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ASCO 2010
Highlights
for Patients
Compiled by Lynne Lederman, PhD
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ASCO 2010 Myeloma Highlights for Patients
Introduction
stem cell transplant (ASCT) for multiple
The 46th Annual Meeting of the American
myeloma (MM).
Society of Clinical Oncology (ASCO) was held
There is a need for maintenance therapy because
from June 4 through June 8, 2010, in Chicago,
induction therapy followed by autologous stem
Illinois. This year's education sessions on myeloma
cell transplant (ASCT) alone reduces the number
addressed older patients with lymphoma and
of myeloma cells, but does not cure the disease for
myeloma and complications of myeloma and
most patients with myeloma. The Cancer and
myeloma
therapies.
The
clinical
science
Leukemia Group B (CALGB) 100104 clinical trial
symposium
presented
novel
therapies
for
included patients younger than age 70 years who
myeloma. The lymphoma and plasma cell
were treated with at least 2 months of induction
disorders poster discussion concerned personalized
(initial) therapy to which they had a response of at
therapy and new agents in myeloma, and included
least stable disease (SD). Patients were also 1 year
two main themes: 1) improving on the efficacy of
or less from the start of therapy, and had adequate
lenalidomide (Revlimid®) with or without
numbers of stem cells (SC). Patients received one
dexamethasone, especially for relapsed and/or
round of high-dose (HD) melphalan followed by
refractory myeloma, and 2) 1q21 amplification as
autologous stem cell transplantation (MEL200
a poor-risk feature.
ASCT), then were restaged 90 to 100 days after
recovery. Patients who had a response of SD or
The most encouraging developments presented at
better were randomly assigned to receive placebo
this meeting include the following:
(inactive pill) or to lenalidomide at 10 mg per day,
Lenalidomide maintenance therapy
which could be increased to 15 mg/day or
decreased to 5 mg/day as tolerated. The study also
Progress in the development of new anti-
took into account the patients; beta 2
myeloma agents
microglobulin (B2M) levels, which is a risk factor
The role of transplant in the era of novel
and whether patients had received lenalidomide as
agents
induction therapy. The objectives of the study
were to determine if lenalidomide prolonged time
Identification of risk factors
to progression (TTP) following ASCT. The study
Anti-myeloma effects of zoledronic acid
was designed to detect an increase in TTP from 24
(Zometa®)
months to 33.6 months. Secondary objectives
included the rate of complete remission (CR)
post-ASCT, progression-free survival (PFS),
LenalidomideBased Maintenance Therapy
overall survival (OS), and how practical it was to
give lenalidomide for long-term maintenance.
CALGB 100104 A phase III randomized,
doubleblind
study
of
maintenance
In November, 2009, results were analyzed for 418
therapy with lenalidomide (CC5013) or
patients, half randomly assigned to either
placebo following autologous stem cell
lenalidomide or placebo. Patients receiving
lenalidomide for maintenance therapy generally
transplantation for multiple myeloma.
had more serious side effects, the most significant
Dr. Philip L. McCarthy, Roswell Park Cancer
of which were decreased white blood cell counts,
Center, Buffalo, New York, presented Abstract
and to a lesser extent, decreased numbers of red
8017 on behalf of CALGB, ECOG, and BMT
blood cells and platelets. Patients who received
CTN (Blood and Marrow Transplant Clinical
lenalidomide also had higher rates of infections.
Trials Network). The original title was Phase III
The use of lenalidomide was associated with a
intergroup study of lenalidomide versus placebo
longer TTP, and fewer deaths. The follow-up is
maintenance therapy following single autologous
3
not long enough to determine a difference in OS.
or better after ASCT. This suggests that the major
In December, 2009, the study was unblinded, that
role for thalidomide was to reduce residual
is, it was revealed which patients received
myeloma that was still present after ASCT rather
lenalidomide vs. placebo. This allowed patients
than to prolong the duration of CR or VGPR.
who received placebo to then receive lenalidomide.
This result could be explained by the high rate of
Those
patients
treated
with
lenalidomide
peripheral neuropathy (PN) that shortened the
maintenance therapy do better regardless of their
duration of thalidomide treatment.
B2M level or whether they had previously been
Therefore, the IFM designed the trial reported on
treated with thalidomide or lenalidomide. For
here, IFM 2005-02 phase III randomized trial, to
those who received prior thalidomide, the benefit
determine if lenalidomide could be safe and
of lenalidomide maintenance is not seen early on,
effective when administered for a long time.
but develops over time.
Lenalidomide is an oral agent, so administration is
Dr. McCarthy concluded that maintenance with
convenient, and it is known to be active in
lenalidomide vs. placebo significantly prolongs
myeloma when HD therapy had failed, and is less
TTP. There is no difference in OS at a median
likely to be associated with PN than other drugs.
follow-up of 1 year post-ASCT. Lenalidomide
The IFM 2005-02 trial included 614 patients
prolonged TTP regardless of B2M level or prior
younger than age 65 years with non-progressive
thalidomide or lenalidomide induction therapy.
disease within 6 months of ASCT as their first
The side effects associated with lenalidomide
therapy. Patients received 2 months of treatment
maintenance therapy were not severe.
(consolidation) with 25 mg/day of lenalidomide,
then were randomly assigned to maintenance
Lenalidomide
maintenance
after
therapy with either placebo or 10 to 15 mg/day
transplantation for myeloma: first interim
lenalidomide. The primary endpoint was PFS; the
analysis of a prospective randomized study
secondary endpoints were CR rate, TTP, OS, and
feasibility of long-term lenalidomide therapy. In
of the Intergroupe Francophone du
December, 2009, the results were examined.
Myélome (IFM 200502 trial)
For
patients
treated
with
lenalidomide
Dr. Michel Attal, Hôpital Purpan, Toulouse,
consolidation both CR and VGPR rates increased,
France, presented Abstract 8018 on behalf of the
although not significantly, and PFS doubled,
IFM.
which was significant. The benefit of lenalidomide
Relapse of myeloma after single or double ASCT
maintenance was observed in all of patients
occurs because this treatment does not destroy all
regardless of the initial response, B2M levels,
myeloma cells, leaving behind what is known as
presence or absence of del 13, or type of induction
residual myeloma. The ideal maintenance
therapy. Longer PFS was seen in patients who
treatment is not known. What is known is that
received lenalidomide maintenance or had a
maintenance with conventional chemotherapy,
response of VGPR or better after ASCT or
interferon, or corticosteroids is not effective.
consolidation. Therefore, even with effective
Thalidomide maintenance after ASCT increases
maintenance therapy, having a response of VGPR
the rates of CR, event-free survival (EFS) or
or better is still predictive of a better outcome.
progression-free survival (PFS), and OS. In a
Lenalidomide maintenance was well tolerated.
previous trial conducted by the Intergroupe
Similar numbers of patients had side effects or
Francophone du Myélome (IFM), the benefit of
discontinued from the study for each treatment
thalidomide was not seen if a part of chromosome
group, although more patients treated with
13 was missing [deletion 13 (del 13)] or if the
lenalidomide had decreased numbers of white
response was a very good partial response (VGPR)
blood cells. The OS for both groups was similar
4
after 3 years from the beginning of the study,
because, at least for areas of the world where cost
which was 4 years after diagnosis. Dr. Attal said
is an issue, thalidomide is much cheaper.
that the survival rates 80% to 88% are higher than
Dr. Giralt noted the similarities of these two
has been seen in all previous IFM trials.
studies, which involved young patients receiving a
Dr. Attal concluded that maintenance with
single ASCT. In the IFM study, 10 to 15 mg/day
lenalidomide was well tolerated, resulted in a low
lenalidomide is administered until relapse with
discontinuation rate due to severe side effects, and
dose modification for toxicity. He thought the
caused no increased risk of serious blood clots
best responses were somewhat disappointing, with
[deep vein thrombosis (DVT)] or PN. Longer
CR of 25% in the lenalidomide arm, but 77% of
follow-up is required to see the effect of
patients had at least VGPR. What is most
lenalidomide on OS. The final analysis of this trial
important is that the benefit of lenalidomide is
is expected in August, 2010.
seen regardless of the response to transplant.
Lenalidomide maintenance cancels the bad effects
Formal Discussion
of del 13. The response after consolidation is the
most important factor for determining outcome.
After the presentations, Dr. Sergio Giralt,
The most important side effect is decreased white
Memorial Sloan-Kettering Cancer Center, New
York, New York, discussed these two studies
blood cells counts, and it will be interesting to see
(abstracts 8017 and 8018) in a presentation
why this was significantly lower than in the
entitled: Post-transplant maintenance therapies.
CALGB study and to see if they were monitoring
What do these studies mean for the practicing
more often or if it was due to the pre-ASCT
physician?
induction regimen. The most important message
is that as of today, there is no survival benefit for
Dr. Giralt said that these are two of the most
lenalidomide maintenance, and this needs further
important presentations in myeloma in the last
study.
couple of years. The question is now what to do in
The CALGB study also showed that the PFS was
the clinic based on the results presented at this
better with lenalidomide maintenance, with no
meeting. The goals of treatment should be to
benefit for OS. This trial also showed that the
provide patients with the longest life and best
benefit of lenalidomide is seen regardless of
quality of life (QoL) with a minimum burden of
whether thalidomide or lenalidomide were used
therapy. Maintenance is important in myeloma
for induction. Decreased white blood cells counts
therapy because induction therapy followed by
were significant side effect. Because there was a
ASCT alone will reduce the number of myeloma
significant increase in fever associated with
cells but will not cure most myeloma. He thinks
decreased white blood cells counts, this therapy
maintenance therapy should be called "post-
should be monitored when it is used in the
transplant continuous therapy." Post-transplant
community to prevent severe side effects, such as
therapy is active treatment, as it implies further
severe, general infections.
reduction of myeloma cells, may involve more
effective drugs, and is not seen as long-term
If the goal of treatment is to delay progression of
treatment. The maximum time this treatment can
myeloma, patients should probably receive
be given should be investigated. Post-transplant
lenalidomide maintenance whether they are in CR
therapy generally shows a benefit for thalidomide
after ASCT, or there is residual disease after
in PFS and OS, although side effects are an issue.
ASCT. However, maintenance therapy may not
Thalidomide maintenance might need to be
prolong survival. Other important questions to
compared
with
lenalidomide
maintenance,
answer include what is the role of consolidation
post-transplant, how long should maintenance be
5
given, and what is the role of transplantation in
New AntiMyeloma Agents
the era of novel therapies?
A trial is planned to answer the questions, "What
Progress is being made in the development of new
is the best consolidation regimen for patients
therapies for myeloma. Some of these are second
undergoing a single ASCT in the context of
and third generations of already approved classes
lenalidomide
maintenance?
Should
patients
of
anti-myeloma
agents,
e.g.,
proteasome
receive a second ASCT, or nothing at all, or 4
inhibitors,
e.g.,
bortezomib,
and
cycles of lenalidomide plus Velcade (bortezomib)
immunomodulatory
agents
(IMiDs),
e.g.,
and dexamethasone (RVD)?" Lenalidomide
thalidomide and lenalidomide. Others represent
maintenance is planned for 3 years, and it will be
classes that may have been approved for other
interesting to compare the results to 1 year of
cancers, e.g., histone deacetylase (HDAC)
maintenance or maintenance until myeloma
inhibitors, and mTOR (mammalian target of
progression.
rapamycin)
inhibitors.
Yet
others,
e.g.,
monoclonal antibodies (mAbs) may be designed
Dr. Giralt concluded that both studies show that
specifically to treat myeloma.
lenalidomide prolongs TTP when compared with
placebo, with no OS benefit, although follow-up
is short. An OS benefit may not be seen because
Pomalidomide
when the trials were unblinded, patients who had
not received lenalidomide maintenance could
Dr. Martha Lacy, Mayo Clinic, Rochester,
receive it. There is a lenalidomide benefit
Minnesota, presented Abstract 8002: Activity of
regardless of B2M, abnormal chromosomes, type
pomalidomide plus dexamethasone (Pom/dex) in
of induction therapy, or response to initial
dual lenalidomide/bortezomib-refractory mul-
therapy. Neither study addresses issues of duration
tiple myeloma (MM).
of therapy, if there is a benefit for patients in CR
after ASCT, the effect of early vs. late treatment,
Pomalidomide is a novel IMiD derived from
or the effect of the depth of CR. It is also not
thalidomide. Although similar to thalidomide and
possible to determine yet who would and who
lenalidomide, pomalidomide has a different
would not need maintenance.
clinical
efficacy
and
side
effect
profile.
Dr. Giralt also said that thalidomide maintenance
Pomalidomide plus dexamethasone has shown
should be considered. It is essential for the global
activity in patients with relapsed myeloma and
community, because thalidomide is what will be
myeloma that dose not respond to lenalidomide
available in the developing world. The best post-
(lenalidomide-refractory disease).
transplant therapy is an open question. There is
This phase II trial of pomalidomide plus
also a need to figure out the best way to measure
dexamethasone in relapsed myeloma refractory to
residual disease. Dr. Giralt said that if there is any
both lenalidomide and bortezomib (defined as
sign of residual disease after ASCT, he
progression on or within 60 days of last therapy)
recommends
they
go
on
lenalidomide
measured response rates (RR) and side effects.
maintenance. If the response was CR but patients
Patients
received
2
mg
pomalidomide
have high-risk disease, he recommends they go on
continuously every day and 40 mg dexamethasone
lenalidomide maintenance. For the few patients
once a week. Patients also received 325 mg aspirin
with low-risk disease who do not have a lot of
daily to prevent blood clots, although investigators
myeloma cells, maintenance can be discussed with
could administer full-dose anticoagulant if they
their healthcare provider. He wouldn't switch
thought it necessary. If there was no response or
patients on thalidomide maintenance who tolerate
progressive disease after 2 cycles, the dose of
it well to lenalidomide.
pomalidomide could be increased to 4 mg.
6
Of the 35 patients enrolled, there were 15 patients
is very rapid, and he wondered if Dr. Lacy
with high-risk myeloma by mSMART (Mayo
thought there are enough data to be certain. If the
clinic) criteria. The median number of prior
response is really so rapid, it would be the best
treatments was 6 regimens, and all patients had at
treatment to be given up front. Dr. Lacy said she
least 3 prior regimens, including 100% prior
suspected it would be very effective up front. Dr.
lenalidomide and bortezomib (by definition), and
Barlogie then commented that when his group
most had received thalidomide and ASCT. Dose
treats patients with everything available using
reductions were both per protocol and for side
TT3, the median time to CR is 6 to 8 months,
effects, primarily decreased white blood cell counts
and it's gradual, so what Dr. Lacy is seeing in this
(neutropenia). The median follow-up was 5
trial may be due to small numbers of patients. He
months, at which time 66% of patients
wanted to warn about high- vs. low-risk and
experienced no progression.
incidence of remission. He thinks the issue for
Neutropenia was the major serious side effect
patients with high-risk disease is not remission but
concerning the blood in 34% of patients; side
rather durability of response. He doesn't think
effects not affecting the blood were not common,
there are data showing that patients with high-risk
and included one event of blood clots. Mild to
disease do less well with initial response. Dr. Lacy
moderate neuropathy occurred in 5 patients. Four
agreed. DOR with high-risk disease is hugely
of the five patients had neuropathy at the time
important, but in their experience, once relapse
they entered this study that worsened with
occurs, it's hard to get the disease into remission.
treatment.
Dr. Lacy said that the median follow-up was not
long enough to look at TTP in high- vs. standard-
The RR of confirmed PR or better was 26%, and
risk disease.
of minimal response (MR) or better was 54%.
There was no difference in best response for
patients with high compared with standard risk
Carfilzomib
factors (determined by mSMART). Of nine
patients with stable disease(SD) who received an
Dr. Ravi Vij, Washington University School of
increased dose of pomalidomide, one had an
Medicine, St. Louis, Missouri, presented Abstract
increased response. The median time to response
8000: Results of an ongoing open-label phase II
(TTR) was 1 month and duration of response
study of carfilzomib in patients with relapsed
(DOR) and OS have not yet been reached. PFS
and/or refractory multiple myeloma.
was 8.0 months.
Carfilzomib is a novel, selective proteasome
Dr. Lacy concluded that the pomalidomide plus
inhibitor with highly selectable and irreversible
dexamethasone combination had significant
proteasome binding and target inhibition and
activity in lenalidomide- and bortezomib-
minimal
off-target
activity.
It
overcomes
refractory myeloma. Responses were rapid. Side
bortezomib resistance and has not been associated
effects were manageable and were mostly
with nervous tissue damage or neutropenia in
decreased white blood cell counts. Further studies
animal studies.
are ongoing to see if starting with a 4-mg dose of
pomalidomide will result in higher response rates.
The PX-171-004 trial enrolled 155 patients with
relapsed or refractory myeloma following 1 to 3
prior treatment regimens. Two groups of patients
Discussion
were enrolled. The first group consisted of 34
Dr. Bart Barlogie, University of Arkansas for
patients who had received bortezomib previously
Medical Sciences, Little Rock, Arkansas, pointed
and 53 patients who had not. The second group
out that the median time to response of 1 month
included 53 patients who had not received
7
bortezomib. These numbers refer to patients who
Discussion
could be evaluated at the end of the trial. The first
A participant pointed out that in bortezomib-
group was treated with 20 mg/m2; the second
resistant disease, the responses are lower but the
group received a dose of 20 mg/m2 in cycle 1 that
TTP is equal to that in bortezomib-responsive
was increased to 27 mg/m2 in subsequent cycles.
disease, and asked why. Dr. Vij responded that he
ORR, clinical benefit response (CBR), defined as
can't say why the response is lower, but the
at least MR, and median TTP were highest for the
durability of response is encouraging even in this
second group of patients and lowest for the
patient population. Someone asked why, given the
patients in the first group who had previously
mild side effect profile and the increasing
received bortezomib. Nearly half of the patients
responses observed with increasing doses, the dose
had mild to moderate neuropathy when they
was not increased beyond 27 mg/m2. Dr. Vij said
enrolled in the study, and occurred in 12% to
that in phase I trials, two different dosing
17% of patients during the study; a few patients
regimens were tested. What was thought to have
developed more serious neuropathy. The highest
been side effects affecting the kidney could also
rates of neuropathy occurred in bortezomib-
have been the result of tumor lysis syndrome, a
treated patients. The most common side effects
serious condition resulting from rapid destruction
included manageable, mild to moderate fatigue,
of cancer cells. It could also have been due to
nausea, difficulty breathing, and decreased blood
generalized infection, myeloma disease, or the
counts. There were 5 on-study deaths, 2 due to
drug, so the choice of dose was conservative. Now
progressive disease, 2 due to study treatment, and
it is known that patients with solid tumors have
1 unrelated to treatment. At follow-up about 25%
received 70 mg/m2 via a 30-minute infusion.
of patients remain on trial, about 25% have been
Doses of 36 and 45 mg/m2 are tolerable in
treated with the full 12 cycles, and 9% (n=14) are
myeloma patients. Perhaps higher doses with
on an extension protocol.
longer infusion times would result in a side effect
Dr. Vij concluded that single-agent carfilzomib
profile that is no different from that seen with
shows significant activity in relapsed or refractory
lower doses and might improve the response rate.
myeloma; although responses were seen in
bortezomib-treated patients, responses were higher
Vorinostat
in patients who had not been treated with
bortezomib, with durable responses in all
treatment groups. Preliminary results suggest
Dr. Paul Richardson, Dana-Farber Cancer
Institute, Boston, Massachusetts, presented the
higher response rates with higher doses. Side
poster, Abstract 8031: Phase I study of combined
effects were generally mild and clinically
vorinostat
(V),
lenalidomide
(L),
and
manageable. Severe PN was rare and does not
dexamethasone (D) in patients (pts) with
limit therapy despite pre-existing symptoms.
relapsed or refractory multiple myeloma (MM).
Carfilzomib was tolerated for at least 12 cycles.
The lack of significant side effects suggests that
At this time, all data are preliminary, but they
carfilzomib could be used in combination with
suggest vorinostat, a histone deacetylase (HDAC)
other anti-myeloma agents, and combinations are
inhibitor, combined with lenalidomide and
being tested. This trial is ongoing at a dose of 27
dexamethasone may be a convenient, effective,
mg/m2. In other trials in solid tumors, carfilzomib
and generally well-tolerated oral regimen for
has been administered in doses up to 70 mg/m2
patients with relapsed or relapsed and refractory
using slower infusion rates.
myeloma, including those who have received prior
lenalidomide therapy. There were no treatment-
8
related deaths and no maximum tolerated dose
mg panobinostat 3 times a week with 1.3 mg/m2
reported. A phase II study is planned.
bortezomib. Two groups that included a total of
17 patients were given this dose.
Discussion
Side effects included a high rate of seriously
Dr. Robert Orlowski, University of Texas, MD
reduced platelet counts, which was manageable
Anderson Cancer Center, co-chair of the
with changing the dose and/or transfusions of
Lymphoma and Plasma Cell Disorders Poster
platelets. Decreased numbers of white and red
Discussion, discussed this poster. He observed that
blood cells also occurred. Other side effects were
this study enrolled patients with a median of 4
primarily related to the digestive system as well as
prior lines of therapy, so they were further along
fatigue and weakness, and were mostly mild to
in the disease process than those in the study of
moderate. The combination was associated with
combination panobinostat reported by Dr.
minimal serious PN, and there was no dose-related
Mateos, which is discussed below. Of the 31
effects on the heart of the type that have been
patients, the majority had received prior
reported with other HDACs.
thalidomide and/or lenalidomide, most had at
least SD, that is, experienced a clinical benefit, and
Responses were seen even at the lowest doses.
the response rate of at least PR in about half of the
About three-quarters of the patients receiving the
patients is encouraging. Responses in patients who
highest dose had a clinical benefit response. ORR
had received lenalidomide and in patients whose
was 70% for all 47 patients, and was 60% for
disease was lenalidomide-refractory suggest that
patients whose disease didn't respond to
vorinostat may help overcome resistance.
bortezomib. Panobinostat side effects limited the
time many patients stayed on therapy.
Dr. Anderson concluded that oral panobinostat
Panobinostat
can be safely combined with bortezomib and
dexamethasone, and that this is among the most
Dr. Kenneth Anderson, Dana-Farber Cancer
active combinations in bortezomib-resistant
Institute,
Boston,
Massachusetts,
presented
myeloma. Future directions include a large,
Abstract 8001 on behalf of Jesus San-Miguel and
their colleagues: Phase Ib study of oral
international, randomized phase III trial of
panobinostat
(LBH589)
plus
intravenous
bortezomib plus panobinostat vs. bortezomib
bortezomib in patients (Pts) with relapsed (Rel)
(PANORAMA 1) in relapsed myeloma that is
or Rel and refractory (Ref) multiple myeloma
ongoing, and in the US a phase II trial of
(MM).
bortezomib plus panobinostat at the maximum
tolerated dose (PANORAMA 2) in patients with
Panobinostat,
another
histone
deacetylase
relapsed and bortezomib-refractory myeloma.
(HDAC) inhibitor, has limited activity as a single
agent, so it is being tested in combination with
Dr.
María
Victoria
Mateos,
Hospital
other anti-myeloma drugs.
Universitario de Salamanca, Salamanca, Spain
The LBH589B2207 study of increasing doses of
presented poster Abstract 8030: Phase Ib study of
oral panobinostat (LBH589) + lenalidomide
panobinostat enrolled 47 patients with relapsed or
(LEN) + dexamethasone (DEX) in patients (Pts)
relapsed and refractory myeloma. Panobinostat
with relapsed (Rel) or Rel and refractory (Ref)
was given three times a week every week,
multiple myeloma (MM).
bortezomib was given on the "classic" schedule for
2 weeks on and 1 week off, and dexamethasone
Dr. Robert Orlowski, co-chair of the Lymphoma
was given on the day of and the day after
and Plasma Cell Disorders Poster Discussion,
bortezomib. The maximum tolerated dose was 20
9
Personalized Therapy and New Agents in
8020,
Elotuzumab
in
combination
with
myeloma, discussed this poster.
lenalidomide and low-dose dexamethasone in
relapsed or refractory multiple myeloma: a phase
High-dose dexamethasone plus lenalidomide and
I/II study.
oral panobinostat was administered on an every-
other-day schedule to the 46 patients enrolled.
The presentation was an update of data presented
Patients with primary refractory myeloma
at ASH, 2009. Elotuzumab is a monoclonal
(myeloma that didn't respond to the first
antibody (mAb) that has been designed to
treatment) were excluded. About half of the
resemble a human antibody of the IgG1 type. It
patients had myeloma that was refractory to last
targets CS1, a modified protein that occurs in
line of therapy; only 17% of them had prior
large amounts on the surface of myeloma cells. It
lenalidomide. There was a 48% response of at
occurs to a lesser extent on one type of immune
least MR, but none of these were in patients in the
cell, natural killer (NK) cells, and occurs to little
lenalidomide-refractory group.
or no extent on normal cells or tissues. Preclinical
Hematologic
side
effects
were
commonly
studies (studies in cells, tissues, or animals, which
observed, with about half of patients having
are done before drugs are tested in people) suggest
serious reductions in white blood cell or platelet
that elotuzumab works by attaching to myeloma
counts. There were 7 deaths, three of which were
cells and helping natural killer (NK) cells to
suspected of being treatment-related; 10 patients
destroy the myeloma cells. As a single agent it has
discontinued due to side effects. Dr. Orlowski
a safety profile that resembles that of other mAbs.
thinks this is a high rate of deaths, comparable to
Elotuzumab side effects are mostly infusion-
those seen in the study combining lenalidomide
related reactions, and responses have been mostly
with high-dose dexamethasone. Future studies will
SD. Combination studies in cells showed
use a lower dose of dexamethasone and less
increased activity when elotuzumab is combined
frequent administration of panobinostat.
with lenalidomide.
The study objectives for the phase Ib portion of
this trial were to determine the maximum
Dr. Melissa Alsina, H. Lee Moffitt Cancer
tolerated dose of elotuzumab in combination with
Center and Research Institute, Tampa, Florida,
presented poster Abstract TPS308 (Trials In
lenalidomide and low-dose dexamethasone. The
Progress Session), PANORAMA 2: A phase II
phase II primary objective was to evaluate the
study of panobinostat (LBH589) in combination
safety and efficacy of two doses of elotuzumab,
with bortezomib (BTZ) and dexamethasone
either 10 or 20 mg/kg, and to determine the best
(DEX) in patients with relapsed and BTZ-
treatment to give prior to elotuzumab to prevent
refractory multiple myeloma.
infusion-related reactions. In this phase, 60
additional patients with advanced disease were
The design of this study was presented. It is
enrolled and those with prior lenalidomide
enrolling approximately 47 patients in the US to
treatment were excluded. In phase Ib, doses of
determine, in part, if this combination can
elotuzumab were 5, 10, and 20 mg/kg in
overcome bortezomib resistance in a population
combination with 25 mg lenalidomide and low-
with an unmet medical need.
dose dexamethasone. For the first 2 weeks,
elotuzumab was given weekly; then it was given
every other week until disease progression
Elotuzumab
occurred. The phase I portion of the study was
originally supposed to end after 6 months, but
Dr. Sagar Lonial, Emory University School of
based on favorable responses, it was amended to
Medicine, Atlanta, Georgia, presented Abstract
continue to progressive disease (PD).
10
In the phase Ib portion, 28 patients were treated,
alkylating agents, steroids, or other classes of drugs
and 12 are still on study. There were no dose-
would be good in combinations.
limiting toxicities. The side effects were similar to
Dr.
Michael
Bishop
(NCI)
asked
why
those seen in lenalidomide trials except for
dexamethasone was included if steroids inhibit the
infusion reactions thought to be related to
immune response by reducing NK cells, if part of
elotuzumab, which occurred in 2 patients. The
the way elotuzumab works is to enhance NK
ORR was 82% for all 28 evaluable patients and
activity. Dr. Lonial replied that inclusion of
95% for the 21 patients who had not received
dexamethasone was due to practical issues. There
lenalidomide; VGPR rates were 25% and 27%.
is concern about lenalidomide plus dexamethasone
Responses are improved over those reported at
decreasing
the
number
of
NK
cells.
ASH, and are relatively independent of prior
Dexamethasone was not used in the preclinical
treatment with lenalidomide, thalidomide, or
model. The effects on NK cells in the phase II
bortezomib. TTP was not reached at a follow-up
expansion trial are being evaluated, but results are
of a median of 8 months. After initiation of new
not available. Dr. Bishop observed that it is hard
premedication treatments, there were no serious
to argue with the results, and Dr. Lonial agreed he
infusion reactions in the phase II expansion trial.
made a good point.
Enrollment is continuing. Analysis of bone
marrow-derived myeloma cells from patients in
the phase II expansion group show that
Dr. Andrzej J. Jakubowiak presented Abstract
elotuzumab binds to all the CS1 present on the
8003:
Elotuzumab
in
combination
with
myeloma cells at both doses.
bortezomib in patients with relapsed/refractory
multiple myeloma: A phase I study.
Dr. Lonial concluded that elotuzumab plus
lenalidomide plus low-dose dexamethasone has a
The objectives of this study included establishing
manageable safety profile in the phase Ib trial in
the maximum tolerated dose of elotuzumab in
28 treated patients with a median of 2 prior
combination with bortezomib, determining safety
therapies. There were no additional side effects
and tolerability, and evaluating efficacy and
over what is seen with lenalidomide and low-dose
immunogenicity (ability of elotuzumab to cause
dexamethasone other than infusion reactions. The
allergic reactions). Elotuzumab was given on days
phase II expansion is ongoing to identify the best
1 and 11, bortezomib was given at the standard
dose of elotuzumab in this combination.
dose and regimen. Dose-limiting side effects were
measured after cycle 1; the dose of elotuzumab
Discussion
only was increased for 3 more cycles. If PD
occurred at cycles 2 or 3, dexamethasone could be
Dr. Todd Zimmerman, University of Chicago
added; if at cycle 4 there was no PD or toxicity,
Medical Center, Chicago, Illinois, the session co-
the patient could continue therapy. The study
chair, asked what drugs could be combined with
enrolled 28 patients with a median of 2 prior
elotuzumab. Dr. Lonial answered that the results
therapies; 25% had high-risk cytogenetics. Of
with lenalidomide suggest immune-enhancing
these, 15 patients were treated in the phase of
effects of IMiDs, so lenalidomide or maybe even
increasing dose, and there were no dose limiting
pomalidomide
might
be
interesting
for
toxicities in this phase; 13 patients were added at
combination therapy; Dr. Jakubowiak's results
the expansion phase at a maximum tolerated dose
(presented below) suggest that the combination
of 20 mg/kg for elotuzumab.
with bortezomib might be able to overcome
bortezomib resistance. Dr. Lonial said what
The side effects were mostly mild, with the most
happens after CS1 is bound by the antibody needs
common serious events being decreased numbers
to be understood, which could suggest whether
of lymphocytes (a type of white blood cell),
11
fatigue,
decreased
numbers
of
platelets,
Abstract 8032: Results of a phase I study of
abnormally high blood sugar, decreased numbers
RAD001 in combination with lenalidomide in
of white blood cells, pneumonia, and decreased
patients with relapsed or refractory multiple
numbers of red blood cells. The elotuzumab-
myeloma.
related side effects were mostly mild and were
mostly infusion-related reactions. There were two
Lenalidomide was added to RAD001, an mTOR
elotuzumab-related serious side effects, chest pain
(mammalian target of rapamycin) inhibitor that
and inflamed stomach and intestines. The best
does not have single-agent activity in myeloma, to
confirmed responses in 27 evaluable patients were
create a non-steroid-containing regimen. The
PR or better of 48% and MR or better of 63%.
phase I trial was conducted to determine side
There were responses in patients who had prior
effects and maximum tolerated dose as primary
bortezomib or whose disease was refractory to
objectives, and to determine activity of the
bortezomib or their last therapy. Median TTP was
combination as a secondary objective. Doses of
9.5 months for all patients (n=27) and for patients
both drugs were increased and given for 21 days of
not previously treated with bortezomib (n=16).
a 28-day cycle until disease progression or dose-
limiting toxicity. Results are available for 26
Dr. Jakubowiak concluded that the combination
patients who had a median of 4 prior lines
was well tolerated. The maximum tolerated dose
therapy; 50% had prior lenalidomide; of those, 10
was not reached at doses up to the planned
patients had a relapse and 3 had myeloma that was
maximum dose of 20 mg/kg, and the key side
refractory. Dose-limiting toxicities included
effects attributable to elotuzumab were infusion
severely reduced white blood cell counts and
reactions. The RR, including responses in
platelet counts at doses of 20 mg lenalidomide and
bortezomib-refractory disease, and the median
5 mg RAD001, so 15 mg lenalidomide and 5 mg
TTP of 9.5 months are encouraging. In this study,
RAD001 for 21 days with a 7-day rest period was
as well as the one reported by Dr. Lonial,
determined to be the maximum tolerated dose.
elotuzumab binds to all the CS1 present on the
Common mild to moderate side effects, which
myeloma cells at both doses. The possibility that
were manageable with supportive care, included
elotuzumab and bortezomib have increased
nausea, fatigue, difficulty breathing, diarrhea,
activity in combination will be investigated in
constipation, neuropathy, and muscle cramps.
further studies.
One patient discontinued due to RAD001-related
non-infectious lung inflammation. A response of
Discussion
at least SD occurred in 68% of evaluable patients
A participant noted that given that bortezomib is
at a median follow-up of 8.7 months. PFS is 4.3
at least additive to or increases activity with a mAb
months. The authors concluded that the
called anti-CD20 in lymphoma. Perhaps weekly
combination, which provides an oral, steroid-free
bortezomib could be used with elotuzumab. Dr.
regimen, warrants further evaluation in phase II
Jakubowiak said that they are looking at the
studies.
combination compared with bortezomib, and are
considering different schedules for giving the
General Discussion of Newer Agents
drugs.
Dr. Sagar Lonial discussed abstracts 8002 and
RAD001
8003, and called his presentation "The Death
and Rebirth of Immunotherapy in Myeloma."
Dr. Anuj K Mahindra, Massachusetts General
IMiD
agents
(thalidomide
and
especially
Hospital,
Boston,
Massachusetts,
presented
lenalidomide) are effective as both single agents
12
and in combination in all phases of myeloma
alkylating agents. The median PFS in the trials
therapy; this activity is likely associated with
reported by Dr. Jakubowiak and Dr. Lacy is
improving immune function and allowing
between 8 and 9 months despite patient
naturally-occurring
anti-tumor
activity
to
populations with refractory myeloma, which is
contribute to responses. The use of IMiDs and
significantly longer than might be expected.
mAbs together may increase the response of
Questions remain, including how much is
myeloma by improving immune function, which
enough? What are the right doses and schedules?
has been seen in other types of cancer.
Is 5, 10, or 20 mg of elotuzumab the right dose?
Pomalidomide acts in myeloma in a way similar to
Dr. Lonial said that they hope to have an answer
lenalidomide and thalidomide; lenalidomide and
to that question based on the combination trial
pomalidomide might have more immune-
with lenalidomide he is updating at this meeting.
enhancing activity, but this has not been shown
If a dose of mAb binds to all of its targets on the
formally. Thalidomide is useful as the first novel
myeloma cell, does giving a higher dose increase
agent in myeloma; lenalidomide is able to
the
side
effects
or
enhance
response?
overcome
resistance
to
thalidomide;
can
Pomalidomide responses have been seen with 1, 2,
pomalidomide
overcome
resistance
to
or 4 mg in different studies, so is there a
lenalidomide?
relationship of the dose to the response? There
In asking how to make immunotherapy better,
may need to be a patient-specific dose or trial-
Dr. Lonial observed that it is an oncologic irony
specific approach, and the same may apply to
that myeloma is a disease that makes too much
mAbs. Dr. Lonial concluded that new agents are
monoclonal antibody, yet there currently is no
very exciting even if they are new versions of old
therapeutic antibody to treat myeloma. There are
drugs; particularly encouraging is activity in high-
at least 10 potential mAb candidates in clinical
risk disease. Identifying how different drugs act
development, some directed against proteins on
together to create a better than expected response
the surface of myeloma cells, others against factors
should be a high priority in order to define the
that increase the growth of myeloma cells, and still
best combination. It is critical to investigate this
others aimed at the interaction of myeloma cells
with bortezomib combinations because it may give
with their microenvironment within the bone
insight into other effective combinations.
marrow.
However, Dr. Lonial believes there is cause for
Dr. Paul Richardson discussed abstracts 8000
celebration: refractory is the new relapsed; both
and 8001, Novel proteasome and HDAC
elotuzumab studies presented at this meeting
inhibitors in myeloma: The emerging role of
demonstrate significant efficacy in the context of
novel second generation proteasome inhibitors
refractory disease. Other trials show adding
and HDAC inhibition in myeloma.
panobinostat
to
bortezomib
overcomes
bortezomib resistance; adding elotuzumab to
His key take-home points included the following:
bortezomib overcomes bortezomib resistance, and
Proteasome inhibition has emerged as a
adding pomalidomide to bortezomib overcomes
highly active therapeutic approach for a
bortezomib resistance. In the last year, studies
range of cancers and in particular multiple
have shown that the new agents in development,
myeloma.
vorinostat, romidepsin, and even perifosine, can
overcome bortezomib resistance as well. So
Bortezomib has efficacy as a single agent
resistance and refractoriness may need to be
in myeloma and is approved for this
modified, because refractory is not what it was 10
indication.
years ago, when all that was available were
13
Second-generation proteasome inhibitors
on/rapid off properties that is orally bioavailable
are showing promise, with carfilzomib
and in phase I trials.
and others in clinical development,
Proteasome
inhibition
with
first-generation
demonstrating
different
tolerability
bortezomib and second-generation proteasome
profiles and potentially greater potency.
inhibitors constitutes the backbone of myeloma
Combination
approaches
with
therapy with novel, rational combinations,
proteasome
inhibitors,
specifically
including
HDAC
inhibitors,
to
improve
bortezomib, and now carfilzomib, have
responses. This reflects the new treatment model
shown remarkable activity in myeloma,
of targeting both the tumor cell and its bone
especially when rationally combined with
marrow microenvironment and other complex
other targeted agents, such as IMiDs and
interactions that lead to resistance. Rational
HDAC inhibitors, and may help
combinations may be able to target myeloma that
overcome resistance.
occurs outside the bone marrow (extramedullary
disease). Tailored approaches may provide new,
more specific, and less toxic combinations
The first-generation novel agents are now used
therapies. Challenges include the best order in
throughout the treatment course of myeloma, and
which to give drugs, drug resistance, and side
improve the outcome of ASCT. Information from
effect management to have the best anti-myeloma
the International Myeloma Working Group
effect and further improve patient outcome.
(IMWG) suggest an average survival for patients
Myeloma remains incurable and the need for new
with myeloma that is relapsed or refractory after
agents and continued studies is of highest
treatment with these agents to be 6 to 9 months,
importance.
which is dismal and an area of unmet need.
Carfilzomib is the lead second-generation
proteasome inhibitor with a side effect profile that
The Role of Transplant in the Era of Novel
is different from that of bortezomib. The lack of
Agents
severe side effects has allowed carfilzomib to be
combined
with
other
agents,
including
Dr. Antonio P. Palumbo presented abstract
lenalidomide. It is controversial whether all
8015, A phase III trial of melphalan/prednisone/
proteasome inhibitors cause peripheral neuropathy
lenalidomide (MPR) versus melphalan (200
(PN). There may be important differences
mg/m2)
and
autologous
transplantation
between the drugs at different sites in nervous
(MEL200) in newly diagnosed myeloma patients.
tissue. Other second-generation proteasome
inhibitors include NPI-0052, a natural compound
This study challenges the use of ASCT for
with a unique side effect profile that has been
younger patients with the introduction of newer
shown to be active against bortezomib-resistant
drugs. The aims of the study were safety and
cells. A phase I trial is ongoing and has shown
efficacy
of
lenalidomide
plus
low
dose
both tolerability, particularly for a new
dexamethasone (Rd) induction for ASCT, and
formulation, and clinical activity. Several other
compared
conventional
chemotherapy
second-generation
compounds
are
in
incorporating a new drug vs. ASCT with a new
development, including a second-generation
drug as induction, and examined the role of
boronate proteasome inhibitor, CEP-18770,
lenalidomide
maintenance
after
which is entering clinical trials; and MLN 9708, a
chemotherapy/ASCT. There are no results for
high-potency and reversible compound with rapid
maintenance therapy in this trial yet.
14
The study enrolled 402 patients younger than age
Paul Richardson presented abstract 8016 on
65 years. All patients received Rd for four 28-day
behalf of Kenneth C. Anderson and colleagues,
cycles as induction; stem cells were collected;
entitled
Lenalidomide,
bortezomib,
and
patients
were
randomly
assigned
to
dexamethasone in patients with newly diagnosed
melphalan/prednisone/lenalidomide (MPR) for six
multiple myeloma (MM): final results of a
28-day cycles or to 2 courses of MEL200 ASCT.
multicenter phase I/II study.
There was then a second random assignment to
either no maintenance or maintenance with 10 mg
Results presented here are an update with a longer
per day of lenalidomide until disease progression.
follow-up, a median of over 27 months, of a trial
of
RVD
(lenalidomide,
bortezomib,
and
In this trial, Rd had one of the best safely profiles
dexamethasone). Important features of the study
for combinations containing novel agents. Within
design include giving of bortezomib twice weekly,
this study, a sub-study compared the use of low-
giving dexamethasone on the day of bortezomib
molecular-weight heparin (LMWH; enoxaparin
administration and the day after, and giving
40 mg per day) vs. aspirin (100 mg per day) to
lenalidomide daily for 14 days followed by 7 days
prevent blood clots in patients who were taking
off. If the response was PR or better after 4 cycles,
MPR. The incidence of clots was slightly greater
patients could receive an ASCT. After 8 cycles
than 1% with LMWH; with aspirin, the
patients could have maintenance, with the
combined risk was about 2.5%. Stem cell
frequency of bortezomib reduced to weekly,
mobilization was adequate using chemotherapy
lenalidomide continued, and dose reduction or
(cyclophosphamide) plus a growth factor (G-
elimination of dexamethasone. The study required
CSF).
tests of bone marrow and the use of X-rays to
The response rates, PFS, and OS were similar for
determine the response.
both treatments after a median follow-up of 14
Side effects were related to the use of high-dose
months, but this is a short follow-up time.
(HD) dexamethasone, which has been seen in the
Combination therapy with new agents appears to
ECOG trial. In the phase II portion of this trial
reduce the difference between standard treatment
the doses were: 1.3 mg/m2 of bortezomib, 25 mg
and ASCT. Patients with International Staging
of lenalidomide, and 20 mg of dexamethasone for
System (ISS) stage 1 myeloma (least severe disease)
cycles 1 to 4, reduced to 10 mg for cycles 5 to 8
appear to do somewhat better regardless of
and 66 patients were treated. At a follow-up of
treatment. Patients with high-risk disease, defined
almost 4 years, 15% patients remain on treatment,
as having del 17 or t(4;14) or t(14;16), appear to
47% went on to ASCT, and 59% received 8 or
respond less well to either treatment than patients
more cycles of all three drugs together. The most
with standard-risk disease. The major advantage
common side effects were PN in most patients,
for MPR over ASCT is in side effects, with much
which was primarily mild to moderate, reversible
fewer effects on the blood, and fewer infections
in most, and manageable. Side effects affecting
and
digestive
tract
side
effects.
The
blood cells were manageable. The rate of clots was
discontinuation rate is similar between therapies,
6%. Only 1 patient died, unrelated to drug
and there were no early deaths. Dr. Palumbo
treatment.
concluded that Rd induction is effective with an
excellent safety profile. Longer follow-up is needed
All 66 patients in the study and all 35 patients in
to assess PFS and OS, and to evaluate the effect of
the phase II portion had at least PR as their best
maintenance on patients receiving conventional
response. Response improved with continued
therapy vs. ASCT.
therapy in 75% of patients from cycle 4 to 8, and
in 53% of patients beyond cycle 8, with a median
time to best overall response of 2.1 months. Of
15
the 47% patients that went on to ASCT, stem cell
Dexamethasone presents challenges, and it may
harvesting and engraftment were successful.
affect the side effects of bortezomib. PN may
Updated outcomes at a median follow-up of 27.3
involve inflammation that dexamethasone may
months show that 44 patients were alive without
modify, so the lower doses of dexamethasone are
PD. Median DOR, median PFS, and OS were not
important, not just for side effects in general, but
reached. An analysis of PFS at one year by whether
for preventing nerve damage. HD dexamethasone
patients received ASCT or not showed no
is a problem.
difference between those who received ASCT and
Dr. Richardson was asked about the best
those who did not. This is encouraging, but it is
lenalidomide dosing schedule, and said that they
early, with a short follow-up. Although the patient
know from phase I and II trials of lenalidomide
numbers are small, there seem to be no differences
development that giving lenalidomide every other
in quality of response or in PFS according to
day may have fewer side effects but is not as
genetic abnormalities. Patients with ISS stage 1
effective. In this study, the lenalidomide dosing of
disease do very well, those with stage 2 and 3
3 weeks on and 1 week off was developed in phase
disease do not do as well, which is significant and
I trials. The 2 weeks on and 1 week off for the
similar to results reported by Dr. Palumbo.
RVD combination was designed to avoid
Dr. Richardson concluded that RVD is highly
overlapping side effects and to allow for a period
effective in previously untreated myeloma, and is
of rest. So he thinks lenalidomide dosing is highly
the first combination to give results of a 100%
flexible, but daily dosing for a period of time is
response rate of at least PR, with high rates of
important, and he doesn't want healthcare
CR/nCR and VGPR, and promising estimated
providers to think they can give lenalidomide
PFS and OS with or without ASCT. There are
however they want. It can clearly be used for a 2
ongoing trials to investigate the addition of other
weeks on 1 week off schedule in combination
agents, e.g., alkylating agents or anthracyclines.
effectively, and can be used for 3 weeks on and 1
Large phase III trials are ongoing to compare
week off in combination with low-dose
lenalidomide
plus
dexamethasone
with
dexamethasone, and continuously for maintenance
bortezomib plus dexamethasone, and RVD after
therapy.
ASCT with other treatments; a study assessing
RVD followed by continuous lenalidomide with
Dr. Jean-Luc Harousseau discussed abstracts
or without ASCT will be conducted by the
8015 and 8016, concerning the role of transplant
partnership of the IFM and the Dana-Farber
for myeloma in the era of novel agents.
Cancer Institute. Other studies that are ongoing
or planned of novel combinations to reduce side
Until now ASCT has been shown to be superior
effects and enhance efficacy will look at HDAC
to conventional chemotherapy in at least 7
inhibitors such as vorinostat, and "RVD light,"
randomized trials, with 6 trials showing an
with a weekly schedule of bortezomib in elderly
increased response rate, 5 trials showing an
patients.
increased PFS, and only 3 trials showing an
Dr. Zimmerman noted that there are different
increased OS because of shorter survival after
schedules used for dexamethasone dosing. Dr.
relapse (some patients received ASCT after relapse
Richardson said that in the study he reported, the
from conventional chemotherapy). Novel agents
reason for giving dexamethasone on the day of and
used as frontline therapy in the last few years have
day after bortezomib was based on their experience
completely changed the outcome for elderly
in relapsed and refractory myeloma. In the
patients. The use of novel agents, even in elderly
EVOLUTION trial they used a different schedule,
patients, can achieve results comparable or even
administering
weekly
dexamethasone.
better than those achieved with ASCT. In studies
16
of novel agents used prior to ASCT in 2- and 3-
Is lenalidomide plus dexamethasone the best
drug combinations, the 3-drug combinations are
induction treatment prior to ASCT? In the
better, and both 2- and 3-drug combinations are
ECOG study, after 4 cycles, lenalidomide plus
better than standard therapy if the combinations
low-dose
dexamethasone
was
inferior
to
include at least one novel agent. When
lenalidomide plus high-dose dexamethasone,
thalidomide was used as maintenance therapy after
which was not true in the study presented by Dr.
ASCT, it improved the greater-than-VGPR
Palumbo at this meeting. However, in other
response rate and extended the PFS in 4 trials, and
studies, treatment with vTD (reduced-dose
increased the OS in 3 of the 4 trials. With Total
bortezomib plus thalidomide and dexamethasone
Therapy (TT), addition of novel agents improves
presented by Dr. Moreau at this meeting) or VTD
event-free survival (EFS) and OS.
(presented by Dr. Cavo at last year's ASH
These results lead to asking if, in the era of novel
meeting) resulted in higher response rates before
agents, HD MEL plus ASCT (HDM) should be
and after ASCT. For the non-intensive arm RVD
used. Dr. Harousseau thinks this question should
might be a better treatment to use for comparison
be answered in the context of clinical trials to
because of the response rates and PFS reported
avoid selection bias in the choice of therapy by
here by Dr. Richardson. So is RVD the best non-
physicians and patients. The study presented by
intensive frontline treatment? This question can't
Dr. Palumbo is the first randomized trial to
be answered without a randomized trial to
address this important question. The updated
compare non-intensive upfront treatments. The
results presented at this meeting indicate there is
high response rates with RVD reported at this
no difference in response rates, PFS, or OS. The
meeting have not been seen before with other
follow-up is short, so it may not yet be time to
combinations, treatment was generally well
abandon upfront ASCT. Questions raised by this
tolerated except for PN, and the results look better
presentation include the statistical hypothesis and
than those seen with lenalidomide plus low-dose
design. The study may not be designed to detect a
dexamethasone (in the ECOG trial) or induction
difference between MPR and HDM due to
with lenalidomide plus low-dose dexamethasone
improved PFS in both arms. Two questions were
followed by MPR/HDM (in the trial presented by
addressed: 1) MPR vs. HDM, and 2) maintenance
Dr. Palumbo). However, in the RVD trial, 47%
vs. no maintenance, which results in 4 arms if the
of patients went on to ASCT, whereas no patients
effect of lenalidomide is not the same after MPR
did in the MPR/HDM trial, and only 20% of
and HDM. With only 402 patients it might be
patients in the ECOG trial did. Dr. Harousseau
difficult to show a benefit of HDM, and it will be
concluded that the results of MPR vs. HDM do
impossible to compare MPR with HDM in some
not show differences in RR, PFS, or OS, and that
subgroups of disease risk. The follow-up is short at
a longer follow-up is needed before drawing a
a median of 14 months, which is too early for OS
definite conclusion. Upfront ASCT might be
(and because effective treatments exist in the case
useful only in certain patients, and a large number
of relapse), and it is also too early to determine
of patients is needed to determine differences
PFS because lenalidomide maintenance prolongs
across subgroups with different risk factors. The
PFS after either ASCT or non-intense therapy. So
IFM/DFCI trial to start in July will study VRD
currently for MPR vs. HDM the most important
induction,
stem
cell
collection,
random
information is the response rate, which has only
assignment to VRD, lenalidomide maintenance,
been evaluated in 239 patients of the 402 who
and HDM at relapse vs. MEL200 ASCT, VRD,
were randomly assigned, and for which no
then lenalidomide maintenance, and is planned to
difference by treatment is seen. The results of the
enroll 1000 patients, which will allow the
final analysis are needed.
investigators to look at subgroups with different
risk factors. Dr. Harousseau thinks this trial is
17
using the best induction and non-intensive
with VD). There was no difference in the recovery
treatments.
of cells and there were no toxic deaths in either
arm. Side effects during induction were similar for
the two treatment arm except for PN leading to
Initial Therapy Prior to Transplant
discontinuations, which occurred only with VD.
There were low rates of other serious side effects.
Dr. Philippe Moreau, University Hospital,
One study goal was to reduce the PN rate, and
Nantes, France, presented abstract 8014 on
they did see significantly lower rates of at PN that
behalf of the IFM: Comparison of reduced-dose
was moderate to serious in patients treated with
bortezomib plus thalidomide and dexamethasone
(vTD) to bortezomib plus dexamethasone (VD)
vTD arm (28%) vs. VD (34%).
as induction treatment prior to ASCT in de novo
Dr. Moreau concluded that vTD was more
multiple myeloma (MM): results of IFM2007-02
effective than VD after induction and after ASCT,
study.
with a similar CR rate and a better CR+VGPR
rate. Decreasing the doses of bortezomib and
This study was designed to compare the two best
thalidomide does not decrease the efficacy of the
treatments identified in the IFM 2005-01 and
combination. Cyclophosphamide is needed to
GIMEMA 26866138-MMY-3006 trials, VD and
collect stem cells with vTD. The incidence of
VTD. In this trial, the dose of bortezomib was
serious side effects is low and the rate of moderate
reduced to 1 mg/m2 and the dose of thalidomide
to serious PN is dramatically reduced. This new
was reduced from 200 to 100 mg/day in an
triple combination of vTD is superior to VD with
attempt to reduce the PN rate. IFM2007-02
good efficacy and low toxicity.
enrolled newly diagnosed patients up to age 65
years who were randomly assigned to VD for four
In discussing the IFM study, Dr. Michael Wang,
21-day cycles, or to reduced-dose bortezomib
MD Anderson Cancer Center, Houston, Texas,
(v)TD. ASCT MEL200 followed 4 cycles of
asked if there is already a 90% response after 2
induction.
cycles, wouldn't the 2 additional cycles not reduce
the myeloma but increase PN? If so, then why not
After 2 cycles, vTD resulted in a significantly
have induction with 2 to 3 cycles using a higher
higher PR than VD. After 4 cycles the CR rate
dose of bortezomib with faster response and lower
was similar between arms, and the response of at
total dose delivered? Dr. Moreau answered that
least VGPR was significantly higher for vTD.
the PR rate is 90% after 2 cycles, but their goal is
After ASCT, the rate of at least VGPR was
not to achieve PR but to achieve VGPR or better,
significantly higher with vTD than with VD.
which is associated with a better outcome.
Again, there was no difference in the CR rate
Therefore, 2 additional cycles of induction (4 total
between arms. In previous studies rate of at least
cycles) are needed prior to ASCT, especially with
VGPR both after induction and after ASCT was
low toxicity.
an important goal because it was related to better
outcome. In other VTD studies, the rate of at least
Dr. Joseph Mikhael, Mayo Clinic, Scottsdale,
VGPR is comparable, especially after ASCT, and
Arizona, said that this study is important in
is superior to VD. Stem cell (CD34 positive cells)
moving ahead to understanding the correct dose of
collection was lower with vTD. Collection was not
these agents, including bortezomib. One option is
possible in 21% patients with the growth factor
to reduce the dose of bortezomib with twice-
G-CSF alone as planned (vs. 6% with VD).
weekly administration of 1.0 mg/m2, which gives a
Therefore
the
chemotherapy
agent
total dose of 4 mg/m2 (vs. 5.3 mg/m2 with twice-
cyclophosphamide was used, so that in the end
weekly doses of 1.3 mg/m2), or once-weekly
there was a similar low failure rate (2% vs. 1%
bortezomib, as in the Italian study (with a total
dose of about 4.5 mg/m2). In the long run, will
18
the objective be once-weekly dosing with time
less than PR before ASCT. Dr. Niesvizky
between doses to reduce PN, or is it really a dose
concluded that induction therapy must be
reduction? What was the total dose delivered
improved to offer a VGPR or better of 70%. It
compared with the planned dose? Dr. Moreau said
not clear if the best approach is combination
that the answer is different in two different
therapy or sequential therapy (one agent at a
situations: one is in elderly patients where the goal
time). He cautioned about the benefit of weekly
is to keep patients on treatment for a long time
bortezomib; it is always used in combination with
with reduced side effects, so weekly bortezomib is
other anti-myeloma drugs, and the results may not
favored. For patients going to ASCT, the goal is to
apply to all settings. If a patient has high-risk
lower the amount of myeloma cells as fast as
disease, he hopes healthcare providers would use
possible with induction therapy, so twice-weekly
higher doses in a more intense fashion, that is,
bortezomib is preferable. Nearly all patients in this
twice weekly.
study received the planned dose of bortezomib
from both treatments, except for the four patients
who discontinued in the VD arm.
Therapy
for
NonTransplant
Eligible
Patients
Dr. Ruben Niesvizky, New York Presbyterian
Antonio Palumbo presented Abstract 8013 on
Hospital-Cornell Campus, discussed sorting
behalf of Mario Boccadoro and the Italian
through the options for initial therapy of
Multiple
Myeloma
Network,
GIMEMA:
myeloma in light of abstract 8014 (as well as
Bortezomib,
melphalan,
prednisone,
and
abstract 8013 in the section on non-transplant-
thalidomide (VMPT) followed by maintenance
eligible patients).
with bortezomib and thalidomide (VT) for initial
treatment of elderly multiple myeloma patients.
Achieving a meaningful sustained response of at
least VGPR has been shown to contribute to long-
This large randomized trial compared two
term survival in various phase II and III trials, and
approaches for treatment of patients who were
in the last several years 40% CR and over 70%
older than age 65 years and not transplant eligible.
VGPR have been achieved and will be the rates for
The treatments included the four-drug approach
comparing future studies. The Arkansas group has
of bortezomib, melphalan, prednisone, and
shown that in addition to high response rates,
thalidomide (VMPT) followed by bortezomib and
having a duration of response of at least 2 years
thalidomide (VT) maintenance compared with
also contributes to survival. Goals in myeloma
what has been considered the best standard of care
therapy should be to achieve a response of at least
for elderly patients, the three-drug combination,
VGPR, define maintenance regimens, and to
bortezomib, melphalan, and prednisone (VMP)
understand
how
to
combine
proteasome
with no maintenance. The study also investigated
inhibitors, IMiDs, steroids, and alkylating agents.
the safety and efficacy of weekly bortezomib. The
study included 511 patients with a median age of
In the IFM2007-02 study, the effect of vTD is less
71 years. The study began with twice-weekly
than desirable before ASCT. There is a need to
bortezomib, but because the first 139 patients
address the effect of IMiDs on stem cell harvest;
experienced neuropathy (PN) as a side effect, the
Dr. Niesvizky suggested an alternative method of
schedule was modified to weekly bortezomib for
mobilizing and collecting stem cells, e.g., using
patients receiving either treatment, and the dose of
Mozobil (plerixafor). The effect of reducing the
thalidomide was reduced to 50 mg per day for
dose of bortezomib is less PN, but the question
patients
treated
with
VMPT.
For
VT
remains whether the response rate can be
maintenance, bortezomib was administered every
improved for the 10% of patients who experience
other week.
19
Patients treated with VMPT followed by VT had
response rate and PFS and increases the CR rate,
a significantly longer time to next treatment and a
with 90% of the improvement in CR rate
significantly longer progression-free survival (PFS)
occurring during the induction phase, and only
after about two years of follow-up. The
10% of the improvement in CR rate occurring
improvement in response was mostly in the CR
during the maintenance phase. VT maintenance
rate, which contributes to increased survival. Most
improves PFS (although the study didn't
PR are seen by the first 5 to 6 months of
randomize for maintenance) and prolongs
treatment, but the majority of CR requires longer
remission duration. Once-weekly bortezomib
treatment, up to almost 1 year. Dr. Palumbo
reduces PN with no change in efficacy, which is a
noted that PFS is usually around 2 years with the
major improvement in the safety profile of the
best current treatment, and the four-drug
VMPT combination.
combination is increasing the probability of
remission duration by a year. There was no
difference in OS due to the short follow-up time.
Discussion
He stressed the concept that the issue is not a
Dr. Jakubowiak and Dr. Harousseau both asked
difference in survival but that probably the median
about how to separate the effects of induction
OS will approach 6 years; for elderly patients this
from the effects of maintenance therapy. Dr.
is a major improvement over the previous median
Palumbo replied that there is a question about
survival of 3 years.
how long to treat to increase the response rate.
Maintenance does look important to increase the
Serious side effects including reduced white and
duration of response. There is a time period
red blood cell counts and platelet counts were
within which CR rate can be maximized. In this
higher for the four drug combination of VMPT
study, 9 cycles of therapy seems to be the right
and were expected for a combination containing
length because most of the CR rate occurred by 9
an alkylating agent and novel agents. Other side
cycles.
effects included PN, infections, and a higher risk
of complications affecting the heart and more
Dr. Anderson commented that at ASH he showed
blood clots for patients receiving VMPT. Fewer
that lenalidomide plus melphalan plus prednisone
patients discontinued the study than has been
(MPR) followed by lenalidomide maintenance
reported in the past for patients in this age group.
also gave good results, and wondered how to
The reduction from twice-weekly to once-weekly
compare his study with VMPT followed by VT
bortezomib did not decrease the CR rate or PFS
maintenance. He asked if it was possible to replace
compared with other studies. The risk of PN
thalidomide here with lenalidomide. Dr. Palumbo
decreased
from
14%
to
2%,
and
the
responded that the major contribution of
discontinuation rate decreased from 16% to 4%,
lenalidomide in the study of MPR followed by
which was attributed to the reduction in PN. The
lenalidomide maintenance is as maintenance
efficacy of the treatment was maintained because
therapy, not induction therapy. If lenalidomide
although patients received less bortezomib each
were substituted for thalidomide, he would be
week, they were able to stay on the study longer
afraid that the side effect of decreased white blood
and therefore received more of the planned dose of
cell counts would lower the efficacy of the four-
the drug overall.
drug combination, which he also saw with MPR.
This might
explain
the results
in
the
Dr. Palumbo concluded that today the best
EVOLUTION study in which the four-drug
available treatment option for elderly patients is
combination
of
bortezomib
plus
VMPT followed by VT maintenance. This
cyclophosphamide
plus
lenalidomide
plus
combination significantly improves PFS in
dexamethasone (VCRD) was not as good as the
comparison with VMP. VMPT improves the
three-drug combination.
20
Dr. Barlogie asked a follow-up to Dr. Anderson's
at the ASCO/ASH Joint Session, which was
question. He wanted to know if maintenance
selected as an abstract of clinical relevance to
could be replaced with bortezomib plus
clinical oncologists that had been presented at
lenalidomide (VR), which should be feasible. Dr.
ASH 2009 (originally by Dr. Palumbo).
Palumbo thought that VMP followed by
lenalidomide maintenance could possibly be best.
Dr. Raje, who was not involved in this trial, felt
Dr. Barlogie wanted to challenge Dr. Palumbo's
she gave an unbiased view about where MPR-R
conclusions about the number of cycles needed to
(lenalidomide added to melphalan plus prednisone
reach CR when it is defined in terms of M-protein
followed by lenalidomide maintenance) fits in the
levels. When response is measured by magnetic
treatment of patients with myeloma who are not
resonance imaging (MRI) to look for areas of
transplant candidates. The primary comparison
remaining myeloma tumors in the bone, these
was MPR-R vs. melphalan plus prednisone (MP).
tumors, known as focal lesions, may take 3 or 4
A secondary comparison done at the request of the
years to disappear. He believes that the proper
European Union regulatory agency, EMEA, of
techniques, e.g., particularly MRI or positron
MPR-R vs. MPR for a stipulated 9 cycles, was to
emission tomography (PET) scanning, should be
determine if lenalidomide maintenance would
used to measure CR over time. He proposed that a
really make a difference in the treatment of
new yardstick, MRI-defined CR, should be
patients at least age 65 years with newly diagnosed
developed. This lags 8 to 12 months behind
myeloma who were not eligible for a transplant. At
immunofixation-negative CR (the point at which
the interim analysis, presented at ASH, there was a
M-protein can no longer be detected in the
statistically significant difference between MPR-R
blood). Dr. Palumbo agreed that CR in this study
vs. MP. The authors concluded that continuous
is defined by M-protein and plasma cell
lenalidomide is superior to regimens of shorter
infiltration of the bone marrow, so more
duration. They further concluded that MPR-R is
sophisticated ways to measure response could
superior to MP with higher and more rapid
change the conclusion about the time to reach best
responses, a 50% reduced risk of progression, and
response.
a favorable safety profile; MPR-R should therefore
be considered a new standard treatment option for
elderly patients.
Dr. Ruben Niesvizky discussed abstract 8013.
Dr. Raje discussed the strengths and limitations of
In the older population the approach of induction
this study. The strengths included that the
followed
by
maintenance
therapy
using
regimen is given by mouth (orally) and fairly well
combination treatments has been effective. In the
tolerated, which is important for older patients,
GIMEMA study, the VMP arm had no
and other patients who are not eligible for
maintenance. Although the experimental arm
transplant because they have other medical
meets the landmarks with CR of 38% and ORR
problems in addition to their myeloma disease.
of 89%, the design is biased because maintenance
MPR-R offers a significant PFS advantage over
therapy is used in only one arm. The safety profile
MP, suggesting that lenalidomide maintenance
is good.
may be a new standard. Limitations of the study
include a short follow-up time, and the lack of
Dr. Noopur S. Raje, Massachusetts General
difference seen among all three arms at 9.4
Hospital, Boston, Massachusetts, presented A
months for PFS. There is no difference in PFS
phase III study to determine the efficacy and
between MP vs. MPR, and no difference in OS to
safety of lenalidomide in combination with
date.
melphalan and prednisone (MPR) in elderly
patients with newly diagnosed multiple myeloma
21
Possible treatment for patients with myeloma who
on various risk factors and see if there is a subset of
are not eligible for transplant currently includes
patients that benefits from therapy.
combinations of thalidomide (T), bortezomib (B),
and lenalidomide (R), as MPT, MPV, MPV-VT,
Rd (lenalidomide with low dose dexamethasone),
Bisphosphonates and Bone Disease
and MPR-R. MPT has been tested in the largest
number of trials: responses in most studies are
Gareth Morgan, Institute of Cancer Research,
close to 60%, OS is 45 to 50 months, and the
Royal Marsden NHS Foundation Trust, London,
United Kingdom, presented Abstract 8021 -
advantage of MPT vs. MP has been confirmed in
Evaluating the effects of zoledronic acid on
an analysis combining several studies. Dr. Raje's
overall survival in patients with multiple
overall conclusions are that MPR-R is certainly
myeloma: results of the Medical Research
one additional possibility for the treatment of
Council (MRC) Myeloma IX Study.
newly diagnosed patients with myeloma who are
not eligible for transplant. The choice of therapy
This study is a randomized comparison of
should be based on patient profile and therapy-
zoledronic acid (Zometa) vs. clodronate (Clasteon,
related side effects such as neuropathy, risk of
which is not available in the US, but is available in
clots, and kidney problems. The use of
Canada and in the UK where this study was
maintenance therapies in addition to anti-
done). An important observation is that myeloma
myeloma therapy is showing some promise.
cells are in close contact with stromal cells in the
bone marrow. Interactions between osteoclasts,
Discussion
cells that break down bone, and osteoblasts, cells
that form bone, contribute to the survival of
Dr. Douglas Blayney, University of Michigan,
myeloma cells. Treatment that affects these
Ann Arbor, Michigan, and ASCO president,
interactions may be beneficial. The objective of
observed that at this meeting lenalidomide
this trial was to ask the question, "Can bone-
maintenance does seem to be an emerging theme,
targeted therapy improve survival in patients with
but it is a toxic therapy, and it's interesting that
multiple myeloma?" Studies in myeloma cells and
there is no OS benefit. Dr. Raje responded that
in mouse models of myeloma suggest that
the follow-up of 9.4 months is short, and that
bisphosphonates, the class of drug that includes
those patients who did not receive lenalidomide at
zoledronic acid and clodronate, may have anti-
first did receive some of these new drugs later in
myeloma effects.
the study. For patients with myeloma it's become
incredibly difficult to see a survival benefit [when
The MRC Myeloma IX trial design enrolled 1960
comparing newer treatment s] because of all of the
patients receiving either intensive (transplant) or
treatment options available. In response to a
non-intensive therapy. Within each therapy group
follow-up question asking Dr. Raje what she
patients were randomly assigned to either
recommended, she said she would take the patient
zoledronic acid or clodronate until disease
profile into consideration. For an elderly patient
progression. The basic conclusion is that
who prefers an oral regimen, MPR is reasonable.
zoledronic acid improved OS by about 5.5
For someone with severe kidney failure who needs
months, which is both clinically and statistically
rapid myeloma control, bortezomib makes sense.
significant. Zoledronic acid significantly reduced
For maintenance therapy, results support using
the relative risk of death vs. clodronate, and
maintenance therapy even though there is no OS
significantly reduced skeletal related events (SRE),
advantage. What will need to be done in the
such as broken bones. The survival benefit was not
future is to divide patients into subgroups based
due to prevention of SREs, but is an anti-myeloma
effect.
22
In analyzing side effects over both intensive and
be best to continue zoledronic acid beyond disease
non-intensive therapies, there were no differences
progression, but they didn't collect those results.
between the two bisphosphonates for acute kidney
The doses of zoledronic acid and clodronate used
failure, blood clots, or infections. However,
in this study have an anti-myeloma effect and are
zoledronic acid was associated with an increased
safe, but giving them more frequently, e.g., every 2
incidence of osteonecrosis of the jaw (ONJ), but it
weeks, might not be justifiable because of side
was at the rate of 3.6% vs. 0.3% rate of ONJ with
effects. Dr. Morgan said he thinks zoledronic acid
clodronate. ONJ associated with zoledronic acid
is the new standard of care for patients with
tended to heal on its own without surgery. After a
myeloma.
median follow-up of 3.7 years, zoledronic acid
During a discussion of the Education Session on
significantly prolonged OS and PFS and
Complications of Myeloma and Myeloma
significantly reduced the proportion of patients
Therapies, session chair Dr. Todd Zimmerman
with SRE compared with clodronate. Both
asked Dr. David Roodman, University of
bisphosphonates were generally well tolerated with
Pittsburgh,
Pittsburgh,
Pennsylvania,
who
expected side effects. Zoledronic acid might work
reviewed myeloma bone disease, about the MRC
by directly causing myeloma cells to die, adding
IX trial that included patients with non-lytic bone
on to the effects of chemotherapy, and breaking
disease, that is, patients whose bones don't show
the loop between osteoblasts and stromal cells.
the thinned areas on X-ray typical of myeloma
This is not isolated to myeloma, because there is
bone destruction. Treatment of patients with non-
evidence in other cancer types that zoledronic acid
lytic bone disease is not a typical practice
prolongs survival.
according to ASCO guidelines, so he wanted to
Dr. Morgan concluded that zoledronic acid is
know what the approach would be for patients
superior to clodronate for the prevention of SRE
with osteopenia (general reduction of bone
in patients with newly diagnosed myeloma.
density) but not overt lytic bone disease. Dr.
Adding zoledronic acid to standard anti-myeloma
Roodman replied that previously the ASCO
therapy is generally well tolerated and prolongs
guidelines
were
clear
on
not
giving
OS vs. clodronate, and the survival benefit is
bisphosphonates unless the patient had diffuse
independent of SRE reduction. These results
osteopenia or documented bone disease. In the
further support the anti-cancer activity of
MRC trial, 20% or 25% of those patients had no
zoledronic acid and provide evidence that it
bone disease. Dr. Morgan reported that those
should be considered for early addition to
patients had prolonged OS, like those patients
treatments for patients with newly diagnosed
who did have bone disease. This is an exciting
myeloma.
result, similar to the situation in patients with
breast cancer where bisphosphonates, particularly
zoledronic acid, are considered as adjuvant therapy
Discussion
in patients on aromatase (hormone) therapy. Dr.
In response to questions, Dr. Morgan said that
Roodman said he thinks there is a need to see the
70% of patients had bone disease at the time they
published results and see what the comments by
entered the study, and the benefit of zoledronic
the reviewers are before everyone is treated with
acid on SRE and OS was seen in patients with or
bisphosphonates, because they do have side effects,
without bone disease. They expect by next ASH to
although small. No one knows how long to treat
have results comparing older and younger patients
with bisphosphonates.
and patients in CR vs. those not in CR. There
seems to be an increased VGPR rate in the elderly
Dr. Richardson added that in patients with
patients, suggesting an anti-myeloma effect. Dr.
smoldering myeloma (SMM), there have been
Morgan said in his opinion he thought it would
randomized trials looking at bisphosphonates, and
23
a fact that is not well appreciated is that there is a
another bisphosphonate. Patients who receive
significant reduction of time to first SRE. In their
pamidronate plus zoledronic acid are more likely
group, for patients with SMM and osteopenia,
to get ONJ than those who receive pamidronate
they are comfortable using periodic infusions of
alone. Novartis makes both drugs and the
bisphosphonates. Dr. Roodman replied that
company reports that after reviewing 3 million
patients with MGUS have an increased fracture
patients, the incidence of ONJ is no higher with
risk, but they have osteoporosis (significantly
zoledronic acid than with pamidronate, but Dr.
decreased overall bone density) not myeloma bone
Roodman said to remember the source is the
disease, so they should be treated like patients with
company producing both drugs. He thinks that
osteoporosis, e.g., with oral bisphosphonates. He
the more active the bisphosphonate, the higher the
also pointed out that patients should have their
risk of ONJ. However, the incidence has fallen
vitamin D levels checked because studies have
dramatically with current recommendations for
shown that up to 60% to 70% of patients with
preventive dental care, dental hygiene, and follow-
myeloma at diagnosis are vitamin D-deficient, so
up at least in patients with breast cancer, and
replenishing vitamin D is important when treating
possibly with myeloma. He used to see ONJ once
myeloma bone disease. The question is how much
a month in his clinic, but hasn't seen any in the
vitamin D to give? The NIH is expected to
last two years with rigorous monitoring. Dr.
provide
new
recommendations
on
Richardson agreed that there has been a dramatic
supplementation. Now there are no good
reduction in ONJ in his practice. The dental
recommendations. The zoledronic acid prescribing
expert he collaborates with believes the reduction
information says to give patients calcium and
could be due to the more widespread use of
vitamin D unless their calcium levels are
bortezomib, which activates osteoblasts. This
abnormally high. Dr. Roodman pointed out that
needs to be proven, but it is interesting. Dr.
the current ASCO guidelines suggest to treat for
Roodman replied that the change in incidence of
two years, re-evaluate the patient, and consider
ONJ in patients with breast cancer, who don't
stopping zoledronic acid if the myeloma is in CR
receive bortezomib, is the same, and probably the
or plateau, and to continue treatment if there is
result of better dental hygiene.
active disease. Other guidelines exist. Information
A participant pointed out that results suggest that
from other cancers suggests that if treatment with
pamidronate and zoledronic acid are equally
zoledronic acid continues beyond two years,
effective, so he wondered why zoledronic acid is
patients will continue to benefit. The question is
being discussed rather than pamidronate, which is
how long to continue, and there is a question
available at lower cost. Dr. Roodman replied that
about whether measuring bone resorption markers
it was a valid question because pamidronate is now
is useful. In a review of all trials of zoledronic acid,
generic. Zoledronic acid is given in a 15-minute
the response isn't maximized, because the bone
infusion. Pamidronate requires two hours to
can take up large, possibly unlimited, quantities of
administer, not including the time patients need
bisphosphonates. There is now a concern about
to add to get to the clinic, check in, start the I.V.,
unusual fractures associated with bisphosphonates,
etc., increasing the total time to 6 hours, so the
the cause of which is not clear. Dr. Richardson
choice is mostly patient convenience. However,
commented that patients in the MRC trial were
now there is evidence from both the MRC trial
taking bisphosphonates for more than four or five
and in breast cancer that zoledronic acid has the
years.
potential for anti-tumor activity, which has never
Dr. Roodman said that the incidence of ONJ has
been reported for pamidronate, although he would
increased over the last five years in step with the
like to review the results to confirm this. That
increased use of zoledronic acid over pamidronate,
suggests an additional reason to give zoledronic
24
acid over pamidronate. Dr. Richardson mentioned
rate independent of 1q21 amplification despite the
the IFM study giving pamidronate with
subgroup with 1q21 amplification containing
thalidomide as maintenance therapy. This large
more patients with higher ISS stage disease, so
randomized trial showed no evidence of survival
bortezomib may be preferred as an induction
benefit, which provides additional support for
regimen. Follow-up is needed to see if this
zoledronic acid over pamidronate.
translates into a PFS and survival benefit.
Risk Factors
Dr. Bart Barlogie presented Abstract 8019,
Defining the prognostic variables in gene
Dr. Orlowski discussed 1q21 amplification as a
expression profiling (GEP)-defined high-risk
poor-risk feature as presented in posters,
multiple myeloma (MM): distinguishing early
Abstracts 8027 and 8028.
failures (EF) from sustained control (SC).
Abstract 8027, first author Dr. John Shaughnessy,
Dr. Shaughnessy's GEP 70-gene risk model re-
University of Arkansas Medical Center, Little
identified and repeatedly validated that the 85%
Rock, Arkansas, was titled Outcome with Total
of patients with low-risk disease had a superior
Therapy 3 (TT3) compared to Total Therapy 2
EFS and OS with TT2, whereas the 15% of
(TT2): role of gene expression profiling (GEP) 70-
patients with high risk had a median survival of
gene array-defined high-risk disease with trisomy
only 2 years. For TT3, at 6 years 90% of patients
of 1q21 and activation of the proteasome gene
are alive and event free, but the high-risk
PSMD4. Amplification of 1q21 has already been
population shows a median survival of only 2.5
shown to be a poor prognostic factor. A lower
years, with a subsequent plateau emerging. His
copy number of 1q21 is associated with a better
impression is that as new agents have progressively
outcome (EFS and OS). Bortezomib neutralizes
been introduced along with new concepts of
the effects of 3 copies but not 4 copies. This study
consolidation and maintenance therapy, the major
looked at what genes in the 1q21 region might be
beneficiary has been the low-risk population, not
conferring the high-risk feature and there are some
the high-risk population.
interesting genes with respect to myeloma in the
The curves of OS and EFS (Kaplan-Meier curves)
region, including PSMD4. PSMD4 expression is
show a breakpoint for patients with high-risk
sensitive to 1q21 copy number, and may be a
disease at 3 years. The curve is steeper before the
marker for the proteasome inhibitor bortezomib in
breakpoint, which Dr. Barlogie calls "early
myeloma. PSMD4 (S5a) may be involved in
failures" (EF), and declines after that point less
proteasome function. This needs further study,
steeply to a plateau-like phase that he calls
along with the roles of the other genes in the
"sustained control" (SC). This presentation looked
region.
at what distinguishes EF from SC for patients with
Abstract 8028, first author Dr. David Joshua,
high-risk disease. The objectives are now to
Royal Prince Alfred Hospital, Sydney, Australia,
determine, among the 15% patients with high-risk
was titled Response of newly diagnosed myeloma
disease enrolled in TT2 and TT3 who had gene
with 1q21 amplification to bortezomib-based
array data (most of the patients in TT3), if EF and
PAD induction therapy. To overcome 1q21
SC subsets can be distinguished at entry into the
amplification as a poor-risk feature, PAD
study by either standard risk factors or GEP of
(bortezomib
plus
doxorubicin
plus
plasma cells. Biopsy samples are also available to
dexamethasone) was tested in a phase II study in
look at the bone marrow. The ultimate goal is to
newly diagnosed patients who were eligible for
define genes for EF and SC and find new targets
stem cell transplants. There was a good response
of therapy.
25
EF and SC subgroups of 123 patients with high-
In conclusion, Dr. Barlogie said that compared
risk disease in TT2 and TT3 were identified and
with SC, EF is characterized by higher GEP70 risk
GEP and standard tests were performed. There
scores ("super risk") among other abnormalities.
were no differences between the two groups in
Among 14 EF- vs. SC-discriminating genes, one is
standards tests such as B2M, albumin, lactate
of particular interest, because over-expression in
dehydrogenase
(LDH),
and
cytogenetic
SC is linked to cell death and better clinical
(chromosome) abnormalities. However, there were
outcome. This gene is rapidly increased by
differences between EF and SC subgroups in the
melphalan and bortezomib in patients with low
GEP median score. There are 14 genes that
levels of expression. Therefore, it is not only a
distinguish the EF and SC subgroups. The
marker, but a therapeutic target. Issues under
expression of 6 are increased and 8 are decreased.
study include the development of a "super high-
Among the genes with decreased expression are
risk" model; examination of the potential for super
one involved in bone disease, one that controls cell
high risk among patients who seem to have low-
division, and one involved in B-cell development.
risk myeloma but who do poorly, and the role of
Among the genes with increased expression is one
the model in predicting survival after relapse.
involved cell death. The Arkansas group has
They are also planning to examine the super high-
performed GEP analysis at study entry, and after
risk-associated genes in the setting of molecular
single-agent therapy, e.g. before and after
subgroups; and to determine the features of EF vs.
thalidomide-dexamethasone in TT2, and 48 hours
SC that are unique to the bone marrow
after single-agent bortezomib in TT3, and they are
environment. In addition, they want to examine
now also doing GEP after high dose melphalan
how anti-myeloma agents like MEL and
(MEL) in TT4 and TT5. One of the interesting
bortezomib affect super high-risk genes to restore
genes involved in cell death, when low before
myeloma cell sensitivity these agents.
treatment, was increased after bortezomib, VTD-
PACE, or MEL.
26
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hollywood, CA 91607 USA
Telephone:
800-452-CURE (2873)
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
www.myeloma.org
Document Outline
- ASCO2010-PatientHighlights cover
- ASCO2010-PatientHighlights p2
- ASCO2010-PatientHighlights body
- ASCO2010-PatientHighlights back