ORR
sone (DEX) in patients with relapsed and BTZ-refrac-
was 82% for all 28 evaluable patients and 95% for the 21
tory multiple myeloma.
lenalidomide-naïve patients; VGPR rates were 25% and 27%.
Responses are improved over those reported at ASH, and
The design of this study was presented. It is enrolling
are relatively independent of prior exposure to lenalido-
approximately 47 patients in the US to determine, in part, if
mide, thalidomide or bortezomib. TTP was not reached
10

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at a follow-up of a median of 8 months. After initiation of
of elotuzumab in combination with bortezomib, deter-
a new premedication regimen including H2 blockers and
mining safety and tolerability, and evaluating efficacy and
other agents, there were no serious infusion reactions in the
immunogenicity. Elotuzumab was infused on days 1 and 11,
phase II expansion trial. Enrollment is continuing. Analysis
bortezomib was given at the standard dose and regimen.
of bone marrow-derived myeloma cells from patients in the
DLT were assessed after cycle 1; elotuzumab only was dose
phase II expansion cohort show complete target saturation
escalated for 3 more cycles. If PD occurred at cycles 2 or
of CS1 at both doses.
3, dexamethasone could be added; if at cycle 4 there was
no PD or toxicity, the patient could continue therapy. The
Dr. Lonial concluded that elotuzumab plus lenalidomide
study enrolled 28 patients with a median of 2 prior thera-
plus low-dose dexamethasone has a manageable safety pro-
pies; 25% had high-risk cytogenetics. Of these, 15 patients
file in the phase Ib trial in 28 treated patients with a median
were treated in the escalation phase, and there were no
of 2 prior therapies. There were no additional toxicities over
DLTs in the dose-escalation phase; 13 patients were added at
what is seen with lenalidomide and low-dose dexametha-
the expansion phase at an MTD of 20 mg/kg for elotuzumab.
sone other than infusion reactions. The phase II expansion
is ongoing to identify the optimal dose of elotuzumab in
The AE were mostly mild, with the most common grade 3
this combination.
and 4 events being lymphopenia, fatigue, thrombocytope-
nia, hyperglycemia, neutropenia, pneumonia, and anemia.
Discussion
The elotuzumab-related AE were mostly mild and were
Dr. Todd Zimmerman, University of Chicago Medical Cen-
mostly infusion-related reactions. There were two elotu-
ter, Chicago, Illinois, the session co-chair, asked what drugs
zumab-related serious AE, chest pain and gastroenteritis.
could be combined with elotuzumab. Dr. Lonial answered
The best confirmed responses in 27 evaluable patients by
that the lenalidomide data suggest immune-enhancing
EBMT criteria (with which the study was designed) were PR
effects of IMiDs, so lenalidomide or maybe even pomalid-
or better of 48% and MR or better of 63%. The responses
omide might be interesting for combination therapy; Dr.
using modified Uniform Modified Criteria were slightly
Jakubowiak's data (presented below) suggest that the com-
higher. There were responses seen in patients who had
bination with bortezomib might be able to overcome bort-
prior bortezomib or whose disease was refractory to bort-
ezomib resistance. Dr. Lonial said what happens after CS1
ezomib or their last therapy. Median TTP was 9.5 months
is ligated by the antibody needs to be understood, which
for all patients (n=27) and for bortezomib-naïve patients
could suggest whether alkylating agents, steroids, or other
(n=16).
classes of drugs would be good in combinations.
Dr. Jakubowiak concluded that the combination was well
Dr. Michael Bishop (NCI) asked why dexamethasone was
tolerated. MTD was not reached at doses up to the planned
included if steroids inhibit the immune response by reduc-
maximum dose of 20 mg/kg, and the key toxicities attribut-
ing NK cells, and part of the MOA of elotuzumab is to
able to elotuzumab were infusion reactions. The RR, includ-
enhance NK activity. Dr. Lonial replied that inclusion of
ing responses in bortezomib-refractory disease, and the
dexamethasone was due to practical issues. There is con-
median TTP of 9.5 months are encouraging. Saturation of
cern about down-regulation of NK cell number in the con-
the CS1 target on myeloma cells occurs at doses of 10 mg/
text of lenalidomide plus dexamethasone. Dexamethasone
kg and 20 mg/kg. There may be synergism between elotu-
was not incorporated in the preclinical model, as Dr. Bishop
zumab and bortezomib that will be investigated in further
noted. The effects on NK cells in the phase II expansion
studies.
trial are being evaluated, but data are not available. Dr.
Bishop observed that it is hard to argue with the results, and
Discussion
Dr. Lonial agreed he made a good point.
A participant noted that given that bortezomib is at least
additive to or synergistic with anti-CD20 mAb in lymphoma,
Dr. Andrzej J. Jakubowiak presented Abstract 8003: Elo-
perhaps weekly bortezomib could be used with elotuzumab.
tuzumab in combination with bortezomib in patients
Dr. Jakubowiak said that they are looking at the combina-
with relapsed/refractory multiple myeloma: A phase I
tion compared with bortezomib, and are considering differ-
study.
ent schedules.
The objectives of this study included establishing the MTD
11

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Someone asked if they looked at the kinetics in combination
likely associated with enhancement of immune function
with bortezomib. Dr. Jakubowiak answered that one objec-
and allowing innate anti-tumor activity to contribute to
tive in this study was to look at NK cells from the bone mar-
responses. The use of IMiDs and mAbs in concert may have
row of these patients, which is still ongoing. Synergy was
enhanced efficacy, likely as a result of augmented immune
very clear in preclinical studies, more so than what has been
function, and has been demonstrated in other malignancies.
seen in this clinical study, so they may find reasons for the
Pomalidomide in myeloma has a MOA similar to those of
additive effect not being as pronounced in these patients.
lenalidomide and thalidomide; lenalidomide and pomalido-
RAD001
mide might have more immune-enhancing activity, but this
has not been formally demonstrated. Thalidomide is useful
Dr. Anuj K Mahindra, Massachusetts General Hospi-
as the first novel agent in myeloma; lenalidomide is able to
tal, Boston, Massachusetts, presented Abstract 8032:
overcome thalidomide resistance; can pomalidomide over-
Results of a phase I study of RAD001 in combination
come lenalidomide resistance?
with lenalidomide in patients with relapsed or refrac-
In asking how to make immunotherapy better, Dr. Lonial
tory multiple myeloma.
observed that it is an oncologic irony that myeloma is a dis-
Lenalidomide was added to RAD001, an mTOR inhibitor that
ease that makes too much monoclonal antibody, yet there
does not have single-agent activity in myeloma, to create a
currently is no therapeutic antibody to treat myeloma. There
non-steroid-containing regimen. The phase I trial was con-
are at least 10 potential mAb candidates in clinical devel-
ducted to assess toxicity and determine the MTD as primary
opment, directed against myeloma cell surface antigens or
objectives, and to determine activity of the combination as
growth factors and myeloma-bone marrow microenviron-
a secondary objective. Both drugs were dose-escalated and
ment interaction.
given for 21 days of a 28-day cycle until disease progres-
However, he believes there is cause for celebration: refrac-
sion or DLT. Data are available for 26 patients who had a
tory is the new relapsed; both elotuzumab studies demon-
median of 4 prior lines therapy; 50% had prior lenalido-
strate significant efficacy in the context of refractory disease.
mide; of those, 10 patients relapsed and 3 were refractory.
Other trials show adding panobinostat to bortezomib
DLT included grade 4 neutropenia and thrombocytopenia
overcomes bortezomib resistance; adding elotuzumab to
at 20 mg lenalidomide and 5 mg RAD001, so 15 mg lenalid-
bortezomib overcomes bortezomib resistance, and adding
omide and 5 mg RAD001 for 21 days with a 7-day rest period
pomalidomide to bortezomib overcomes bortezomib resis-
was determined to be the MTD. Common grade 1 and 2
tance. In the last year, studies have shown that vorinostat,
AE, which were manageable with supportive care, included
romidepsin, and even perifosine can overcome bortezomib
nausea, fatigue, dyspnea, diarrhea, constipation, neuropa-
resistance as well. So resistance and refractoriness may need
thy, and muscle cramps. One patient discontinued due to
to be modified, because refractory is not what it was 10 years
RAD001-related non-infectious pneumonitis. Of 19 patients
ago, when all that was available were alkylating agents. The
evaluable for response, 12 received the MTD. A response
median PFS in the trials reported by Jakubowiak and Lacy is
of at least SD occurred in 68% of evaluable patients at a
between 8 and 9 months despite patient populations with
median follow-up of 8.7 months. PFS is 4.3 months. The
refractory myeloma, which is significantly longer than might
authors concluded that the combination, which provides
be expected.
an oral, steroid-free regimen, warrants further evaluation in
phase II studies.
Questions remain, including how much is enough? What are
General Discussion of Newer Agents
the right doses and schedules? Is 5, 10, or 20 mg of elotu-
zumab the right dose? Dr. Lonial said that they hope to have
Dr. Sagar Lonial was the discussant of abstracts 8002
an answer to that question based on the combination trial
and 8003, and called his presentation "The Death and
with lenalidomide he is updating at this meeting. If a dose of
Rebirth of Immunotherapy in Myeloma."
mAb saturates receptors, does over-saturation increase tox-
icity or enhance response? Pomalidomide responses have
IMiD agents (thalidomide and especially lenalidomide)
been seen with 1, 2, or 4 mg in different studies, so is there
demonstrate significant single-agent and combination
a dose-response curve? There may need to be a patient-spe-
efficacy in all phases of myeloma therapy; this activity is
cific dose or trial-specific approach, and the same may apply
12

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to mAbs. Dr. Lonial concluded that new agents are very
are encouraging. The ongoing trial of the 27 mg/m2 dose is
exciting even if they are new versions of old drugs; particu-
critical, as is increasing the dose judiciously to improve the
larly encouraging is activity in high-risk disease. Identifying
quality of the response. Low toxicity has allowed carfilzomib
the intracellular mechanism for synergy should be a high
to be combined with other agents, including lenalidomide.
priority in order to best define combination. It is critical to
It is controversial whether PN is a class effect of proteasome
investigate this with bortezomib combinations because it
inhibitors. There may be important differences between
may give insight into other effective combinations.
the drugs at different sites in nervous tissue. Other second-
generation proteasome inhibitors include NPI-0052, a non-
Dr. Paul Richardson discussed abstracts 8000 and 8001,
peptide-based natural compound with a unique toxicity
Novel proteasome and HDAC inhibitors in myeloma:
profile that has been shown to be active against bortezomib-
The emerging role of novel second generation protea-
resistant cells. A phase I trial is ongoing and has shown both
some inhibitors and HDAC inhibition in myeloma.
tolerability, particularly for a new formulation, and clinical
His key take-home points included the following:
activity. Several other second-generation compounds are
in development, including a second-generation boronate
· Proteasome inhibition has emerged as a highly active
proteasome inhibitor, CEP-18770, which is entering clinical
therapeutic approach for a range of cancers and in par-
trials; and MLN 9708, a high-potency and reversible com-
ticular multiple myeloma.
pound with rapid on/rapid off properties that is orally bio-
· Bortezomib has efficacy as a single agent in myeloma and
available and in phase I trials.
is approved for this indication.
Proteasome inhibition with first-generation bortezomib and
· Second-generation proteasome inhibitors are showing
second-generation proteasome inhibitors constitutes the
promise, with carfilzomib and others in clinical develop-
backbone of myeloma therapy with novel, rational combi-
ment, demonstrating different tolerability profiles and
nations, including HDAC inhibitors, to improve responses.
potentially greater potency.
This reflects the new treatment paradigm of targeting both
· Combination approaches with proteasome inhibitors,
the tumor cell and its bone marrow microenvironment and
specifically bortezomib, and now carfilzomib, have
other complex interactions that lead to resistance. Rational
shown remarkable activity in myeloma, especially when
combinations may be able to target extramedullary disease.
rationally combined with other targeted agents, such
Tailored approaches are now feasible to provide for new,
as IMiDs and HDAC inhibitors, and may help overcome
more specific, and less toxic combinations therapies. Chal-
resistance.
lenges include optimal sequencing, drug resistance, and
side effect management to optimize the therapeutic index
NCCN practice guidelines for myeloma show that the first-
and further improve patient outcome. Myeloma remains
generation novel agents are now used throughout the
incurable and the need for new agents and continued stud-
treatment course of myeloma, and augment the outcome
ies is paramount.
of ASCT. But there is a thorny issue concerning the man-
agement of patients with myeloma that has relapsed on,
The Role of Transplant
or is refractory to, novel agents, portending short survival.
in the Era of Novel Agents
According to Dr. Shaji Kumar, updated data from the Inter-
national Myeloma Working Group (IMWG) suggest an aver-
Dr. Antonio P. Palumbo presented abstract 8015,
age survival in this group of 6 to 9 months, which is dismal
A phase III trial of melphalan/prednisone/lenalidomide
and an area of unmet need.
(MPR) versus melphalan (200 mg/m2) and autologous
transplantation (MEL200) in newly diagnosed myeloma
Carfilzomib is the lead second-generation proteasome inhib-
patients.
itor, in the epoxyketone class, that binds to the proteasome
This study challenges use of ASCT for younger patients with
irreversibly. Bortezomib is a boronate peptide, and the two
the introduction of newer drugs. The aims of the study were
agents have different toxicity profiles. Hydration and low-
safety and efficacy of Rd induction for ASCT, and compared
dose dexamethasone, particularly in the first cycle, have
conventional chemotherapy incorporating a new drug vs.
helped reduce renal toxicity seen in early trials with carfil-
ASCT with a new drug as induction, and examined the role
zomib. The ORR and TTP in the trial presented by Dr. Vij
13

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of lenalidomide maintenance after chemotherapy/ASCT.
Paul Richardson presented abstract 8016 on behalf of
There are no data on maintenance yet.
Kenneth C. Anderson and colleagues, entitled Lenalido-
mide, bortezomib, and dexamethasone in patients with
The study enrolled 402 patients younger than age 65 years.
newly diagnosed multiple myeloma (MM): final results
All patients received Rd for four 28-day cycles as induction;
of a multicenter phase I/II study.
stem cells were collected; patients were randomly assigned
to MPR for six 28-day cycles (n=202) or to 2 courses of
This is an updated analysis of the phase I/II study. The first
MEL200 ASCT (n=200). There was then a second ran-
prospective study of RVD was published in Blood online in
dom assignment to either no maintenance or maintenance
April. It was the first regimen with a 100% response rate.
with 10 mg per day of lenalidomide until progression. The
Data presented here update results with a longer follow-up,
median age was 58 years for both groups.
a median of over 27 months. Phase I was to determine the
MTD/maximum planned dose (MPD); phase II was to deter-
The best response to Rd after 4 cycles (n=370) was: CR
mine the response rates at the MTD/MPD, DOR, PFS, OS,
6%, VGPR 31%, and PR 49%. Rd had a good safety profile,
and toxicity. For patients going on to ASCT, data were col-
with less than 10% neutropenia, 3% thrombocytopenia, and
lected on stem cell collection and engraftment. Important
less than 2% DVT. This is one of the best safely profiles for
characteristics of the study design include administration of
combinations containing novel agents. Within this study, a
bortezomib twice weekly, dexamethasone administration
sub-study compared the use of low-molecular-weight hepa-
on the day of bortezomib administration and the day after,
rin (LMWH; enoxaparin 40 mg per day) vs. aspirin (100 mg
and lenalidomide administration daily for 14 days followed
per day) for prophylaxis of thromboembolic events (TE).
by 7 days off. Aspirin prophylaxis (81 or 325 mg daily) was
Prophylaxis was continued for patients assigned to the MPR
required, anti-zoster therapy was required, an algorithm
arm, and discontinued for patients assigned to the MP arm.
for dose reduction for neurotoxicity and the use of supple-
The incidence of DVT was slightly greater than 1% with
ments was used, and bisphosphonates were permitted. If
LMWH; with aspirin, the combined risk of DVT plus PE
the response was PR or better after 4 cycles, patients could
was about 2.5%. PE was not observed in patients receiving
receive an ASCT. After 8 cycles patients could have main-
LMWH. Stem cell mobilization was adequate using cyclo-
tenance, with the frequency of bortezomib reduced to
phosphamide plus G-CSF.
weekly, lenalidomide continued, and dose reduction or
The response rate after 3 cycles of MPR (n=117) vs. one
elimination of dexamethasone. The study required bone
cycle of MEL200 (n=122) was: CR 13% vs. 16%, VGPR 42%
marrow aspiration and biopsy and radiologic assessments to
vs. 37%, and PR 36% vs. 38%, with no bone marrow con-
determine response.
firmation. There was no difference in PFS after a median
Toxicity was related to high-dose (HD) dexamethasone; HD
follow-up of 14 months. PFS was projected to be 91% at 1
dexamethasone with lenalidomide is problematic, as has
year for both arms, with an OS of 97% to 98%, but this is a
been seen in the ECOG trial. In the phase II portion of the
short follow-up time. Combination therapy with new agents
trial the doses were: 1.3 mg/m2 of bortezomib, 25 mg of
appears to reduce the difference between standard treat-
lenalidomide, and 20 mg of dexamethasone for cycles 1 to
ment and ASCT. By ISS stage, patients with stage 1 appear
4, reduced to 10 mg for cycles 5 to 8. Of the 68 enrolled,
to do somewhat better regardless of treatment. Patients
2 patients with rapidly progressing disease were removed
with high-risk disease, defined as having del 17 or t(4;14)
from the study, so 66 patients were treated, with a median
or t(14;16), appear to respond less well to either treatment
age of 58 years, age range 22 to 86 years. At a follow-up
than patients with standard-risk disease. The major advan-
of almost 4 years, 15% patients remain on treatment, 47%
tage for MPR over ASCT is in AE, with much less hematologic
went on to ASCT, and 59% received 8 or more cycles of all
toxicity, and fewer infections and GI toxicities. The discon-
three drugs together. The most common AE were PN in
tinuation rate is similar between therapies, and there were
most patients, which was primarily grades 1 and 2, revers-
no early deaths. Dr. Palumbo concluded that Rd induction
ible in most, and manageable. Hematologic toxicities were
is effective with an excellent safety profile. Longer follow-up
manageable. The rate of DVT/PE was 6%. Only 1 patient
is needed to assess PFS and OS, and to evaluate the effect
died, unrelated to drug treatment.
of maintenance on patients receiving conventional therapy
vs. ASCT.
Best responses in all 66 patients were CRn/CR 39%, VGPR
or better 67%, at least PR 100%; for the phase II portion
14

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(n=35) the rates were 57%, 74%, 100% respectively.
Dr. Richardson was asked about the best lenalidomide dos-
Response improved with continued therapy in 75% of
ing schedule, and said that they know from phase I and II
patients from cycle 4 to 8, and in 53% of patients beyond
trials of lenalidomide development that alternate-day dos-
cycle 8, with a median time to best overall response of 2.1
ing may be better tolerated but not as effective. In this study,
months. Of the 47% patients that went on to ASCT, stem
the lenalidomide dosing of 3 weeks on and 1 week off was
cell harvesting and engraftment were successful. Updated
developed in phase I trials. The 2 weeks on and 1 week off
outcomes at a median follow-up of 27.3 months show that
for the RVD platform was to avoid overlapping toxicities and
44 patients were alive without PD. Median DOR, median
allow a period of rest. So he thinks lenalidomide dosing is
PFS, and OS were not reached. The estimated 2-year PFS
highly flexible in this context, but daily dosing for a period
is 68%, and the OS is 95%. The one-year landmark analysis
of time matters, and he doesn't want clinicians to think they
of survival by ASCT status showed no difference between
can give lenalidomide however they want. It can clearly be
those who received ASCT vs. those who did not for PFS.
used for a 2 weeks on 1 week off schedule in combination
This is encouraging, but it is early, with a short follow-up.
effectively, and can be used for 3 weeks on and 1 week off in
Although the patient numbers are small, there seem to be
combination with low-dose dexamethasone, and continu-
no differences in quality of response or in PFS according
ously in the maintenance setting.
to cytogenetic abnormalities. There is a difference by ISS:
patients with stage 1 disease do very well, those with stage
Dr. Jean-Luc Harousseau discussed abstracts 8015 and
2 and 3 do not do as well, which is significant and similar to
8016, concerning the role of transplant for myeloma in
results reported by Dr. Palumbo.
the era of novel agents.
Until now ASCT has been shown to be superior to conven-
Dr. Richardson concluded that RVD is highly effective in pre-
tional chemotherapy in at least 7 randomized trials, with 6
viously untreated myeloma, and is the first regimen to yield
trials showing an increased response rate, 5 trials showing
results of a 100% response rate of at least PR, with high rates
an increased PFS, and only 3 trials showing an increased OS
of CR/nCR and VGPR, and promising estimated PFS and OS
because of shorter survival after relapse (the data reflects
with or without ASCT. There are ongoing trials to investi-
some patients who received ASCT after relapse from con-
gate the addition of other agents, e.g., alkylating agents or
ventional chemotherapy). Novel agents used as frontline
anthracyclines. Large phase III trials are ongoing to compare
therapy in the last few years have completely changed the
lenalidomide plus dexamethasone with bortezomib plus
prognosis of elderly patients. The use of novel agents, even
dexamethasone, and RVD after ASCT with other treatments;
in elderly patients, can achieve results comparable or even
a study assessing RVD followed by continuous lenalidomide
better than those achieved with ASCT. In studies of novel
with or without ASCT will be conducted by the partnership
agents used prior to ASCT in 2- and 3-drug combinations,
of the IFM and the Dana-Farber Cancer Institute. Other
the 3-drug combinations are better, and both 2- and 3-drug
studies that are ongoing or planned of novel combinations
combinations are better than standard therapy if the combi-
to reduce toxicity and enhance efficacy will look at HDAC
nations include at least one novel agent. When thalidomide
inhibitors such as vorinostat, and "RVD light," with a weekly
was used as maintenance therapy after ASCT, it improved
schedule of bortezomib in elderly patients.
the greater-than-VGPR response rate and extended the PFS
Dr. Zimmerman noted that there are different schedules
in 4 trials, and increased the OS in 3 of the 4 trials. With
used for dexamethasone dosing. Dr. Richardson said that
Total Therapy (TT), addition of novel agents improves EFS
the rationale for the use of dexamethasone on the day of
and OS.
and day after bortezomib was based on their experience in
These results lead to asking if, in the era of novel agents,
relapsed and refractory myeloma. In the EVOLUTION trial
HD MEL plus ASCT (HDM) should be used. Dr. Harousseau
they used a different schedule, administering weekly dexa-
thinks this question should be answered in the context of
methasone. Dexamethasone presents challenges, and it may
clinical trials to avoid selection bias in the choice of ther-
affect toxicity of bortezomib. PN may have an inflammatory
apy by physicians and patients. The study presented by Dr.
component that dexamethasone may modify, so the lower
Palumbo is the first randomized trial to address this impor-
doses of dexamethasone matter, not just for toxicity in gen-
tant question. The updated results presented at this meet-
eral, but for neurotoxicity. HD dexamethasone is a problem.
ing indicate there is no difference in response rates, PFS,
15

---

or OS. The follow-up is short, so it may not yet be time to
in subgroups of patients, and a large number of patients is
abandon upfront ASCT. Questions raised by this presenta-
needed to assess differences across prognostic subgroups.
tion include the statistical hypothesis and design. The study
The IFM/DFCI trial to start in July will study VRD induction,
may be underpowered to detect a difference between MPR
SC collection, random assignment to VRD, lenalidomide
and HDM due to improved PFS in both arms. Two ques-
maintenance, and HDM at relapse vs. MEL200 ASCT, VRD,
tions were addressed: 1) MPR vs. HDM, and 2) mainte-
then lenalidomide maintenance, and is planned to enroll
nance vs. no maintenance, which results in 4 arms if the
1000 patients, which will allow them to look at prognostic
effect of lenalidomide is not the same after MPR and HDM.
subgroups. He thinks this trial is using the best induction
With only 402 patients it might be difficult to show a benefit
and non-intensive treatments.
of HDM, and it will be impossible to compare MPR with
HDM in some prognostic subgroups. The follow-up is short
Initial Therapy Prior to Transplant
at a median of 14 months, which is too early for OS (and
Dr. Philippe Moreau, University Hospital, Nantes,
because effective salvage treatments exist), and it is also too
France, presented abstract 8014 on behalf of the IFM:
early to determine PFS because lenalidomide maintenance
Comparison of reduced-dose bortezomib plus thalido-
prolongs PFS after either ASCT or non-intense therapy. So
mide and dexamethasone (vTD) to bortezomib plus
currently for MPR vs. HDM the most important information
dexamethasone ( VD) as induction treatment prior to
is the response rate, which has only been evaluated in 239
ASCT in de novo multiple myeloma (MM): results of
patients of the 402 who were randomly assigned, and for
IFM2007-02 study.
which no difference by treatment is seen. The results of the
final analysis by intent-to-treat population are needed.
The rationale of this study was to compare the two best
treatments identified in the IFM 2005-01 and GIMEMA
Is lenalidomide plus dexamethasone the best induction
26866138-MMY-3006 trials, VD and VTD. In this trial, the
treatment prior to ASCT? In the ECOG study, after 4 cycles,
dose of bortezomib was reduced to 1 mg/m2 and the dose
lenalidomide plus low-dose dexamethasone was inferior to
of thalidomide was reduced from 200 to 100 mg/day in an
lenalidomide plus high-dose dexamethasone, which was
attempt to reduce the PN rate. IFM2007-02 enrolled newly
not the case in the study presented by Dr. Palumbo at this
diagnosed patients up to age 65 years (median age about
meeting. However, in other studies, treatment with vTD
58 years) who were randomly assigned to VD (n=99) for
(reduced-dose bortezomib plus thalidomide and dexameth-
four 21-day cycles, or to reduced-dose bortezomib (v)TD
asone presented by Dr. Moreau at this meeting) or VTD
(n=100). ASCT MEL200 followed 4 cycles of induction.
(presented by Dr. Cavo at last year's ASH meeting) resulted
There were more patients with del 17 or t(4;14) in the vTD
in higher response rates before and after ASCT. For the
arm despite stratification by del 13.
non-intensive arm RVD might be a better control given the
After 2 cycles, vTD resulted in 90% at least PR vs. 78% for the
response rates and PFS as reported here by Dr. Richardson.
VD arm, which was significantly higher. After 4 cycles the CR
So is RVD the best non-intensive frontline treatment? This
rate was similar between arms, and the response of at least
question can't be answered without a randomized trial to
VGPR was significantly higher for vTD. After ASCT, the rate
compare non-intensive upfront treatments. The response
of at least VGPR was higher in vTD, 73% vs. 59% with VD,
rates with RVD are unprecedented, treatment was gener-
which is significant. Again, there was no difference in the CR
ally well tolerated except for PN, and the results look better
rate between arms. In previous studies the >/=VGPR rate
than those achieved with lenalidomide plus low-dose dexa-
both after induction and after ASCT was an important goal
methasone (in the ECOG trial) or induction with lenalido-
because it was related to better outcome. In other VTD stud-
mide plus low-dose dexamethasone followed by MPR/HDM
ies, the rate of at least VGPR is comparable, especially after
(in the trial presented by Dr. Palumbo). However, in the
ASCT, and is superior to VD. Stem cell (CD34 positive cells)
RVD trial, 47% of patients went on to ASCT, whereas no
collection was lower with vTD. Collection was not possible
patients did in the MPR/HDM trial, and only 20% of patients
in 21% patients with G-CSF alone as planned (vs. 6% with
in the ECOG trial did. Dr. Harousseau concluded that the
VD). Therefore cyclophosphamide was used, so that in the
results of MPR vs. HDM do not show differences in RR, PFS,
end there was a similar low failure rate (2% vs. 1% with VD).
or OS, and that a longer follow-up is needed before drawing
There was no difference in the recovery of cells and there
a definite conclusion. Upfront ASCT might be useful only
were no toxic deaths in either arm. Toxicity during induc-
16

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tion was similar between the arms except for AE leading to
Dr. Ruben Niesvizky, New York Presbyterian Hospital-
discontinuations related to PN, which occurred only in the
Cornell Campus, discussed sorting through the options
VD arm. There were low rates of other grade 3 and 4 toxici-
for initial therapy of myeloma in light of abstract 8014
ties. One study goal was to reduce the PN rate, and they did
(as well as abstract 8013 in the section on non-trans-
see significantly lower rates of at least grade 2 PN in the vTD
plant-eligible patients).
arm (28%) vs. the VD arm (34%).
The goals of frontline therapy for HD chemotherapy pro-
Dr. Moreau concluded that vTD was more effective than VD
grams in the younger population are induction, consolida-
after induction and after ASCT, with a similar CR rate and
tion, maintenance. This approach has been able to reverse
a better CR+VGPR rate. Decreasing the doses of bortezo-
comorbidities, providing drugs in a non-cross resistant
mib and thalidomide does not decrease the efficacy of the
fashion to maximize response. In the older population this
combination. Cyclophosphamide is needed to collect stem
approach has also been effective for long-term treatment
cells with vTD. The incidence of grade 3 and 4 AE is low and
with induction followed by maintenance therapy using
the rate of grade 2 and 3 PN is dramatically reduced. This
combination treatments. Achieving a meaningful sustained
new triple combination of vTD is superior to VD with good
response of at least VGPR has been shown to contribute to
efficacy and low toxicity.
long-term survival in various phase II and III trials. A new
bar for induction therapy in the last several years has been
In discussing the IFM study, Dr. Michael Wang, MD Anderson
set at 40% CR and over 70% VGPR for comparing future
Cancer Center, Houston, Texas, asked if there is already a
studies. The Arkansas group has shown that in addition to
90% response after 2 cycles, wouldn't the 2 additional cycles
high response rates, DOR of at least 2 years also contributes
not reduce the myeloma but increase PN? If so, then why
to survival. Goals in myeloma therapy should be to achieve
not have induction with 2 to 3 cycles using a higher dose of
a response of at least VGPR, define maintenance regimens,
bortezomib with faster response and lower total dose deliv-
and to understand how to combine proteasome inhibitors,
ered? Dr. Moreau answered that the PR rate is 90% after 2
IMiDs, steroids, and alkylating agents.
cycles, but their goal is not to achieve PR but to achieve
VGPR or better, which is associated with a better outcome.
In the IFM2007-02 study, the effect of vTD is suboptimal
Therefore, 2 additional cycles of induction (4 total cycles)
prior to ASCT. There is a need to address the effect of IMiDs
are needed prior to ASCT, especially with low toxicity.
on SC harvest; Dr. Niesvizky suggested an alternative mobi-
lization regimen, e.g. Mozobil (plerixafor). The impact of
Dr. Joseph Mikhael, Mayo Clinic, Scottsdale, Arizona, said
dose reduction of bortezomib is reduced PN, but the ques-
that this study is important in moving ahead to under-
tion remains whether the response rate can be improved for
standing the correct dose of these agents, including bort-
the 10% of patients with less than PR before ASCT. Dr. Nies-
ezomib. One option is dose reduction of bortezomib with
vizky concluded that induction therapy must be optimized
twice-weekly administration of 1.0 mg/m2, which gives a
to offer a VGPR or better of 70%. It is unclear if the optimal
total dose of 4 mg/m2 (vs. 5.3 mg/m2 with 1.3 mg/m2), or
approach is combination therapy or sequential therapy.
once-weekly bortezomib, as in the GIMEMA study (with a
He cautioned about the benefit of weekly bortezomib; it
total dose of about 4.5 mg/m2). In the long run, will the
is always used in combination, and the results should not
objective be once-weekly dosing with time between doses
be extrapolated to all settings. If a patient has high-risk dis-
to reduce PN, or is it really a dose reduction? What was
ease, he hopes clinicians would use higher doses in a more
the total dose delivered vs. planned? Dr. Moreau said that
intense fashion, i.e., twice weekly.
the answer is different in two different situations: one is in
elderly patients where the goal is to keep patients on treat-
Therapy for Non-Transplant Eligible
ment for a long time with reduced toxicity, so weekly bort-
Patients
ezomib is favored. For patients going to ASCT, the goal is to
lower the tumor burden with induction as fast as possible,
Antonio Palumbo presented Abstract 8013 on behalf of
so twice-weekly bortezomib is preferable. Nearly all patients
Mario Boccadoro and the Italian Multiple Myeloma Net-
in this study received the planned dose of bortezomib in
work, GIMEMA: Bortezomib, melphalan, prednisone,
both arms, except for the four patients who discontinued
and thalidomide ( VMPT) followed by maintenance
in the VD arm.
with bortezomib and thalidomide ( VT) for initial treat-
ment of elderly multiple myeloma patients.
17

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This large randomized trial compared two approaches, the
this population, the discontinuation rate has been 30% to
four-drug approach of VMPT followed by VT maintenance,
40%; here, it was about 15% for VMP and about 20% for
and what has been considered the best standard of care for
VMPT. The discontinuation rate for PN was about 7% for
elderly patients, the three-drug combination VMP with no
both arms. The reduction from twice-weekly to once-weekly
maintenance. The study also investigated the safety and effi-
bortezomib did not decrease the CR rate or PFS compared
cacy of weekly bortezomib. The study included 511 patients
with other studies. The risk of PN decreased from 14% to
older than age 65 years (or younger if they were not trans-
2%, and the discontinuation rate decreased from 16% to 4%,
plant eligible), n=257 for VMP, n= 254 for VMPT to VT.
which was attributed to the reduction in PN; thus efficacy
The median age was 71 years in both groups. The study
was maintained because the cumulative dose was similar.
began with twice-weekly bortezomib, but because the first
139 patients experienced neurotoxicity, the schedule was
Dr. Palumbo concluded that today the best available treat-
modified to weekly bortezomib for both arms and 50 mg
ment option for elderly patients is VMPT followed by VT
per day thalidomide for the VMPT arm. For VT maintenance,
maintenance. This regimen significantly improves PFS in
bortezomib was administered every other week. The results
comparison with VMP. VMPT improves the response rate
are presented in Table 2.
and PFS and increases the CR rate, with 90% of the improve-
ment in CR rate occurring during the induction phase, and
The improvement was mostly in CR rate, which contributes
only 10% of the improvement in CR rate occurring during
to increased survival. Most PR are seen by the first 5 to 6
the maintenance phase. VT maintenance improves PFS
months of treatment, but the majority of CR requires longer
(although the study didn't randomize for maintenance)
treatment, up to almost 1 year. Dr. Palumbo noted that PFS
and prolongs remission duration. Once-weekly bortezomib
is usually around 2 years with the best current treatment,
reduces PN with no change in efficacy, which is a major
and the four-drug combination is increasing the probability
improvement in the safety profile of the VMPT combination.
of remission duration by a year. There was no difference in
OS due to the short follow-up time. He stressed the concept
Discussion
that the issue is not a difference in survival but that probably
Dr. Jakubowiak and Dr. Harousseau both asked about distin-
the median OS will approach 6 years; for elderly patients
guishing between the effects of induction and maintenance.
this is a major improvement over the previous median sur-
Dr. Palumbo replied that there is a question about how long
vival of 3 years.
to treat to increase the response rate. Maintenance does
look important to increase DOR. There is a window within
Grade 3 and 4 hematologic AE included 30% to 35% severe
a given schema to maximize the CR rate; in this setting 9
neutropenia (higher for VMPT), 20% thrombocytopenia,
cycles seems to be the right length because most of the CR
and 10% anemia, all of which are expected for a combina-
rate occurred by 9 cycles.
tion containing an alkylating agent and novel agents. Non-
hematologic AE included 5% PN, 10% infections, and a
Dr. Anderson commented that at ASH he showed that MPR
higher risk of cardiac complications and TE in the VMPT
followed by lenalidomide maintenance also gave good
arm. Aspirin prophylaxis was used. In previous studies in
results, and wondered how to compare his study with VMPT
Table 2. Results of VMPT followed by VT vs. VMP
VMPT to VT
VMP
250 evaluable
253 evaluable
CR
38%
24%
at least VGPR
59%
50%
at least PR
89%
81%
TTNT (median follow-up
69%*
55%*
26.5 months)
PFS (estimated)
54%*
40%*
* differences are significant
18

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followed by VT maintenance. He asked if it was possible to
to melphalan plus prednisone followed by lenalidomide
replace thalidomide here with lenalidomide. Dr. Palumbo
maintenance) fits in the treatment of patients with myeloma
responded that the major contribution of lenalidomide in
who are not transplant candidates. The primary comparison
the MPR-R study is as maintenance; if lenalidomide were
was MPR-R vs. MP, and a secondary comparison done at the
substituted for thalidomide, he would be afraid that neutro-
behest of EMEA, of MPR-R vs. MPR for a stipulated 9 cycles,
penia toxicity would lower the efficacy of the four-drug com-
was to determine if lenalidomide maintenance would really
bination, which he also saw with MPR. This might explain
make a difference in the treatment of patients at least age
the results in the EVOLUTION study in which the four-drug
65 years with newly diagnosed myeloma who were non-
combination (VCRD) was not as good as the three-drug
transplant eligible. At the interim analysis, presented at
combination.
ASH, there was a statistically significant difference between
MPR-R vs. MP (p < .001). The authors concluded that con-
Dr. Barlogie asked a follow-up to Dr. Anderson's question.
tinuous lenalidomide is superior to regimens of limited
He wanted to know if maintenance could be replaced with
duration. They further concluded that MPR-R is superior to
VR, which should be feasible. Dr. Palumbo thought that VMP
MP with higher and more rapid responses, a 50% reduced
followed by lenalidomide maintenance could possibly be
risk of progression, and a favorable safety profile; MPR-R
best. Dr. Barlogie wanted to challenge Dr. Palumbo's con-
should therefore be considered a new standard treatment
clusions about the number of cycles needed to reach CR
option for elderly patients.
when it is defined in terms of M-protein. When response is
measured by MRI, the disappearance of focal lesions may
Dr. Raje discussed the strengths and limitations of the
take 3 or 4 years; the proper techniques, e.g. MRI and PET,
MM-015 study. The strengths included that the regimen is
should be used to measure CR, particularly MRI over time.
orally administered and fairly well tolerated, which is impor-
He proposed that a new yardstick, MRI-defined CR, should
tant for older patients, and those who, being ineligible for
be developed. This lags 8 to 12 months behind immunofix-
transplant, may have co-morbidities. MPR-R offers a signifi-
ation-negative CR. Dr. Palumbo agreed that CR in this study
cant PFS advantage over MP, contributing to the emerging
is defined by M-protein and plasma cell infiltration, so more
theme that lenalidomide maintenance may be a new stan-
sophisticated ways to measure response could change the
dard. Limitations of the study include a short follow-up
conclusion about the time to reach best response.
time, and the lack of difference seen between all three arms
at 9.4 months for PFS. There is no difference in PFS between
Dr. Ruben Niesvizky discussed abstract 8013.
MP vs. MPR, and no OS advantage to date.
In the older population the approach of induction followed
The landscape of therapy for non-transplant-eligible patients
by maintenance therapy using combination treatments has
with myeloma currently includes combinations of thalido-
been effective. In the GIMEMA study, the VMP arm had no
mide, bortezomib, and lenalidomide, as MPT, MPV, MPV-VT,
maintenance. Although the experimental arm meets the
Rd, and MPR-R. MPT has been tested in the largest number
landmarks with CR of 38% and ORR of 89%, the design is
of trials: responses in most studies are close to 60%, OS is
biased because maintenance therapy is used in only one
45 to 50 months, and the advantage of MPT vs. MP has been
arm. The safety profile is good.
confirmed in a meta-analysis. Dr. Raje's overall conclusions
Dr. Noopur S. Raje, Massachusetts General Hospital,
are that MPR-R is certainly one additional strategy in the
Boston, Massachusetts, presented A phase III study to
treatment of newly diagnosed patients with myeloma who
determine the efficacy and safety of lenalidomide in
are not candidates for transplant. The choice of therapy
combination with melphalan and prednisone (MPR)
should be based on patient profile and emergent therapy-
in elderly patients with newly diagnosed multiple
related toxicities such as neuropathy, risk of TE, and renal
myeloma at the ASCO/ASH Joint Session, which was
dysfunction. An emerging theme is that maintenance thera-
selected as an abstract of clinical relevance to clinical
pies are an important adjunct to anti-myeloma therapy.
oncologists that had been presented at ASH 2009 (origi-
Discussion
nally by Dr. Palumbo).
Dr. Douglas Blayney, University of Michigan, Ann Arbor,
Dr. Raje, who was not involved in this trial, felt she gave
Michigan, and ASCO president, observed that at this meet-
an unbiased view about where MPR-R (lenalidomide added
ing lenalidomide maintenance does seem to be an emerg-
19

---

ing theme, but it is a toxic therapy, and it's interesting that
were skeletal related events (SRE) and safety. The median
there is no OS benefit. Dr. Raje responded that the follow-
follow-up was almost 4 years. The basic conclusion is that
up of 9.4 months is short, and that those patients who did
zoledronic acid improved OS by about 5.5 months, which
not receive lenalidomide initially crossed over and then did
is both clinically and statistically significant. There was a
receive some of these new drugs; in myeloma it's become
reduction in the hazard ratio for OS and PFS. Zoledronic
incredibly difficult to see a survival benefit because of all
acid significantly reduced the relative risk of death by 16%
of the treatment options available. In response to a follow-
vs. clodronate, and significantly reduced SREs (24% relative
up question asking Dr. Raje what she recommended, she
reduction, from 35% to 27%). Is the survival benefit due to
said she would take the patient profile into consideration.
an anti-myeloma effect or because of reduced SRE? When
For an elderly patient who prefers an oral regimen, MPR is
analyzed in a Cox model with SRE as a time-dependent
reasonable. For someone with fulminant renal failure who
covariant, the survival benefit was not due to prevention of
needs rapid myeloma control, bortezomib makes sense. For
SREs, but is an anti-myeloma effect.
maintenance therapy, data support maintenance strategies
even though there is no OS advantage. What will need to be
In analyzing AE in the safety population over both inten-
done in the future is to risk-stratify patients and see if there
sive and non-intensive regimens, there were no differences
is a subset of patients that benefits from therapy.
between the two bisphosphonates for acute renal failure,
thromboembolic events, or infections. However, zoledronic
Bisphosphonates and Bone Disease
acid was associated with an increased incidence of osteo-
necrosis of the jaw (ONJ), but it was at the rate of 3.6%,
Gareth Morgan, Institute of Cancer Research, Royal
was generally not acute, and was self-resolving with no sur-
Marsden NHS Foundation Trust, London, United King-
gical intervention (vs. 0.3% rate of ONJ with clodronate).
dom, presented Abstract 8021, Evaluating the effects of
After a median follow-up of 3.7 years, zoledronic acid sig-
zoledronic acid on overall survival in patients with mul-
nificantly prolonged OS and PFS and significantly reduced
tiple myeloma: results of the Medical Research Council
the proportion of patients with SRE compared with clodro-
(MRC) Myeloma IX Study.
nate. Both bisphosphonates were generally well tolerated
This study is a randomized comparison of zoledronic acid
with expected safety profiles. Zoledronic acid might work
vs. clodronate. An important biologic concept in myeloma is
by directly inducing apoptosis in myeloma cells, synergiz-
that the myeloma cells are in close interaction with stromal
ing with chemotherapy, breaking feed-back loop between
cells. An additional loop that is important is the interaction
osteoblasts and stromal cells, and up-regulating the gamma-
between osteoclasts and osteoblasts, which feeds a pro-
delta T cell effect. This is not isolated to myeloma, because
survival loop; treatment that could break the loop might be
there is evidence in other cancer settings that it prolongs
beneficial. The objective of the trial was to ask the question,
survival.
"Can bone-targeted therapy improve survival in patients
Dr. Morgan concluded that zoledronic acid is superior to
with multiple myeloma?" There is preclinical indirect evi-
clodronate for the prevention of SRE in patients with newly
dence (inhibition of bone resorption and angiogenesis,
diagnosed myeloma. Adding zoledronic acid to standard
stimulation of gamma-delta T cell cytotoxicity) and direct
anti-myeloma therapy is generally well tolerated and pro-
evidence (induction of plasma cell apoptosis, modulation of
longs OS vs. clodronate, and the survival benefit is inde-
adhesion molecules, reduced tumor burden in mouse mod-
pendent of SRE reduction. These data further support the
els for zoledronic acid, but not clodronate) for the potential
anti-cancer activity of zoledronic acid and provide evidence
anticancer effects of aminobisphosphonates. There has also
that it should be considered for early integration into treat-
been some clinical evidence for the anticancer effects of
ment regimens in patients with newly diagnosed myeloma.
zoledronic acid and clodronate in myeloma.
Discussion
The MRC Myeloma IX trial design enrolled 1960 patients
receiving either intensive (transplant) or non-intensive
In response to questions, Dr. Morgan said that 70% of
therapy. Within each therapy group patients were randomly
patients had bone disease at baseline, and the benefit of
assigned to either zoledronic acid (n=981) or clodronate
zoledronic acid on SRE and OS was seen in patients with or
(n=979) until disease progression. The primary end-
without bone disease. They will present subgroup analysis,
points were OS, PFS, and ORR. The secondary endpoints
e.g., differences between the older and younger patients or
20

---

between patients in CR vs. those not in CR, at ASH when
vitamin D levels checked because studies have shown that
they have a clean data set. There seems to be an increased
up to 60% to 70% of patients with myeloma at diagnosis
VGPR rate in the elderly patients, suggesting an anti-
are vitamin D-deficient, so replenishing vitamin D is impor-
myeloma effect. Dr. Morgan said in his opinion he though
tant when treating myeloma bone disease. The question is
it would be best to continue zoledronic acid beyond pro-
how much vitamin D to give? This fall the NIH will provide
gression, but they didn't collect those data. The doses used
new recommendations on supplementation. Now there are
in this study have an anti-myeloma effect and are safe, but
no good recommendations. The zoledronic acid prescrib-
giving them more frequently, e.g., every 2 weeks, might not
ing information says to give patients calcium and vitamin
be justifiable on safety grounds. Dr. Morgan said he thinks
D unless they are hypercalcemic. Dr. Roodman pointed out
zoledronic acid is the new standard of care for patients
that the current ASCO guidelines suggest to treat for two
with myeloma.
years, re-evaluate the patient, and consider stopping zole-
dronic acid if the myeloma is in CR or plateau, and to con-
During a discussion of the Education Session on Compli-
tinue treatment if there is active disease. Other guidelines
cations of Myeloma and Myeloma Therapies, session chair
exist. Retrospective data in other malignant diseases suggest
Dr. Todd Zimmerman asked Dr. David Roodman, Univer-
that if treatment with zoledronic acid continues beyond two
sity of Pittsburgh, Pittsburgh, Pennsylvania, who reviewed
years, patients will continue to benefit. The question is how
myeloma bone disease, about the MRC IX trial that included
long to continue, and there is a question about whether
patients with non-lytic bone disease. Treatment of patients
measuring bone resorption markers is useful. In a review
with non-lytic bone disease is not a typical practice accord-
of all trials of zoledronic acid, the response isn't maximized,
ing to ASCO guidelines, so he wanted to know what the
because the bone is an infinite sink for bisphosphonates.
approach would be for patients with osteopenia but not
Although it appears that bone can't be saturated, there is
overt lytic bone disease. Dr. Roodman replied that previ-
now a concern about atypical fractures, the cause of which
ously the ASCO guidelines were clear on not administering
is unclear. Dr. Richardson commented that patients in the
bisphosphonates unless the patient had diffuse osteope-
MRC trial were taking bisphosphonates for more than four
nia or documented bone disease. In the MRC trial, 20%
or five years.
or 25% of those patients had no bone disease. Dr. Morgan
reported that those patients had prolonged OS, like those
Dr. Roodman said that the incidence of ONJ has increased
patients who did have bone disease. This is an exciting
over the last five years in step with the increased use of zole-
result, similar to the situation in patients with breast cancer
dronic acid over pamidronate. Patients who receive pami-
where bisphosphonates, particularly zoledronic acid, are
dronate plus zoledronic acid are more likely to get ONJ
considered as adjuvant therapy in patients on aromatase
than those who receive pamidronate alone. Novartis makes
therapy. Dr. Roodman said he thinks there is a need to see
both drugs and the company reports that after reviewing
the published results and see what the comments by the
3 million patients, the incidence of ONJ is no higher with
reviewers are before everyone is treated with bisphospho-
zoledronic acid than with pamidronate, but Dr. Roodman
nates, because they do have toxicity, although small. No one
said to remember the source of that data. He thinks that the
knows how long to treat with bisphosphonates.
more potent the activity of the bisphosphonate, the higher
the risk of ONJ. However, the incidence has fallen dramati-
Dr. Richardson added that in patients with smoldering
cally with current recommendations for dental prophylaxis,
myeloma (SMM), there have been randomized trials look-
dental hygiene, and follow-up at least in patients with breast
ing at bisphosphonates, and the underappreciated fact
cancer, and anecdotally with myeloma. He used to see ONJ
is that there is a significant reduction of time to first SRE.
once a month in his clinic, but hasn't seen any in the last
In their group, for patients with SMM and osteopenia,
two years with rigorous monitoring. Dr. Richardson agreed
they are comfortable using periodic infusions of bisphos-
that there has been a dramatic reduction in ONJ in his prac-
phonates. Dr. Roodman replied that patients with MGUS
tice. The dental expert he collaborates with believes the
have an increased fracture risk, but they have osteoporo-
reduction could be associated with the more widespread
sis not myeloma bone disease, so they should be treated
use of bortezomib, which activates osteoblasts. This hypoth-
like patients with osteoporosis, e.g., with oral bisphospho-
esis needs to be proven, but it is interesting nonetheless. Dr.
nates. He also pointed out that patients should have their
Roodman replied that the change in incidence in patients
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with breast cancer, who don't receive bortezomib, is the
newly diagnosed myeloma with 1q21 amplification to bort-
same, and probably attributable to better dental hygiene.
ezomib-based PAD induction therapy. To overcome 1q21
amplification as a poor-risk feature, PAD (bortezomib plus
A participant pointed out that data suggest that pamidro-
doxorubicin plus dexamethasone) was tested in a phase II
nate and zoledronic acid are equally effective, so he won-
study in newly diagnosed, SCT-eligible patients. There was
dered why zolendronic acid is being discussed rather than
a good response rate independent of 1q21 amplification
pamidronate, which is available at lower cost. Dr. Roodman
despite the subgroup with 1q21 amplification containing
replied that it was a valid question because pamidronate is
more patients with higher ISS stage disease, so bortezo-
now generic. Zoledronic acid is given in a 15-minute infu-
mib may be preferred as an induction regimen. Follow-up
sion. Pamidronate requires two hours to administer, not
is needed to see if this translates into a PFS and survival
including the time patients need to add to get to the clinic,
benefit.
check in, start the I.V., etc., increasing the total time to 6
hours, so the choice is mostly patient convenience. How-
Dr. Bart Barlogie presented Abstract 8019, Defining the
ever, now there is evidence from both the MRC trial and in
prognostic variables in gene expression profiling (GEP)-
breast cancer that zoledronic acid has the potential for anti-
defined high-risk multiple myeloma (MM): distinguish-
tumor activity, which has never been reported for pamidro-
ing early failures (EF) from sustained control (SC).
nate, although he would like to review the data to confirm
this. That suggests an additional reason to give zoledronic
Dr. Shaughnessy's GEP 70-gene risk model re-identified and
acid over pamidronate. Dr. Richardson mentioned the IFM
repeatedly validated that the 85% of patients with low-risk
study giving pamidronate with thalidomide as maintenance
disease had a superior EFS and OS with TT2, whereas the
therapy. This large randomized trial showed no evidence of
15% of patients with high risk had a median survival of only
survival benefit, which provides other tangential support for
2 years. For TT3, at 6 years 90% of patients are alive and
zoledronic acid over pamidronate.
event free, but the high-risk population shows a median
survival of only 2.5 years, with a subsequent plateau emerg-
Risk Factors
ing. His impression is that as new agents have progressively
been introduced along with new concepts of consolidation
Dr. Orlowski discussed 1q21 amplification as a poor-
and maintenance therapy, the major beneficiary has been
risk feature as presented in posters, Abstracts 8027
the low-risk population, not the high-risk population.
and 8028.
The Kaplan-Meier curves of OS and EFS show a breakpoint
Abstract 8027, first author Dr. John Shaughnessy, University
for patients with high-risk disease at 3 years. The curve is
of Arkansas Medical Center, Little Rock, Arkansas, was titled
steeper before the breakpoint, which Dr. Barlogie calls "early
Outcome with Total Therapy 3 (TT3) compared to Total
failures" (EF), and declines after that point less steeply to
Therapy 2 (TT2): role of gene expression profiling (GEP)
a plateau-like phase that he calls "sustained control" (SC).
70-gene array-defined high-risk disease with trisomy of 1q21
This presentation looked at what distinguishes EF from SC
and activation of the proteasome gene PSMD4. Amplifica-
for patients with high-risk disease. The objectives are now to
tion of 1q21 has already been shown to be a poor prog-
determine, among the 15% patients with high-risk disease
nostic factor. A lower copy number of 1q21 is associated
enrolled in TT2 and TT3 who had gene array data (which is
with a better outcome (EFS and OS). Bortezomib abrogates
the majority of the patients in TT3), if EF and SC subsets can
the effects of 3 copies but not 4 copies. This study looked
be distinguished at baseline by either standard prognostic
at what genes in the 1q21 region might be conferring the
factors or GEP of plasma cells. Biopsy samples are also avail-
high-risk feature and there are some interesting genes with
able to look at the bone marrow microenvironment. The
respect to myeloma in the region, including PSMD4. PSMD4
ultimate goal is to define genes to distinguish EF and SC and
expression is sensitive to 1q21 copy number, and may be a
find new targets of therapy.
biomarker for bortezomib in myeloma. PSMD4 (S5a) may be
involved in proteasome function. This needs further study,
There were 123 patients with high-risk disease in TT2 and
along with the roles of the other genes in the region.
TT3. SC was distinguished from EF by at least a 3-year OS
and, more stringently, at least a 3-year sustained CR vs.
Abstract 8028, first author Dr. David Joshua, Royal Prince
an event within 1 year. A logistic regression analysis was
Alfred Hospital, Sydney, Australia, was titled Response of
22

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performed to segregate EF from SC based on GEP and stan-
by anti-myeloma agents, e.g., MEL and bortezomib, as rapid
dard variables. For the two subgroups within the high-risk
inducers of TP53INP1 to restore myeloma cell sensitivity.
population, there are no differences in standard variables
with more challenging cut-offs, e.g., B2M, albumin, lactate
Erythropoietin Receptors
dehydrogenase (LDH), and cytogenetic abnormalities. How-
on Myeloma Cells
ever, there were differences between EF and SC subgroups
Dr. Pamela S. Becker, University of Washington,
in the GEP median score, which was significantly higher in
Seattle, Washington, was first author of a poster,
the EF subgroup, for both the survival and CR DOR model,
Abstract 8124, entitled Plasma cells from patients
with the shift to an increased score in the EF subgroup
with multiple myeloma express erythropoietin recep-
indicating very high risk. The presence of delTP53 was sig-
tors: potential relevance to pharmacological use of
nificantly more likely in the EF subgroup for the survival
erythropoietin.
model, but not for the CR model. This is supported by the
results of the multivariate logistic regression analysis of vari-
A retrospective study of patients with myeloma showed that
ables linked to EF vs. SC.
the use of erythropoiesis-stimulating agents (ESAs) was an
independent risk factor for reduced survival, even after con-
There are 14 genes that distinguish the EF and SC sub-
trolling for other prognostic indicators in myeloma, with a
groups; 6 are upregulated and 8 are down-regulated.
significant reduction in median survival from 67 moths for
Among the down-regulated genes are a Wnt suppressor, a
no ESAs to 31 months with ESAs.(Katodritou E, et al., Am J
kinase that regulates cell division, and a transcription fac-
Hematol 2008; 83:697-701).
tor involved in B-cell development. Among the upregulated
genes is TP53INP1, which induces TP53-phosphorylation
This study used flow cytometry to analyze patient bone mar-
and TP53-mediated apoptosis, and is located on chromo-
row mononuclear cells for the presence of myeloma markers
some 8q22. The Arkansas group has performed GEP analy-
and the extracellular domain of the human erythropoietin
sis at baseline, and after single-agent therapy, e.g. before
(Epo) receptor (EpoR). Non-erythroid cancer cell lines were
and after thalidomide-dexamethasone in TT2, and 48 hours
also tested for Epo-R expression. The highest expression of
after single-agent bortezomib in TT3, and they are now also
EpoR was seen among myeloma cell lines. The expression
doing GEP after MEL in TT4 and TT5. TP53INP1, when low
of EpoR was detected in 40% of patient myeloma cell sam-
before treatment, was upregulated after bortezomib, VTD-
ples (n=32), but was not detected on lymphocytes from the
PACE, or MEL.
same patients. Expression studies are in progress in bone
marrow cells from patients with other hematologic malig-
In conclusion, Dr. Barlogie said that compared with SC, EF
nancies and in normal bone marrow samples. Signal trans-
is characterized by higher GEP70 risk scores ("super risk"),
duction could be detected through the EpoR in the U266
and lower delTP53 scores. Among 14 EF- vs. SC-discrimi-
myeloma cell line within 5 minutes of stimulation, and will
nating genes, TP53INP1 is of particular interest, because
be studied in primary patient myeloma cells. They also want
over-expression in SC is linked to apoptosis and better clini-
to look at RNA expression and correlate that to cytogenetics
cal outcome. TP53INP1 is rapidly inducible by melphalan
in newly diagnosed vs. relapsed, refractory myeloma. These
and bortezomib in patients with low levels of expression.
studies may elucidate the tumor progression associated
Therefore, it is not only a biomarker, but a therapeutic
with ESA administration to patients with cancer.
target. Issues under study include the development of a
"super high-risk" model; examination of the potential for
super high risk among poorly performing outliers in low-
risk myeloma; and the role of the model in predicting post-
relapse survival. They are also planning to examine the
super high-risk-associated genes in the context of molecular
subgroups; and to determine the bone marrow microenvi-
ronment-unique genomic features of EF vs. SC. In addition,
they want to examine modulation of super high-risk genes
23

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International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
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