INTERNATIONAL MYELOMA FOUNDATION
ASH 2009
Highlights
for Patients
with Myeloma
Summaries of Multiple Myeloma Presentations
from the 51st Annual Meeting
of the American Society for Hematology (ASH)
held in New Orleans, Louisiana,
December 58, 2009
Compiled by Lynne Lederman, PhD
Funded by unrestricted educational grants from Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals.
ASH 2009 Summaries of Multiple Myeloma
Presentations for Patients
Introduction
transplantation, venous thromboembolism (blood clots),
stem cell collection, tumor cell biology, and other topics
The 51st Annual Society of Hematology (ASH) Annual Meet-
of interest.
ing was held December 5th through the 8th, 2009, in New
Orleans, LA. On December 4, the International Myeloma
· Three poster sessions featured hundreds of posters about
Foundation (IMF) and the Postgraduate Institute for Medi-
myeloma and related topics, for example, new drugs in
cine sponsored a symposium that provided participants
development.
with an overview of the most recent results from clinical
trials along with expert commentary, analysis, interpreta-
This report summarizes information presented at the 2009
tion of findings, and a discussion of how this might affect
ASH Annual Meeting, organized by topics rather than by ses-
treatment of myeloma. Dr. Brian G.M. Durie introduced the
sions, presenting an overview of information on new drugs
presenters and topics at the symposium.
in development, clinical trial results, treatment by patient
characteristics such as eligibility for transplant or stage of
Multiple myeloma was the topic of many presentations at
disease, disease risk and stage, and a brief summary of some
ASH, including the following:
presentations that might be of interest to patients with
myeloma and their families and caregivers.
· The PETHEMA/GEM clinical trial of bortezomib/mel-
phalan/prednisone (VMP) vs. bortezomib/thalidomide/
New Drugs in Development
prednisone (VTP) followed by maintenance therapy with
bortezomib/thalidomide (VT) vs. bortezomib/predni-
Relapsed Refractory Myeloma: The Role of New Drugs,
sone (VP) in elderly untreated patients, was presented
was presented by A. Keith Stewart, MD, Mayo Clinic, Scott-
by Maria-Victoria Mateos, Barcelona, Spain. This was one
sdale, Arizona, who chaired the Multiple Myeloma Educa-
of the six talks selected for the plenary session by the ASH
tion Session. This topic was discussed in depth in a paper
program committee as the most groundbreaking abstracts
published in Hematology 2009, which is available through
submitted to the meeting.
the American Society of Hematology. Dr. Stewart reviewed
clinical trial results and the status of the newest therapies
· At the ASH/ASCO Joint Symposium, Sundar Jagannath,
being developed. He pointed out that it is important to
St. Vincent's Comprehensive Cancer Center, New York,
tailor treatment to individual patients at the time their dis-
presented the final results of PX-171-003-A0, part 1 of
ease relapses, taking into consideration the tempo of dis-
an open-label, single-arm, phase II study of carfilzomib
ease, previous side effects and responses, and how long the
(CFZ) in patients with relapsed and refractory multiple
previous remission lasted. Practical issues should also be
myeloma. This joint symposium is a review of what the
considered, and include access to drugs as determined by
ASH meeting organizers feel represents some of the best
country or insurance, where patients live relative to where
science from the 2009 American Society of Clinical Oncol-
they receive treatment, and patient preference. Of the hun-
ogy (ASCO) 2009 Annual Meeting, which was held in June.
dreds of drugs being tested in the laboratory and in animals
(preclinical testing), only a few make it to clinical trials in
· An education session was held on how to treat young
patients, and are then licensed and available for use in treat-
patients, old patients, and patients with relapsed/refrac-
ment. Some drugs that have shown little or no activity as
tory myeloma.
single agents in small trials might still be active when com-
bined with other drugs. There may be subsets of myelomas
· A scientific session, "Scientific Linking of Unusual Mani-
that could respond to any given therapy. Advances in deter-
festations of Myeloma," was held.
mining what genes in the myeloma are more or less active
· At least 15 simultaneous oral sessions (about 6 presen-
could provide information on the subtypes of myeloma that
tations each) were held specifically on myeloma, with
would respond to current therapies and those in devel-
many other sessions presenting related information on
opment, as well as guide development of more specific
Compiled by Lynne Lederman, PhD
therapies. Promising agents still in trials that Dr. Stewart
Funded by unrestricted educational grants from Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals.
3
mentioned include bendamustine, pomalidomide, carfilzo-
was well tolerated across all phase 2 trials. Carfilzomib will
mib, perifosine, vorinostat, tanespimycin, and NPI-0052, all
be tested in a phase 3, randomized, international trial in
of which are discussed below.
combination with lenalidomide later in 2010.
Proteasome Inhibitors
Some additional carfilzomib trials and conclusions
(additional details are provided in the ASH 2009 Sum-
Carfilzomib (PX-171)
mary for Physicians):
Encouraging results for the second-generation protea-
· Updated Results of Bortezomib-Naïve Patients in PX-171-
some inhibitor, carfilzomib, were reported in several talks
004, An Ongoing Open-Label, Phase II Study of Single-
and at least half a dozen posters. The final results of the
Agent Carfilzomib (CFZ) in Patients with Relapsed or
phase 2 study in relapsed and refractory myeloma that were
Refractory Myeloma (MM), resented by Luhua Wang, MD
reported at the ASH/ASCO Joint Symposium by Dr. Jagan-
Anderson Cancer Center, Houston, Texas (Abstract 302)..
nath are summarized below, followed by a list summariz-
Phase 2 (004 trial) in 115 patients. Single agent carfil-
ing the results of other studies and trials of carfilzomib that
zomib shows significant activity in relapsed refractory
were reported at ASH. It is anticipated that pivotal trials sup-
myeloma. Side effects are generally mild and manageable.
porting a new drug application (NDA) for this promising
Trial is ongoing.
agent will be completed by the end of 2010. A randomized
international multicenter phase 3 study will begin enroll-
· PX-171-004, An Ongoing Open-Label, Phase II Study of
ment of 700 patients in early 2010 to compare carfilzomib
Single-Agent Carfilzomib (CFZ) in Patients with Relapsed
plus lenalidomide and low-dose dexamethasone (CRd) with
or Refractory Myeloma (MM); Updated Results From the
lenalidomide plus low-dose dexamethasone (Rd).
Bortezomib-Treated Cohort, presented by David Siegel,
Hackensack University Medical Center, Hackensack, New
Final Results of PX-171-003-A0, Part 1 of an Open-Label,
Jersey (Abstract 303). Phase 2 trial in 35 patients. Single-
Single-Arm, Phase II Study of Carfilzomib (CFZ) in
agent carfilzomib is tolerable, with durable response and
Patients (pts) with Relapsed and Refractory Multiple
disease control, lacks significant side effects, suggesting it
Myeloma (MM) was presented by Sundar Jagannath, St.
is good for combination therapy.
Vincent's Comprehensive Cancer Center, New York, NY. Dr.
Jagannath reviewed carfilzomib and preclinical data show-
· Phase Ib Multicenter Dose-Escalation Study of Carfilzo-
ing that this proteasome inhibitor was active against bort-
mib Plus Lenalidomide and Low-Dose Dexamethasone
ezomib- (Velcade-) resistant solid tumor cells. In the first
(CRd) in Relapsed and Refractory Multiple Myeloma
part of the PX-171-003-A0 trial in patients with relapsed,
(MM), presented by Ruben Niesvizky, Weill Cornell Medi-
refractory myeloma who had received prior therapy includ-
cal College, New York, New York. (Abstract 304). Phase Ib
ing bortezomib and immunomodulatory drugs (IMiDs;
(006 trial) in 32 patients in combination with lenalido-
thalidomide and/or lenalidomide), 26% of the 46 patients
mide and dexamethasone. Combination is well tolerated
had a clinical benefit response (CBR), which included com-
in patients heavily pretreated with bortezomib and IMiDs.
plete response (CR) plus partial response (PR) plus minimal
Maximum tolerated dose (MTD) was not reached, no
response (MR). Dr. Jagannath concluded that single-agent
dose limiting toxicities (DLTs, meaning side effects severe
carfilzomib is active in heavily treated patients including
enough to require a dose reduction). Prolonged admin-
those with bortezomib-refractory myeloma. The A0 part 1
istration is possible for >16 months. More patients are
portion of this trial was expanded to PX-171-003-A1, a piv-
being enrolled.
otal dose-escalation trial, increasing the dose of carfilzomib
after the first cycle from 20 to 27 mg/m2. This trial enrolled
· Carfilzomib (CFZ), a Novel Proteasome Inhibitor for
269 patients as of October, 2009, and a safety review was
Relapsed or Refractory Multiple Myeloma, Is Associated
available for 141 patients who received treatment for at least
with Minimal Peripheral Neuropathic Effects, presented
6 months. Side effects have been minimal, with lower rates
by Ravi Vij, Washington University School of Medicine, St.
of serious side effects than were seen in the A0 portion of
Louis, Missouri (Abstract 430). Phase 2 trials (combined
the trial. The rates of peripheral neuropathy (nerve dam-
analysis of 003 and 004 trials) in 135 patients. No trend
age) and acute kidney failure have also been low. Across
for worsening of neuropathy, 36% patients received more
all trials of carfilzomib to date, in which 357 patients have
than 6 cycles of carfilzomib; peripheral neuropathy (PN)
received the drug, the overall rate of serious neuropathy has
not a significant side effect of carfilzomib.
been less than 2%. Dr. Jagannath concluded that carfilzomib
4
NPI-0052
diarrhea and fatigue, and also decreased numbers of blood
Phase 1 Clinical Trial of the Novel-Structure Protea-
cells. Serious side affects included alterations in the electri-
some Inhibitor NPI-0052 in Patients with Relapsed and
cal activity of the heart associated with vorinostat. There was
Relapsed/Refractory Multiple Myeloma (MM) (Abstract
possible activity in patients who had received prior lenalid-
431) was presented by Paul Richardson, Dana-Farber Can-
omide. Because the MTD was not reached, enrollment in
cer Institute, Boston, Massachusetts. NPI-0052 is a novel
phase 2 will continue.
second-generation proteasome inhibitor that is not based
Vorinostat in Combination with Peg ylated Liposomal
on a protein structure and is different from bortezomib and
Doxorubicin and Bortezomib for Patients with Relapsed/
carfilzomib. It exhibits fast, marked, prolonged inhibition
Refractory Multiple Myeloma: Results of a Phase I Study
of all activities of the proteasome, with side effects that are
(Abstract 306) was presented by Peter M. Voorhees, Line-
different than those reported for bortezomib. There are two
berger Comprehensive Cancer Center, Chapel Hill, North
formulations of NPI-0052, an old liquid formulation and a
Carolina. Although single-agent vorinostat is tolerable, treat-
new lyophile formulation to which studies are being tran-
ment resulted in no responses. There are good reasons to
sitioned. NPI-0052-101 is a phase 1 study in patients with
combine vorinostat with other agents, because in preclini-
relapsed and relapsed/refractory myeloma for which no
cal studies there was increased activity when vorinostat was
other approved treatment is available. To date 32 patients
combined with bortezomib and anthracyclines (drugs like
are enrolled. The study started at low doses of the liquid
doxorubicin). In this study, bortezomib was combined with
formulation and increased to higher doses of both the liq-
standard pegylated, liposomal doxorubicin (PLD), a combi-
uid and the lyophile formulation. NPI-0052 is well tolerated,
nation approved for patients with myeloma, plus increasing
with few serious side effects, mostly at highest dose, that
doses of vorinostat. There are not many patients currently
are manageable with supportive measures. Fatigue, signifi-
enrolling at the highest dose levels. Side effects are com-
cant neuropathy, and decreased blood cell counts were not
mon, and the doses may need to be adjusted for side effects
seen. Some side effects associated with the liquid formula-
affecting blood cells. Side effects include PN, hand-foot syn-
tion (the carrier, not the active drug) were not seen with the
drome (a known side effect of PLD), an allergic-like reaction
lyophile formulation. More trials are planned. Dr. Richard-
to PLD, and heart problems in two patients. The response
son thinks the future of NPI-0052 is in combination therapy.
rate for the small group (8 patients) in this trial was encour-
Histone Deacetylase (HDAC)
aging, but patients were chosen in such a way that they may
Inhibitors
have had less severe disease. Alternate dosing schedules for
the next levels are being explored.
Vorinostat (SAHA, suberoylanilide hydroxamic
Vorinostat in combination with bortezomib in relapsed or
acid)
refractory myeloma was also the subject of two posters,
Combined Vorinostat, Lenalidomide and Dexametha-
Abstract 3886 by Sundar Jagannath, St. Vincent's Compre-
sone Therapy in Patients with Relapsed or Refractory
hensive Cancer Center, New York, and Abstract 3890, by
Multiple Myeloma: A Phase I Study (Abstract 305), was
David Siegel, Hackensack University Medical Center, Hack-
presented by David Siegel, Hackensack University Medical
ensack, New Jersey. In one study, MTD was not reached
Center Hackensack, New Jersey. This study was based on
and doses were recommended for future study. The com-
the observation that in preclinical trials combining vorino-
bination of oral vorinostat and bortezomib was described
stat with IMiDs increased their anti-myeloma activity. The
as showing promising activity with acceptable side effects.
primary objective was to determine MTD, which was not
The second study, a phase 2b open-label trial (Vantage 095)
met. Secondary objectives included safety and response.
is ongoing, and to date shows acceptable tolerability of the
Vorinostat was administered one week on, one week off in
combination. Responses will be evaluated in 2010.
28-day cycles, in combination with lenalidomide adminis-
tered for 21 days of the cycle, and dexamethasone admin-
Panobinostat (LBH589)
istered once a week. In 31 patients with heavily pretreated
Oral panobinostat (LBH589) has been tested in a phase 1b
lenalidomide-refractory myeloma, there was one DLT of
study in combination with bortezomib in relapsed myeloma
diarrhea at the highest dose in the dose-finding trial, and no
(Abstract 3852, Jesús F. San-Miguel, Hospital Universitario
further DLTs when more patients were treated; an expan-
de Salamanca, Salamanca, Spain). The study of increasing
sion cohort was treated at a higher dose. Most patients in
doses is ongoing, and the dosing schedule may need to be
the expansion cohort experienced side effects, commonly
changed to allow better management of thrombocytopenia
5
(a decreased number of platelets, or "thrombocytes," the
monoclonal antibodies are produced to react to a particular
particles in the blood that allow it to clot).
protein, for example, one that is produced on the surface of
myeloma cells but not on the surface of most normal cells.
Low-dose panobinostat has also been tested in a phase 1/2
Elotuzumab, discussed below, was the most promising
dose-escalation study in combination with oral melphalan in
monoclonal antibody reported on at the meeting.
relapsed/refractory myeloma (Abstract 1855, James Beren-
son, Oncotherapeutics, Los Angeles, California). The most
Elotuzumab (HuLuc63, anti-CS1 mAb)
common serious side effects were decreases in platelets and
Phase 1/2 Study of Elotuzumab in Combination with
white blood cells that were reversible. Once the MTD has
Lenalidomide and Low-Dose Dexamethasone in
been determined and the dose and schedule optimized, an
Relapsed or Refractory Multiple Myeloma: Interim
expanded phase 2 trial will be conducted.
Results (Abstract 432) was presented by Sagar Lonial,
Heat Shock Protein 90 (Hsp90)
Winship Cancer Institute, Emory University, Atlanta, Geor-
gia. Elotuzumab is a human monoclonal antibody (mAb) of
Disrupter
the IgG1 type targeting CS1, a cell surface glycoprotein. CS1
Heat shock protein 90 (Hsp90) protects cells against various
is highly and uniformly expressed on myeloma cells, with
stresses. Inhibiting Hsp90 may contribute to the destruction
restricted expression on natural killer (NK) cells, and little
of some of the proteins that enhance the growth and sur-
to no expression on other normal tissues. The anti-tumor
vival of myeloma cells.
activity of elotuzumab was enhanced by lenalidomide in a
mouse model of myeloma. This report is an early look at
Tanespimycin (17-AAG)
results of a phase 1/2 clinical trial in 28 patients. Side effects
Tanespimycin (17-AAG) disrupts heat shock protein 90
were expected for lenalidomide plus dexamethasone, and
(Hsp90), and is being studied in several settings. Ashraf Z.
there were some reactions as expected for monoclonal
Badros, University of Maryland Medical Center, Baltimore,
antibody therapy, including allergic shock and infusion
Maryland, presented the poster, Tanespimycin + Bort-
reactions. The dose determined to be effective in animals
ezomib in Relapsed/Refractory Myeloma Patients: Results
is achievable in patients with biweekly dosing. The results
From the Time-2 Study (Abstract 1871). Paul G. Richard-
look promising, and further studies are planned to deter-
son, Dana-Farber Cancer Institute, Boston, Massachusetts,
mine the best dose, and whether after weekly dosing dur-
presented the poster Tanespimycin + Bortezomib Dem-
ing initial treatment with the higher dose, treatment could
onstrates Safety, Activity, and Effective Target Inhibition in
subsequently be given every other week.
Relapsed/Refractory Myeloma Patients: Updated Results of
A poster, Phase 1/2 Study of Elotuzumab in Combination
a Phase 1/2 Study (Abstract 2890). These studies reported
with Bortezomib in Patients with Multiple Myeloma Fol-
similar findings, concluding that sufficient tolerability and
lowing 1 to 3 Prior Therapies: Interim Results (Abstract
activity were seen to support a phase 3 study of the com-
3876) was presented by Andrzej Jakubowiak, University of
bination of tanespimycin plus bortezomib. The studies in
Michigan Comprehensive Cancer Center, Ann Arbor, Michi-
patients suggested that tanespimycin protects from bortezo-
gan. This was a dose-escalation study of elotuzumab plus
mib-mediated peripheral neuropathy (PN). An animal study,
standard bortezomib. The interim data from 26 patients
Tanespimycin Prevents Bortezomib Toxicity and Preserves
showed manageable side effects, with two serious adverse
Neuronal Morphology in Primary Rat Dorsal Root Ganglion
events (SAEs, or serious side effects) in one patient but no
Cultures (Abstract 2847) presented as a poster by Oliver
DLTs, and MTD was not reached. Enrollment is ongoing.
P. Flint, Research and Development, Discovery Toxicology,
Bristol-Myers Squibb, Princeton, New Jersey, showed that
Immunomodulatory Drugs (IMiDs)
protection from bortezomib neuropathy by tanespimycin
depended on the dose.
Pomalidomide
A Phase 1/2 Multi-Center, Randomized, Open Label
Monoclonal Antibodies (mAbs)
Dose Escalation Study to Determine the Maximum
A monoclonal antibody is an immune protein that is clonal,
Tolerated Dose, Safety, and Efficacy of Pomalidomide
that is, derived from one type of anti-body-producing
Alone or in Combination with Low-Dose Dexametha-
immune cell, and has the ability to bind specifically to one
sone in Patients with Relapsed and Refractory Multiple
target. As you know, the M-protein produced by myeloma
Myeloma Who Have Received Prior Treatment That
cells is a type of monoclonal antibody. Therapeutic
Includes Lenalidomide and Bortezomib (Abstract 301)
6
was presented by Paul Richardson, Dana-Farber Cancer
begin soon comparing perifosine, bortezomib, and dexa-
Institute, Boston, Massachusetts. Pomalidomide is a novel,
methasone to bortezomib plus dexamethasone
third-generation IMiD, structurally similar to thalidomide
and lenalidomide, showing increased activity in preclini-
There are other new drugs that are in early stages of devel-
cal studies and different clinical efficacy and safety profiles.
opment as single agents or in combination therapy. Several
In this study, pomalidomide was administered alone and
drugs are also being developed to target and kill myeloma
with low-dose dexamethasone in patients with relapsed/
cells specifically, leaving other cells untouched. These are
refractory myeloma and prior therapy with at least 2 cycles
based on combining a molecule such as a mAb or bind-
of lenalidomide and bortezomib. Phase 1 determined the
ing agent that attaches to a component on the surface of
MTD; phase 2 was a randomized study of pomalidomide
myeloma cells (but not other cells) with an agent capable of
with and without low-dose dexamethasone, with a white
killing the myeloma cell.
blood cell growth factor (G-CSF) administered after the first
cycle. The most common side effect was decreased blood
Newly Diagnosed Myeloma
cell counts, including white blood cell counts; patients also
Transplant-Eligible Patients
experienced fatigue. Serious blood clots occurred in two
patients and significant PN occurred in one patient. Nearly
Several important issues for transplant-eligible patients con-
half of patients received dexamethasone, which improved
tinue to be investigated, including whether there is a differ-
the response in about half of the patients. Phase 2 is ongo-
ence in early or delayed transplantation in the era of novel
ing, with completion anticipated in the last quarter of 2010
agents; if patients can be considered to be cured; what the
for 200 patients, and will include an analysis of the altered
best combination of drugs is; and how many drugs a combi-
expression of genes that may affect treatment and response.
nation should include.
Pomalidomide (CC4047) Plus Low-Dose Dexametha-
How to Treat a Young Patient, focusing on the role, advan-
sone (Pom/dex) Is Active and Well Tolerated in Lenalid-
tages, and disadvantages of some of the many proposed
omide-Refractory Multiple Myeloma (MM) (Abstract
therapeutic approaches for the newly diagnosed, younger
429) was presented by Martha Q. Lacy, Mayo Clinic,
patient with myeloma (younger than age 65 to 70 years),
Rochester, Minnesota. Results for 60 patients on this trial
was discussed by Jesús F. San Miguel, Hospital Clinico Uni-
have been presented. An additional 34 patients have been
versitario de Salamanca, Salamanca, Spain, at the Multiple
enrolled to further determine response rate and toxicity.
Myeloma Education Session. Dr. San Miguel addressed this
More patients in this study had high-risk disease than in
topic in depth in a paper published in Hematology 2009,
the general patient population. Patients received pomalido-
which is available from ASH. This paper summaries all rel-
mide plus dexamethasone. The combination was generally
evant studies to date. Therefore, only the main points are
well tolerated. The major side effects included decreased
summarized here. For a young patient with high-risk dis-
white blood cell counts and PN. Dr. Lacy concluded that
ease, novel drugs, especially bortezomib, seem to overcome
pomalidomide plus dexamethasone had significant activity
the risk, but the number of patients studied is limited and
in heavily pre-treated myeloma refractory to lenalidomide
follow-up is short. It is premature to base specific therapy
with manageable toxicity. The overall response rate and
on the chromosome pattern (cytogenetics) of a patient's
duration of response appear similar to those obtained with
myeloma. Large clinical trials need to enroll both standard-
novel therapy combinations, such as those containing tha-
risk and high-risk patients and collect information. Experi-
lidomide, lenalidomide, or bortezomib, but pomalidomide
mental pilot studies are a potential option for those with
combinations need further investigation.
high-risk cytogenetics, for example, targeted therapy for
t(4;14), FGFR kinase inhibition, or combinations of thera-
Other New Drugs
pies where each drug kills myeloma cells in a different way.
Outside of clinical trials, one option is induction (initial
Perifosine, an oral drug that modulates signal transduc-
therapy) with a novel agent (bortezomib, lenalidomide, or
tion, is in a phase 1/2 trial in combination with bortezomib
thalidomide) or a drug combination, followed by autolo-
in patients with relapsed/refractory myeloma previously
gous stem cell transplant (ASCT; patients receive their own
treated with bortezomib (Abstract 1869, Paul Richardson,
blood cells) with high-dose melphalan (MEL). Then, if the
Dana-Farber Cancer Institute, Boston, Massachusetts). The
myeloma is in complete remission (CR), maintenance ther-
combination showed activity (ORR 41%), durable responses,
apy with lenalidomide can be given, and if the disease is
a median OS of 25 months, and good tolerability. These
not in CR, consolidation with a novel agent combination
results form the basis of a phase 3 trial that is expected to
7
can be given. An alternative option is to postpone transplant
audience believed that consolidation is needed after ASCT,
and treat with novel combination therapy, although because
Dr. Moreau pointed out that there are no reliable results
there is always a significant increase in CR rate after ASCT,
showing the need for consolidation, which is the subject of
induction with novel therapies and ASCT are complemen-
investigation. There are results that show the importance of
tary. The efficacy of conditioning regimens, with MEL 200 as
maintenance therapy, something much of the audience was
the standard, could be improved with the addition of busul-
aware of. The benefit of thalidomide maintenance has been
fan or bortezomib.
shown; more information is needed to support the use of
lenalidomide, and studies are ongoing to answer that ques-
Young patients at the beginning of therapy are more fit
tion. A topic addressed in Dr. Moreau's presentation was
and may tolerate intensive treatment and SCT better. This
one that was discussed in other presentations at this meet-
is associated with a long survival period free of myeloma-
ing, namely whether combination therapies incorporating
related problems, and good quality of life (QoL). If disease
novel agents without ASCT are superior to ASCT. Most of
relapses after MEL 200, it will still respond to novel agents
the audience thought novel combinations were not more
but it isn't known what will happen after relapse following
effective than ASCT, and Dr. Moreau pointed out that there
treatment with novel agents. Dr. San Miguel pointed out
is no information. The joint IFM/DFCI 2009 clinical study
that early vs. delayed transplant is still being investigated,
in newly diagnosed patients who are SCT candidates will
and the joint randomized IFM/DFCI clinical trial may pro-
answer this question. Patients will be randomly assigned to
vide an answer. Dr. San Miguel believes that allogeneic
one of two groups. One group will receive lenalidomide plus
transplants for patients with myeloma (where patients
bortezomib plus dexamethasone (RVD) induction, stem cell
receive cells from a donor, not their own cells) should be
(SC) mobilization and collection, MEL 200 and ASCT, then
considered an investigational treatment and preferably be
RVD consolidation, followed by lenalidomide maintenance
performed as part of a clinical trial. Although allogeneic
therapy. The other group will receive RVD induction, SC
transplants have the potential to cure myeloma, they are
mobilization and collection, then RVD consolidation, and
associated with high treatment-related death rate, and avail-
lenalidomide maintenance therapy, with the option of SCT
ability of suitable donor cells is limited. His group's policy
at relapse.
is not to use allogeneic transplant for initial therapy, but to
consider it at relapse for high-risk patients, including those
A discussion among the panelists raised several unresolved
with early relapses after ASCT, provided their myeloma is
issues, including the necessity of conducting a phase 3 trial
under control at the time of the allogeneic transplant. The
if early-phase trial results are striking, the effect on trial
role of maintenance in CR, duration of maintenance, and
enrollment when drugs are available in some countries
outcome after relapse need to be investigated further, as
but not others, which combinations should be considered
does which novel therapies can overcome which particular
a standard of care for patients with standard-risk disease,
high-risk factors. Dr. San Miguel observed that progress in
the true efficacy and risks of the novel agents, particularly
the last decade has only been possible because of the par-
for long-term maintenance, and how best to manage newly
ticipation of patients and doctors in clinical trials. There are
diagnosed patients, for example, should all or most patients
now a large number of drugs being developed, such as the
be enrolled into clinical trials or should patients have more
HDAC inhibitors, that are looking for a place in treatment.
choices? There appeared to be a consensus that VGPR and
CR after ASCT resulted in similar survival curves, but par-
Updates in therapeutic approaches for transplanta-
tial response (PR) after ASCT warranted a second ASCT, and
tion-eligible patients was presented by Philippe Moreau,
with no further improvement, more therapy. It was pointed
University Hospital Hôtel-Dieu, Nantes, France, as part of
out that the percentage of eligible patients who receive
the IMF Symposium. He (and the audience) believes that
transplants varies by country, and the eligible age cutoff var-
ASCT remains the standard of care for eligible patients.
ies as well.
The preferred induction regimen prior to ASCT is cur-
rently bortezomib plus dexamethasone, but a bortezomib
Timing of Transplant
plus dexamethasone plus an IMiD combination may soon
Novel Agents for Initial Therapy of Multiple Myeloma:
replace it, because this combination triggers two different
Comparable Results with Continued Initial Therapy and
cell-killing pathways in malignant plasma cells. The audi-
Delayed Transplantation at Relapse Versus Early Trans-
ence agreed with Dr. Moreau that achievement of CR or very
plantation (Abstract 956) was presented by Shaji Kumar,
good partial response (VGPR) prior to ASCT should be the
Mayo Clinic, Rochester, Minnesota. This study looked
primary goal of induction therapy. Although a majority of the
back at results for approximately 290 transplant-eligible,
8
newly diagnosed patients treated with an IMiD at the Mayo
of information include the joint Dana-Farber/IFM clinical
Clinic from 2001 to 2008 to see if there was a difference
trial and the Arkansas trials, TT4 for low-risk myeloma and
in response or survival between those who received early
TT5 for high-risk myeloma, where treatment assignment is
vs. delayed SCT. There did not appear to be a difference in
based on gene expression information. Dr. Shaughnessy
response rates, time to disease progression following SCT,
commented that genes over-expressed in patient tumors
or overall survival. Because the study looked back at infor-
showing the cure fraction appear mostly on chromosome
mation already collected, it was not possible to determine
5, which agrees with Dr. Avet-Loiseau's information that
what influenced the decision to transplant early or late.
patients with increases in chromosome 5 have the best out-
Someone in the audience commented that patients whose
come. Notably, the glucocorticoid receptor (the molecule
disease was likely to have a better outcome could have been
to which dexamethasone and prednisone can bind on the
selected for later transplantation. There were no quality
surface of myeloma cells) occurs on chromosome 5, which
of life measurements (QoL), and no information on the
would explain the efficacy of dexamethasone therapy.
time to next therapy. Dr. Kumar noted that a lot of patients
received IMiD-based therapy until the time of relapse, and
Three-Drug Combinations
that it would be important to collect information about the
A Phase II Trial Comparison of Once- Versus Twice-
decision-making process, specific therapy before and after
Weekly Bortezomib in CyBorD Chemotherapy for
SCT, and QoL in a new trial going forward.
Newly Diagnosed Myeloma: Identical High Response
Rates and Less Toxicity (Abstract 616) was presented by
Cure Rate with Total Therapy (TT)
Craig B. Reeder, MD, Mayo Clinic, Scottsdale. Arizona. This
Modeling for Cure with Total Therapy (TT) Trials for
was a phase 2 single-arm trial investigating the role of novel
Newly Diagnosed Multiple Myeloma (MM): Let the Math
agents plus an alkylating agent that can cause damage to the
Speak (Abstract 744) was presented by Bart Barlogie, Uni-
DNA of myeloma cells. The three-drug combination CyBorD
versity of Arkansas for Medical Sciences, Little Rock, Arkan-
(cyclophosphamide, bortezomib, dexamethasone) was pre-
sas. Dr. Barlogie reviewed the results of the Total Therapy
viously shown to be safe and well tolerated in patients with
(TT) 1, 2, and 3 trials in the context of modeling for cure
relapsed refractory myeloma. The goal of this study was a
in these trials. The model takes into account event-free sur-
high-depth, fast response prior to SCT. Some results have
vival (EFS), including reversion to a state resembling MGUS
been published showing rapid response and ability to col-
(monoclonal gammopathy of undetermined significance)
lect stem cells. However, dose reductions were needed
and duration of complete response, to predict cure frac-
for all drugs due to side effects. A new group received a
tions. The model takes survival curves (known as Kaplan-
modified CyBorD regimen, with weekly bortezomib and
Meier plots) and looks for the presence of a plateau, that
cyclophosphamide, and reduced doses of dexamethasone
is, the time from treatment when the group of surviving
after the first 4 weeks. This resulted in reduced side effects,
patients who received a particular treatment continue to
although moderate PN was still a problem. The modified
survive, with no or few additional deaths in the group. Rela-
regimen resulted in less toxicity, so there were fewer dose
tive survival ratios were calculated by comparing the actual
reductions and higher overall doses could be given; it was
survival of patients with expected survival of a comparable
more convenient, and it allowed for successful stem cell
group of people in the general population. The amount of
harvest. Dr. Reeder said that this regimen doesn't protect
time it takes for the relative survival ratios to be equal are
patients with high-risk myeloma from relapse, and that
17 years for TT1, 10 years for TT2, and 5 years for TT3. Dr.
although the initial response was good for both regimens,
Barlogie concluded that, particularly with more recent treat-
high-risk patients need either a different conditioning regi-
ment regimens, cure is a realistic goal of myeloma therapy.
men or maintenance therapy.
The high cure fraction value in TT3 (55%) for patients with
low-risk myeloma is evidence that inclusion of both bort-
Velcade, Intravenous Cyclophosphamide and Dexa-
ezomib and thalidomide increases efficacy of TT3. However,
methasone ( VCD) Induction for Previously Untreated
more effective therapy is still needed to improve outcomes
Multiple Myeloma (German DSMM XIa Trial) (Abstract
for patients with high-risk disease, which still has a relatively
131) was presented by Hermann Einsele, University of
low average survival. Dr. Barlogie suggested that improve-
Wurzburg, Wurzburg, Germany. The aim of this study was to
ments in looking at the genes expressed in myelomas
improve CR rates before and after transplant by using novel
might allow researchers to identify curable and currently
agents as part of the induction regimen on the assumption
incurable myeloma. Trials that will incorporate this type
that improving CR + VGPR rates could result in further
9
improved long-term outcomes. There were 395 evaluable
more serious reduced white blood cell counts in patients
patients, and a quarter of them had serious side effects. Dr.
receiving cyclophosphamide. During the discussion, Dr.
Einsele concluded that 3 cycles of bortezomib, cyclophos-
Kumar pointed out that more follow-up was needed to
phamide, dexamethasone (VCD) for induction therapy is
determine if the 4-drug combination would result in longer
among one of most active regimens, and overcomes tradi-
progression-free survival, and if it was better to use bortezo-
tionally poor-risk cytogenetics for response, although data
mib plus an IMiD together or sequentially. He said that if the
are not yet available for progression-free survival or overall
use of the 4 drugs resulted in a deep response and changed
survival. This regimen has a good safety profile, with a treat-
the natural history of the disease to get to the lowest mini-
ment-related mortality of less than 1%. With an acceptable
mum residual disease, then it might be possible to use all 4
rate of mild to moderate polyneuropathy and low risk of
drugs again later at relapse.
blood clots, use of VCD is feasible in an outpatient setting.
Final results will be available at the 2010 ASH Meeting. This
Bortezomib, Melphalan, Prednisone and Thalidomide
study is forming the basis for a larger intergroup study. In
( VMPT) Followed by Maintenance with Bortezomib and
response to a question, Dr. Einsele explained that in Ger-
Thalidomide for Initial Treatment of Elderly Multiple
many patients are only eligible for high-dose therapy and
Myeloma Patients (Abstract 128) was presented by Anto-
ASCT up to age 60 years. For patients age 60 to 70 years
nio Palumbo, University of Turin, Turin, Italy. The aim of
there is a different high-dose melphalan 140 (instead of 200
this study was to compare the best experimental treatment
mg of melphalan per square meter of body mass) SCT proto-
to the standard of care for the newly diagnosed, elderly
col, so it is difficult to compare across trials. One reason for
myeloma patient population.. In Dr. Palumbo's opinion, the
using this intravenous treatment regimen was to ensure that
best 4-drug combination is VMPT (bortezomib, melphalan,
newly diagnosed patients are seen weekly and receive treat-
prednisone, thalidomide), and the standard of care is the
ment for infections and other supportive care if necessary.
3-drug combination VMP (bortezomib, melphalan, predni-
sone) for this population. VMPT was followed by VT main-
Three- and Four-Drug Combinations
tenance. Bortezomib was initially given twice weekly, then
Novel Three- and Four-Drug Combinations of Bort-
reduced to once weekly, which reduced the rate and sever-
ezomib, Dexamethasone, Cyclophosphamide, and
ity of PN. Responses, time to next therapy, and progression-
Lenalidomide, for Newly Diagnosed Multiple Myeloma:
free survival were significantly longer for patients receiving
Encouraging Results From the Multi-Center, Random-
VMPT vs. VMP, but there were no differences in overall sur-
ized, Phase 2 EVOLUTION Study (Abstract 127) was
vival. Serious side effects were as expected, and increased
presented by Shaji Kumar, Mayo Clinic, Rochester, Min-
by the inclusion of thalidomide. Dr. Palumbo concluded
nesota. Because three-drug combinations of bortezomib
that VT maintenance improves progression-free survival,
with dexamethasone, cyclophosphamide, or lenalidomide
and longer follow-up is needed to assess overall survival.
have shown significant activity in untreated myeloma, this
Thalidomide / Dexamethasone (TD) Vs. Bortezomib
study looked at all 4 drug classes together. The results
( Velcade) /Thalidomide / Dexamethasone ( VTD) Vs.
of the phase 1 portion have already been presented else-
VBMCP/VBAD/Velcade® as Induction Regimens Prior
where. The safety and efficacy of the phase 2 portion, which
to Autologous Stem Cell Transplantation (ASCT) in
was intended to increase the complete response rate and
Multiple Myeloma (MM): Results of a Phase III PETH-
determine the best phase 3 trial design, were reported at
EMA/GEM Trial (Abstract 130) was presented by Laura
this meeting. Four treatment arms were compared: VDCR
Rosiñol, Barcelona, Spain. There were 306 patients in this
(bortezomib, dexamethasone, cyclophosphamide, lenalido-
study randomized to one of 3 arms: VBMCP/VBAD, TD, or
mide); VDR (bortezomib, dexamethasone, lenalidomide);
VTD. Patients receiving VTD had the highest response rates.
VDC (bortezomib, dexamethasone, cyclophosphamide);
Patients with higher-risk disease based on cytogenetics had
and VDC modified to include an extra dose of cyclophos-
better responses to bortezomib-containing regimens. Side
phamide on day 15 because the response seen with VDC
effects were similar, but TD was associated with a higher
seemed lower than expected from published results. The
rate of blood clots, and VTD was associated with a higher
best response rates are similar in the VDCR and VDR arms.
rate of PN. The CR rates increased after ASCT. Patients
About a third of patients in each arm have had stem cells
receiving TD had significantly shorter times to progression
harvested, with 2 or 3 failures to collect in the VDCR and
and progression-free survival. There is no difference among
VDR arms. This did not occur in the VDC arms. Nearly all of
treatments for overall survival at the current time.
the 138 patients have had had at least one side effect, with
10
Bortezomib in Combination with Peg ylated Liposo-
followed by VT, VMP followed by VP, VTP followed by VT,
mal Doxorubicin and Thalidomide ( VDT), An Effec-
and VTP followed by VP. Study goals included determining
tive Steroid-Independent Regimen for Previously
the best agents to add to bortezomib therapy, decreasing
Untreated Multiple Myeloma Patients: Final Result of a
side effects by reducing doses of bortezomib, and adding
Phase II Study (Abstract 618) was presented by Taimur
maintenance therapy to maintain efficacy. There was no dif-
Sher, Roswell Park Cancer Center, Buffalo, New York. In this
ference in the overall response rate for VMP vs. VTP. The side
study in 40 patients, the steroid-free regimen of bortezo-
effects were generally higher in the VMP group, but serious
mib (every other week schedule) plus PLD plus thalidomide
side effects, including PN, and discontinuations were higher
resulted in good response rates and time to progression.
in the VTP group. The rate of confirmed complete response
There were significant side effects, including hand-foot syn-
increased after maintenance therapy. There is no difference
drome, infections, neuropathy, and some blood clots. Dr.
in progression-free survival with VMP vs. VTP. Dr. Mateos
Sher concluded that this regimen would be an acceptable
concluded that alkylating agents (in this case, melphalan)
alternative for patients who can't tolerate steroids.
should remain important drugs for the treatment of elderly
untreated patients. The weekly schedule of bortezomib sig-
Transplant-Ineligible Patients
nificantly reduced PN. Maintenance therapy increased the
Dr. Maria-Victoria Mateos's presentation during the Plenary
CR rate with low side effects. VT maintenance showed supe-
Session was introduced by Dr. Donna Weber, MD Anderson
rior time to events, but lenalidomide should be explored
Cancer Center, Houston, Texas, who reviewed random-
as maintenance therapy. Currently, the combination of VMP
ized trials in elderly patients who are not transplant candi-
followed by VT is significantly superior to VTP followed by
dates. Dr. Weber noted that there are more questions than
VP in this patient population. Notably, high-risk cytogenet-
answers as the number of possible combinations of novel
ics are overcome by either regimen.
and conventional chemotherapy agents increases. Although
there have been improvements in response rates and pro-
How to Treat an Elderly Patient: Combination Therapy
gression-free survival, these don't necessarily translate into
or Sequencing was presented by Antonio Palumbo, MD,
improved overall survival. Questions remain about the role
University of Torino, Torino, Italy, as part of the Multiple
of consolidation therapy for elderly patients who may go on
Myeloma Education Session. This topic is presented in
to SCT. The study presented by Dr. Mateos is the first time
depth in a paper, co-authored by Dr. Palumbo and Franc-
a combination including a novel agent has been used as the
esca Gay, published in Hematology 2009, which is available
comparator arm for another novel agent-containing regi-
through ASH. This paper reviews diagnosis and treatment
men. A review of trials of maintenance therapy after ASCT
of myeloma in general, and historically for elderly patients,
has shown various results from negative effects to no effect
summarizes current treatment options, including the effi-
to improved results. Novel agents for induction therapy in
cacy of regimens used for front-line treatment of this patient
cytogenetic high-risk myeloma, for example, the inclusion
population, the role of maintenance therapy, and manage-
of bortezomib in TT2, may lead to improved survival, but
ment of AEs. Dr. Palumbo believes that MPT should be con-
the use of novel agents such as lenalidomide in mainte-
sidered a major standard of care in elderly patients. Both
nance therapy needs further study.
thalidomide and lenalidomide treatment should include a
drug to prevent blood clots, and previous clots, infection,
Plenary Session
lack of mobility, conventional chemotherapy, or doxorubi-
cin add to the risk of clots. The best agent to prevent deep
A Prospective, Multicenter, Randomized, Trial of Bort-
vein thrombosis (DVT), a type of life-threatening blood clot,
ezomib/Melphalan/Prednisone ( VMP) Versus Bort-
remains a question; however, low molecular weight heparin
ezomib/Thalidomide/Prednisone ( VTP) as Induction
(LMWH), which has been tested against aspirin and warfa-
Therapy Followed by Maintenance Treatment with Bort-
rin, may be best for patients at highest risk for clots, and
ezomib/Thalidomide ( VT) Versus Bortezomib/Predni-
aspirin, which can protect the heart, may be best for stan-
sone ( VP) in Elderly Untreated Patients with Multiple
dard-risk patients. VMP is also a current standard of care,
Myeloma Older Than 65 Years (Abstract 3) was pre-
with PN as a major side effect. Reduction of bortezomib
sented by Maria-Victoria Mateos, University of Salamanca,
from twice weekly to once weekly may reduce both the risk
Salamanca, Spain, during the Plenary Session. This study
of neuropathy and the discontinuation rate. MPR also has
randomly assigned 260 patients to VMP vs. VTP as induction
the potential to become a standard of care. Dr. Palumbo cur-
therapy followed by maintenance with VT vs. VP for up to
rently suggests MPT (if reduced blood cell counts are a con-
three years. Therefore, there are 4 treatment groups, VMP
cern) or MPR (if neuropathy is a concern) for older patients
11
at standard risk and VMP (if clots and/or kidney failure are
Phase 3b UPFRONT Study: Interim Results From a
concerns) for high-risk younger patients.
Community Practice-Based Prospective Randomized
Trial Evaluating Three Bortezomib-Based Regimens in
Future options include moving to combination therapy
Elderly, Newly Diagnosed Multiple Myeloma Patients
with 4 drugs, e.g., VMPT, to increase response, and add-
(Abstract 129) was presented by Ruben Niesvizky, Cor-
ing maintenance, e.g., with bortezomib, thalidomide, or
nell/New York Presbyterian Hospital, New York. This study
lenalidomide plus low-dose dexamethasone, to improve
is ongoing and still recruiting patients. In this open-label,
the duration of remission. Alternative options include using
community-based trial, patients were randomly assigned to
single agents in a sequential "friendly" approach, with 1 or 2
one of three bortezomib-based regimens: VTD (bortezomib,
drugs up front, and a different drug at relapse. Dr. Palumbo
thalidomide, dexamethasone), VD (bortezomib, dexameth-
recommends adjusting therapy to the patient, with full-dose
asone), or VMP (bortezomib, melphalan, prednisone), fol-
therapy for those age 65 to 75 years if they have normal
lowed by maintenance with bortezomib. Patients receiving
heart, lung, liver, and kidney function. If they are younger
VTD also were given either aspirin, full-dose warfarin, or
than age 65 years they can probably tolerate full-dose ther-
LMWH to prevent clots unless there was a reason not to.
apy even if some organ functions are abnormal. Reduced-
Patients also received treatment to prevent shingles (her-
dose chemotherapy is recommended for those with normal
pes zoster). Results for patients who had received 4 cycles
organ function if they are older than age 75 years. Melpha-
were presented. The highest rate of PN occurred in patients
lan especially requires adjustment for patient age and side
receiving VTD, while side effects affecting blood counts
effects affecting blood cell counts, but so do lenalidomide,
were highest in the VMP arm. There were more deaths and
thalidomide, and bortezomib. As an example, bortezomib
pneumonia in patients receiving VD. In general side effects
may be reduced from twice to once a week to reduce nerve
were similar, and responses were good, but more follow-up
damage.
is needed. In a QoL assessment, improvement was seen for
all treatments, but patients receiving VTD reported worse
Practical recommendations for myeloma patients ineli-
physical and role functions, that is, more interference with
gible for transplantation was presented by Mario Bocca-
activities, including their usual daily activities. The Indepen-
doro, University of Torino, Torino, Italy, as part of the IMF
dent Data Monitoring Committee concluded that the study
Symposium. He reviewed published results of phase 3 trials
should continue with enrollment for all three treatments.
in the non-transplant eligible, newly diagnosed population.
Results show equivalence of TD and MP, superiority of MPT
A Phase III Study to Determine the Efficacy and Safety
and MPV over MP. Trials of MRP vs. MP and VMPT vs. VMP
of Lenalidomide in Combination with Melphalan and
presented at this ASH meeting are described elsewhere in
Prednisone (MPR) in Elderly Patients with Newly Diag-
this summary. Cyclophosphamide plus TD, and lenalido-
nosed Multiple Myeloma (Abstract 613) was presented by
mide plus reduced-dose dexamethasone are also being
Antonio Palumbo, University of Torino, Torino, Italy. In this
tested. Dr. Boccadoro discussed the increasing incidence
study, patients age 65 to 75 years were randomly assigned
of frail patients in the population of age 75 to 101 years
to one of 3 treatment arms: MPR-R (melphalan, prednisone,
at diagnosis, which he believes is the result of an increase
lenalidomide followed by continuous lenalidomide mainte-
in the older population rather than an increase in the inci-
nance), MPR, or MP. All patients could receive lenalidomide
dence of myeloma. This frail population is at risk of early
plus or minus dexamethasone if their disease progressed.
discontinuation from treatment as a result of toxicity, so
The patient population had a higher than usual percentage
regimens must be modified by dose reductions. Dr. Bocca-
of patients with more advanced myeloma. At a short follow-
doro presented a scheme for dose reductions for patients
up time, the data monitoring committee recommended
over age 75 years that could be further modified if necessary
revealing which patients received which therapy because
for frail elderly patients to keep them on therapy longer. It
there was a significant difference between the MPR and MP
was pointed out that although in some settings, thalidomide
groups. MPR combinations had a better overall response
maintenance after SCT is well established, it is not used in
rate and shorter time to response than MP alone. Side
France. Dr. Orlowski observed that it is difficult to compare
effects were as expected, and nearly half of patients receiv-
the non-transplant population in the US to that in Europe
ing MPR-R needed a blood cell growth factor. Dr. Palumbo
because the US population is older and therefore probably
concluded that continuous lenalidomide (MPR-R) was supe-
has a higher rate of other diseases in addition to myeloma.
rior to treatments of more limited duration because it led to
higher and more rapid responses and a 50% reduced risk of
progression. In response to a question, he said that there
12
are no survival data to determine whether bortezomib plus
not be available until later in 2010. He presented the case
MP (MPV) or MPR or MPT would be the better combina-
of a patient whose disease relapsed repeatedly. He pointed
tion in this patient population. He thought an IMiD plus MP
out that if a therapy worked once, it could be repeated or
might be more suitable for frail patients or those at standard
"tweaked" and could continue to provide benefit as long
risk, whereas the bortezomib MP combination could be rec-
as the patient had the relapse while off that therapy, had at
ommended for more fit patients or those with aggressive
least a year of benefit, and tolerated the therapy. Otherwise,
disease.
a regimen containing a class of agent the patient had not
previously received would be a better choice. Dr. Orlowski
Melphalan and Prednisone (MP) Versus Melphalan,
stated that in the relapsed/refractory setting, lenalidomide
Prednisone and Thalidomide (MPT) as Initial Therapy
plus dexamethasone or bortezomib plus PLD are standards
for Previously Untreated Elderly and/or Transplant-Inel-
of care. Carfilzomib and pomalidomide as single agents and
igible Patients with Multiple Myeloma: A Meta-Analysis
new combinations are showing promise, including combi-
of Randomized Controlled Trials (Abstract 615) was pre-
nations of bortezomib with HDAC inhibitors and other new
sented by Prashant Kapoor, Mayo Clinic, Rochester, Minne-
classes of agents. He concluded that patients with relapsed/
sota. This study was a review of previously published results.
refractory myeloma are now doing better than at any other
The authors did not have access to original patient informa-
time in the past.
tion, but are now reviewing that information. They found
that the addition of thalidomide to MP improved response
Diagnosis, Risk Stratification,
rates and progression-free survival, and also increased side
and Staging
effects, but did not support the use of MPT over MP for
improved overall survival. However, Dr. Kapoor thinks that
The evolving role of diagnostic testing and response
once their analysis is updated with results from the HOVON
criteria was presented by Dr. S. Vincent Rajkumar, MD,
study, it will show significant increased overall survival for
Mayo Clinic, Rochester, MN, as part of the IMF Symposium.
MPT vs. MP, but at the cost of additional side effects. He
He presented a case study of a man diagnosed with MGUS
pointed out that other effective regimens in elderly patients
as a result of routine blood tests. Two years later, this patient
include MPR and VMP, which need to be analyzed in com-
developed lytic bone lesions and was then diagnosed with
parison with MP, and concluded that MPT can be consid-
advanced stage multiple myeloma. Dr. Rajkumar reviewed
ered an appropriate front-line regimen in newly diagnosed,
diagnostic tests, including serum protein electrophoresis
transplant-ineligible elderly patients. The role of mainte-
(SPEP), which can show the presence of an M-spike in the
nance therapy has not been analyzed.
immunoglobulin (Ig) region; immunofixation electrophore-
sis (IFE), which is used to identify the type of antibody form-
Relapsed/Refractory Myeloma
ing the M-spike; and the free light chain (FLC) assay, which
can detect unbound Ig light chains. IFE is the test of choice
New approaches for patients with relapsed or refractory
to detect residual monoclonal Ig. He recommended SPEP
disease was presented by Robert Z. Orlowski, MD Anderson
and a 24-hour urine PEP (UPEP) for screening along with
Cancer Center, Houston, Texas, as part of the IMF Sympo-
serum IFE and FLC. He prefers using both the Durie-Salmon
sium. He observed that despite therapeutic improvements
and ISS staging systems because the Durie-Salmon system
for both transplant-eligible and non-eligible patients, most
measures disease burden. Once a patient is diagnosed, the
patients will eventually have relapsed disease. He reviewed
ISS can be used. Criteria in the mSMART (Mayo Clinic) clas-
the 2009 National Comprehensive Cancer Network (NCCN)
sification of high- vs. standard-risk active myeloma need to
guidelines by the quality of evidence for available treat-
be re-examined in the age of the novel and even newer ther-
ments, as well as what is currently known about active
apies. Both PET (positron emission tomography) and MRI
combinations and single agents, and mentioned many of
(magnetic resonance imaging) are useful for imaging. Read-
the studies of new agents being reported at this ASH meet-
ing the discussion of imaging in the International Myeloma
ing. He pointed out that although monoclonal antibodies
Working Group (IMWG) paper in Leukemia (which is avail-
(mAbs) have made a big difference in the treatment of lym-
able through the IMF at http://myeloma.org/pdfs/IMWG_
phomas and leukemias, they have not played a major role in
consensus_imaging.pdf )) was recommended.
the treatment of myeloma. He speculated that CNTO 328,
an anti-interleukin-6 (IL-6) mAb, particularly in combina-
Dr. Rajkumar reviewed the definitions of MGUS, SMM (smol-
tion with bortezomib, may prove useful in the treatment of
dering MM or asymptomatic MMAMM), and MM. In both
myeloma, but the results of a current randomized study will
MGUS and SMM there is neither anemia nor bone lesions,
13
and calcium and kidney function are normal. MGUS and
observed that to change treatment practice, a survival
SMM are distinguished by the amount of M-protein and per-
advantage has to be demonstrated. Dr. Mateos responded
centage of plasma cells (PC), and should not be treated. MM
that it was notable that most of the patients with progressive
is distinguished by the presence of anemia (low red blood
disease in the no treatment arm had bone lesions, which are
cell counts or reduced hemoglobin, the oxygen-carrying
irreversible in myeloma, although only a few patients had
protein in the blood), bone lesions, high calcium, and/or
bone surveys other than the basic skeletal survey at the time
abnormal kidney function related to the PC and M-spike. The
of entry into the study unless they had symptoms. They have
diagnosis of MM should be based on clinical factors (signs
not observed cytogenetic differences between the two treat-
and symptoms), not just laboratory test results. The risk of
ment groups. Longer follow-up is needed, and it is possible
MGUS progressing to MM over time is related to M-spike
that the interim analysis may indicate whether patients with
size and type and FLC. SMM is more likely to progress to
high-risk SMM should be treated. Dr. Durie commented that
MM than MGUS over time. Progression of MGUS to MM may
these were interesting results, but that it was not yet time
require the presence of two cancer-inducing events ("hits"),
to change treatment recommendations from observation to
similar to what has been seen for the development of other
active treatment for patients with SMM.
types of cancers. The first hit resulting in the development
of MGUS is associated with primary cytogenetic abnormali-
Myeloma Biology
ties such as IgH translocation (exchange of pieces between
Natural History of Multiple Myeloma Relapsing After
two different chromosomes involving an immunoglobulin
Therapy with IMiDs and Bortezomib: A Multicenter
or antibody region) and hyperdiploidy (too many copies
International Myeloma Working Group Study (2878),
of chromosomes) The second hit resulting in progression
was presented by Shaji Kumar, on behalf of the IMWG. This
of MGUS to multiple myeloma includes mutations (genetic
was a retrospective case study of 270 patients to determine
changes) in cancer genes (the oncogenes ras and myc), sec-
the overall survival of patients with myeloma that was refrac-
ondary translocations, increased formation of blood vessels
tory to bortezomib and at least one of the IMiDs. Median
(angiogenesis), and other abnormalities. Currently there is
time from diagnosis to development of refractory disease
no way to prevent this progression.
was 32 months. Median overall survival from development
of myeloma refractory to the novel agents is 8 months for
MGUS and SMM
all patients in the cohort, and 7 months for those without a
High-Risk SMM
first SCT. In an analysis taking multiple factors into account,
Open-Label, Phase III Trial of Lenalidomide-Dexameth-
at the time of development of refractory disease, being less
asone (Len/dex) Vs Therapeutic Abstention in Smolder-
than 60 years old and having had at least one SCT predicted
ing Multiple Myeloma at High Risk of Progression to
at least a partial response, and normal creatinine and albu-
Symptomatic MM: Results of the First Interim Analysis
min (suggesting normal kidney function) best predicted
(Abstract 614), was presented by Maria-Victoria Mateos,
better overall survival. A beta-2-M of less than 3.5 mg/dL
University of Salamanca, Salamanca, Spain. This was an
at diagnosis, a measure of disease severity, was associated
interim analysis of a PETHEMA/GEM trial. SMM is defined as
with better event-free survival at the time of development of
M-protein at least 30 g/L and/or bone marrow clonal plasma
refractory disease. Therefore, the factors that have usually
cells (PCs) at least 10%, but no end organ damage. Sev-
been used to predict outcome are still important for sur-
eral factors predict the risk of progression over time, e.g.,
vival outcome for patients with myeloma resistant to novel
the type and amount of M-protein and the percentage of
agents.
abnormal plasma cells in the bone marrow. The standard
of care for managing SMM is close follow-up and no active
Ad Hoc Scientific Committee on Plasma Cell Biol-
therapy. There have been attempts to treat SMM, including
og y: Scientific Linking of Unusual Manifestations of
a comparison of MP to no treatment. Thalidomide has been
Myeloma
shown to cause toxicity, and in one trial, led to responses
Chair Raymond Powles, Parkside Oncology Clinic, Wimble-
but a shorter time to myeloma therapy. This PETHEMA trial
don, United Kingdom, said that although this scientific com-
included patients at high risk for progression. The treat-
mittee is still ad hoc, they were hoping to get full status as a
ment was lenalidomide plus dexamethasone, then lenalido-
scientific committee by 2010. This session was an attempt to
mide maintenance at a lower dose compared to no therapy.
find commonality among the topics of plasma cell leukemia,
Dr. Mateos concluded that the preliminary results are prom-
extramedullary myeloma, and bone-spared myeloma to fur-
ising and the side effects are acceptable. Dr. Dimopolous
ther the understanding of myeloma in general.
14
Plasma Cell Leukemia (PCL) was discussed by Rafael Fon-
extramedullary plasmacytomas (EMPs) may be present at
seca, Mayo Clinic, Scottsdale, Arizona. Plasma cell leukemia
diagnosis or develop during the course of the disease, and
(PCL) represents an aggressive variant of multiple myeloma
occur in up to one third of patients with myeloma. Factors
characterized by the presence of a large number of circu-
associated with the development of EMPs appear to include
lating PC in the peripheral blood. It is arbitrarily defined
aggressive myeloma, relapsed disease, and independence of
as more than 20% of leukocytes being PC in the peripheral
myeloma cells from the bone marrow microenvironment.
blood or more than 2 × 109 cells/L. PCL may be the primary
Possible mechanisms of spread include decreased amounts
indication of a PC tumor, which often responds to treatment,
of proteins that cause cells to adhere to their environment,
occasionally with a durable response and overall survival of
decreased amounts of receptors for chemicals that control
nearly a year. It can also occur as a secondary leukemic trans-
the behavior of cells, decreased oxygen, and decreased
formation of myeloma, with a very poor prognosis and over-
adhesion of PCs to bone marrow stromal cells, leading
all survival of 1.3 to 7 months. The rarity of PCL has limited
to escape of the myeloma cells from the bone marrow.
the ability to study its genetic features. Dr. Fonseca focused
Another possible mechanism is decreased amounts of tet-
his discussion on genetic alterations that he believes drive
raspanins, which are expressed on the cell surface and are
the ability of PC to escape from the bone marrow and con-
involved in cellular adhesion, movement, activation, and
tribute to disease by multiplying out of control. IgH trans-
spread, and interaction with molecules involved in signal-
locations, hypodiploidy (missing chromosomes), del 17p13
ing and immune function. EMP is associated with shorter
at the TP53 locus, mutations in the cancer gene myc, and
survival. EMPs may respond to high-dose therapy, alkylating
del 13 are common. Deletions of p53 are not common, but
agents, and/or radiation therapy, and may be more likely to
are an important prognostic factor, because overall survival
occur after reduced intensity conditioning allogeneic SCT
is greatly reduced for patients with loss of p53 compared
than after ASCT. EMP does not respond to thalidomide but
with those in whom it is present. Deletions of p53 are rare
does respond to bortezomib. There are no formal studies
in MGUS and SMM, and are seen in increasing frequency
of sensitivity to lenalidomide, but case reports suggest the
over the spectrum from newly diagnosed myeloma to first
possible efficacy of lenalidomide plus dexamethasone. Dr.
relapse to second relapse to PCL to myeloma cells becoming
Bladé also referred to an entity known as macrofocal extra-
capable of growing in culture outside the body. Therefore,
medullary myeloma, which occurs in young patients (<40
Dr. Fonseca suggests that long-term maintenance therapy
years old) and is associated with multiple skeletal lesions,
should address pathways affected by p53 deletion, and p53
10% bone marrow plasma cells, and a favorable outcome.
status could be included in a molecular staging scheme that
Dr. Bladé suggested that the focus of future research should
might in the future replace clinical staging (such as ISS).
include investigations of how myeloma cells move out of
PCL is so rare that randomized trials are not possible, and
the bone marrow and around the body, adhere to other
there is no defined standard of care. Therefore, treatment of
cells and structures, and survive; myeloma stem cell charac-
PCL should resemble that of high-risk myeloma, and should
teristics; molecular genetics; and drug sensitivity and resis-
include combinations of IMiDs, bortezomib, doxorubicin,
tance. There are appropriate animal models of EMP that can
and SCT. Dr. Fonseca predicts that with increasing survival
be used for preclinical drug testing. During the question
of patients with myeloma, secondary PCL will become an
session, Dr. Bladé noted that there are 2 types of EMPs: 1)
increasingly common and difficult problem to manage.
those that spread directly from bone and have a better out-
come; and 2) those that spread to organs such as the liver
Extramedullary Myeloma was discussed by Joan Bladé,
and have a worse outcome. Dr. Bladé suggested the use of
Hospital Clinic, Institut d'Investigacions Biomèdiques
VTD or VRD for young patients with EMD.
August Pi i Sunyer (IDIBAPS), Barcelona, Spain. There are
several patterns in the development of extramedullary (out-
Bone-Spared Myeloma was discussed by Gregory R. Mundy,
side the bone marrow) myeloma, including local soft-tissue
Vanderbilt University, Nashville, Tennessee, who pointed
growth from adjacent bone lesions; hematogenous spread
out that the signs, symptoms, and biology of myeloma
(from the blood) resulting in single or multiple large sub-
related to bone are still not well understood. Dr. Mundy
cutaneous plasmacytomas (plasma cell tumors); spread-
reviewed what is known about osteoblast (bone-forming)
ing of nodules to the skin, liver, kidney, breast, lymph
and osteoclast (bone-destroying or remodeling) pathways
nodes, brain, or other organs or tissues; or local spread
and function in myeloma, including various signaling and
occurring after surgery, resulting in plasmacytomas at the
molecular pathways, and the roles of molecules that are
sites of surgical procedures or wounds, and in the case of
known to alter development of osteoblasts and regulation
bone surgery, leading to invasion of muscles. Soft-tissue
of other molecules required for proper bone development
15
and function, some of which are produced by myeloma
Further study is needed to determine if changing the dose
cells. He speculated that osteoporosis (thinning of bones)
of melphalan in obese patients is necessary.
could be considered a cancer-related process because bone
formation is impaired in this condition. As patients live lon-
Conclusions
ger, the probability of experiencing cancer-related bone dis-
The trend of increased survival for patients with myeloma
ease increases for patients with breast and prostate cancer
that began in the era of novel agents (bortezomib, lenalido-
as well as for those with myeloma. Experiments in animal
mide, and thalidomide) is continuing. The novel agents are
models should be useful for determining if myeloma can
no longer so novel, as they are now part of new standards
be separated from bone disease, and if that would alter its
of care. Even newer agents are being developed with prom-
natural history, including response to therapy. In response
ising results. Many of these may work best in combination
to the other presentations in the session, Dr. Mundy noted
therapies, and because many have unique ways of acting
that the staging of myelomas in remission and at relapse
and different types of side effects, combination therapy
is important. Research needs to focus on detecting disease
attacking myeloma cells in several ways should lead to con-
present outside the bone marrow in the absence of symp-
tinued improvement in patient survival and quality of life.
toms. He speculated that treatment, with bortezomib in
particular, might be turning myeloma cells into cells more
capable of spreading.
Of Particular Interest to Patients
Alpha Lipoic Acid and Bortezomib
Alpha Lipoic Acid (ALA) Inhibits the Anti-Myeloma
Effects of Bortezomib (Abstract 3832) was presented
by Eric Sanchez, Institute for Myeloma and Bone Cancer
Research, West Hollywood, California. Alpha lipoic acid
(ALA), an anti-oxidant supplement that is used in the man-
agement of peripheral neuropathy (PN) in myeloma, has
been shown to inhibit the anti-myeloma effects of bortezo-
mib in myeloma cell lines (cells capable of growing in the
laboratory outside the body). This is being investigated fur-
ther in myeloma cells taken from patients and in an animal
model. In addition, possible ways to overcome the inhibi-
tory effects of alpha lipoic acid on bortezomib while pre-
serving the beneficial effects of the supplement in PN are
being looked at.
Obesity and Melphalan
Effect of Obesity and Renal Insufficiency On Toxicity of
High-Dose Melphalan for Multiple Myeloma (Abstract
1177) was presented by Dan T. Vogl, Myeloma Program,
Abramson Cancer Center, University of Pennsylvania, Phila-
delphia, Pennsylvania. This study in 39 patients receiving
high-dose melphalan (MEL) followed by ASCT investigated
the role that obesity and kidney damage play in the side
effects associated with melphalan. The authors concluded
that more obese patients, as measured by percent body
fat, have more severe lesions in the mouth (oral mucositis)
after high-dose melphalan, independent of melphalan dose,
body weight, and kidney function. Dr. Vogl's group is in the
process of looking at how melphalan acts in obese patients.
16
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