InternatIonal MyeloMa FoundatIon
ASH 2008
Highlights
for Patients
with Myeloma
Highlights from the 50th Annual Meeting
of the American Society for Hematology (ASH)
held in San Francisco, California,
December 59, 2008
Compiled by Lynne Lederman, PhD
Funded by unrestricted educational grants from Celgene Corporation and Millennium Pharmaceuticals, Inc.
ASH 2008 Highlights for Patients with Myeloma
Continuing Advances in Treatment
Genetics and Risk
The 50th Annual Meeting of the American Society for
High-Risk Myeloma
Hematology (ASH) was held December 5 through 9, 2008
The High-Risk Multiple Myeloma Ad Hoc Scientific Com-
in San Francisco, California. There were 8 simultaneous
mittee is a new group that will report to the ASH Annual
sessions that included talks about studies related to mul-
Meeting for three years on a probationary basis. This sci-
tiple myeloma, and over 8 poster groupings concerning
entific committee was created in part because at the previ-
myeloma, not including posters on transplantation. In addi-
ous ASH Annual Meeting in 2007 myeloma was the single
tion, the International Myeloma Foundation sponsored a
most frequently discussed disease and was the subject of a
Satellite Symposium on December 5, entitled "Finding Your
large number of simultaneous sessions. The Ad Hoc Scien-
Way Through the Treatment Maze Selecting the Best Treat-
tific Committee Session on Plasma Cell Biology: High-Risk
ment in the Era of Novel Agents." There was also an Educa-
Myeloma was chaired by Dr. Raymond Powles, Parkside
tion Program on Plasma Cell Disorders, as well as a session
Oncology Clinic, Wimbledon, UK.
from the newly formed Ad Hoc Scientific Committee on
Plasma Cell Biology: High-Risk Myeloma.
Dr. Powles said there are many unanswered questions
related to high-risk myeloma, which include the following:
Multiple myeloma treatment continues to advance as more
research results from clinical studies of conventional, novel,
· Does early diagnosis alter risk?
and new therapies are becoming available. Additional
· Which patients are most likely to develop bone disease,
longer-term follow-up results are now available from later
kidney disease, amyloid, bone marrow failure, and/or
(phase III) clinical studies of combination therapies that
failure of their immune response?
include the novel agents bortezomib, lenalidomide, and tha-
lidomide. Preliminary results are promising for some even
· Which individual patients respond best to which drugs?
newer agents that have entered earlier (phase I/II) clinical
· Is early response to treatment an independent risk
studies. Additional agents are being developed, and some of
factor?
these have entered early stage studies in animal models of
· Which patients are "cured" and do these include
myeloma and early clinical studies in patients.
10-year survivors?
This write-up summarizes key presentations at the 2008 ASH
· What is the best method of determining risk?
Annual Meeting, and includes some opinions of presenters
and a few comments made during the limited question and
the Genetic origin of Myeloma
answer discussions. Key issues discussed during the meet-
Dr. Leif Bergsagel, Mayo Clinic, Scottsdale Arizona, began this
ing include those that have been of interest for some time.
presentation with a review of how normal B cells develop
Newer issues were also discussed, and these include the
into plasma cells (the cells that make antibodies), and how
following:
these cells can go on to develop into the cells responsible
· What is the role of autologous stem cell transplant (ASCT)
for MGUS (monoclonal gammopathy of uncertain signifi-
now that the novel therapies are available?
cance), then to SMM (smouldering multiple myeloma), to
myeloma confined to the bone marrow, to myeloma that
· Should the goal of treatment be cure of myeloma at the
spreads outside the bone marrow, and finally to myeloma
risk of severe side effects, or management of myeloma as
cell lines, which are myeloma cells that can be grown out-
a chronic disease with an eye to quality of life?
side the body.
· How should risk factors be determined and how should
information about risk factors be used?
This progression is a multi-step process, and at each stage,
genetic events occur, including changes in the number
of chromosomes, changes in how the plasma cells make
3
antibody molecules, changes in the arrangement of antibody
Diagnosis and Management
genes in the chromosomes, exchange of genes and larger
Dr. Nikhil Munshi, Dana-Farber Cancer Institute, Harvard
sections between chromosomes, and changes in how cer-
Medical School, Boston, Massachusetts, chaired the Plasma
tain genes are controlled. Some genetic changes occur early
Cell Disorders Education Session. He reviewed diagnostic
in the disease, whereas others occur later in disease. Some
advances, including the use of free light chain (FLC) assays,
of these changes may predict how a patient may respond to
fluorescent in situ hybridization (FISH), magnetic resonance
drugs, including dexamethasone and bortezomib. However,
imaging (MRI), and gene expression profiling (GEP). He
other genetic changes that in the past were associated with
reviewed therapeutic approaches that have moved from tar-
a poorer outcome or lack of response to treatment, are now
geting myeloma tumor cells alone with melphalan-predni-
being shown not to affect the reponse to the newer agents,
sone (MP) to targeting myeloma cells along with their bone
including bortezomib, thalidomide, and lenalidomide,
marrow environment. He also discussed how treatment
which may overcome some genetic risk factors or resistance
has progressed from being used just to relieve symptoms
to other drugs.
(palliation), to treatment of myeloma as a chronic illness,
to treatment nearing a cure. He then gave a talk entitled
Indicators of High-risk disease
Investigative Tools for Diagnosis and Management.
Dr. John Shaughnessy's group at the University of Arkansas
for Medical Sciences, Little Rock, Arkansas, is asking if genetic
Dr. Munshi said that analysis of high levels of serum free
studies can help determine risk as well as help oncologists
light chain (FLC) has helped to predict a higher risk of
make decisions about the best therapy to use. Even though
progression in MGUS and SMM. It is not known if a strin-
all myeloma cells look similar, individual patients respond
gent complete response (CR) with normal serum FLC can
differently to treatments. Several research groups have
be used to predict overall survival. Although determining
identified different patterns of gene expression, that is, pat-
FLC in urine is not necessary, determining the presence
terns showing which genes are actively making proteins and
of Bence-Jones proteins (which are antibody light chains)
which genes are not. At this time, there are several different
in a 24-hour urine sample is still important for determinig
models that include gene patterns associated with response
the stage of myeloma and predicting outcome. Other tests
to various treatments and with high-risk myleoma. At this
that are also important are albumin, lactic dehydrogenase
stage of research, the relationship of these models to each
(LDH), and beta-2-microglobulin (beta-2-M) levels, bone
other is not clear.
marrow cytogenetics (the appearance of chromosomes in
myeloma cells from the bone marrow), and FISH.
How New Therapies May Redefine High-Risk Myeloma
Dr. William Dalton, Moffitt Cancer Center and Research
Dr. Munshi believes that the International Staging System
Institute, Tampa, Florida, observed that a high-risk popula-
(ISS) applies to all patients. Cytogenetic tests are useful in
tion can be defined by response to therapy, progression to
about 25% of patients, and the presence of an abnormal
relapse, genetic factors, and epigenetic factors, which are
karyotype (abnormal numbers or arrangements of chro-
changes to genes that are not inherited, and may be due to
mosomes) is an independent predictor of poor outcome.
factors like diet or the environment. One really important
Eventually, the use of other genetic tests, for example, GEP,
question that still needs to be answered is how myeloma
may be useful in helping to predict outcome, but for now,
cells interact with other types of cells within the bone mar-
he agrees with Dr. Shaughnessy that the different GEP mod-
row (the bone marrow microenvironment). These interac-
els only complicate risk assessment. The use of genetics
tions may be influenced by different types of growth factors
in defining risk for patients will have to take into account
and other molecules produced within the bone marrow.
which treatment is being used.
Dr. Dalton believes it is possible to redefine and target high-
In response to a question, Dr. Munshi said the best way to
risk myeloma, for example by using combinations of thera-
evaluate CR was to perform protein electrophoresis and
pies acting on different disease-related pathways within
immunofixation on both serum and urine samples, and also
myeloma cells. This will require development of combina-
to determine the percentage of plasma cells in the bone mar-
tion therapies to improve treatment outcomes. Further-
row. Confirmation of these results should be done 6 weeks
more, understanding of exactly how novel target-based
later. Dr. Barlogie suggested assessment should include
therapies act on myeloma cells as well as on the bone mar-
MRI, and Dr. San Miguel added that he would like to see
row environment will improve the design and use of drug
immunofixation of bone marrow and FLC being performed,
combinations.
although he admitted that neither of these two tests nor MRI
are currently accepted measures of CR.
4
Staging
transplant. Patients who converted to nCR after transplant
Improved survival of patients with myeloma after
had significantly improved event-free survival and overall
introduction of novel agents and applicability of ISS:
survival compared with those who had nCR both pre- and
an analysis of the Greek myeloma study group (GMSG)
post-transplant. Patients with nCR and stable disease (SD)
(abstract #655)
did better than patients with PR post-transplant, as did
patients younger than age 65 years. Patients with SD didn't
Dr. Meletios Dimopoulos, Alexandra Hospital, Athens,
respond to initial therapy, but they also don't have progres-
Greece, presented this study on behalf of Dr. Efstathios Kas-
sive disease. Although these patients may be considered to
tritis and colleagues. Most of the patients in this study were
have myeloma that is resistant to chemotherapy, they may
treated outside of clinical trials. The aim was to see if the
really have slow-growing myeloma. For myeloma that does
ISS could be used in the era of novel agents because it has
not respond to treatment but also does not progress, stem
not been tested as a tool to predict outcome in patients who
cell transplantation may not add anything, and the good
were treated up front with novel agent-based therapies.
outcome may be due to the slow course of the myeloma.
Since 1985, 1376 patients with newly diagnosed myeloma
. For myeloma that does not respond to treatment but also
have been entered into the GMSG database, 859 before 1999
does not progress, stem cell transplantation may not add
and 517 after January 1, 2000, when thalidomide became
anything, and the good outcome may be due to the slow
available in Greece.
course of the myeloma. Although Dr. Blade suggested that
Patients in the more recent of the two treatment groups
CR and nCR shouldn't be combined when analyzing the
were older, had a higher ISS stage and other negative pre-
responses to treatments, one of the session chairs pointed
dictive factors, but also had better response rates. A statisti-
out that because diagnostic tests differentiating CR from
cal analysis taking several factors into account at the same
nCR were not done, it isn't possible in this analysis to distin-
time was performed. Older age, being diagnosed before
guish CR from nCR.
2000, and ISS stage were significant factors that decreased
90% sustained Cr rate projected 4 years after onset of
survival. Treatment with novel agents significantly improved
Cr in GeP (abstract #162)
survival of patients treated outside of specialized cancer
centers. This effect was seen mainly for younger patients,
Dr. Bart Barlogie, University of Arkansas Medical Center, Lit-
whose median survival doubled. Patients with high ISS, kid-
tle Rock, Arkansas, said that current therapies can produce
ney disease, high LDH, anemia (abnormally low red blood
a long-lasting CR. He discussed results of several forms of
cell counts), and poor performance status (that is, patients
Total Therapy (TT). In one comparison, cytogenetics and
in generally poor health) had improved survival after treat-
LDH were still found to be risk factors. CR was found to be
ment with novel agents. However, median survival for
highly significant for a favorable outcome, and he believes
patients with ISS stage III was still less than 3 years.
that the duration of CR is currently the best marker for a
"cure." He also noted that TT3 benefits patients with low-
Response
risk disease but is of no benefit for those with high-risk
effect of pre- and post-transplant responses on out-
disease. The cytogenetic abnormality translocation 4;14 (in
come of patients with myeloma: Cr and nCr should
which parts of chromosomes 4 and 14 exchange places) has
not be considered as equivalent prognostic markers:
been associated with poor outcome. Adding bortezomib to
results of a PetHeMa/Gem prospective study (abstract
TT3 has overcome the contribution of translocation 4;14
#161)
to poor outcome, especially for patients who had myeloma
that was otherwise considered low-risk.
Dr. Joan Blade, Hospital Clinic, Barcelona, Spain, presented
the results of a study on the influence of response on out-
Dr. Barlogie's group has developed a GEP model that is
come for patients in the GEM200 program. This program
being tested to evaluate patient response to a test dose of
evaluated several chemotherapy combinations prior to
bortezomib. This 80-gene model is better at predicting out-
autologous stem cell transplant (ASCT). The results were
come than the 70-gene model that was previously reported.
presented for patients who received one ASCT.
For patients who have low-risk disease at diagnosis, it is
difficult to improve upon current therapy. A clinical study
The CR rate after transplant was related to the degree of
for low-risk disease randomly assigns patients to standard
response to treatment before the transplant. Patients with
TT3 vs. "TT light," or TT4, which is expected to produce
conversion from partial response (PR) to near (n) CR or
fewer side effects and better response. As of the date of the
CR have significantly longer event-free survival and over-
ASH meeting, 20 patients had been enrolled on this study.
all survival compared with patients who remain in PR after
5
For high-risk disease, TT5 is being tested in a phase II clini-
For younger patients, CR/very good partial response (VGPR)
cal study in which a dose-dense, but less dose-intense, treat-
is the goal of high-dose therapy (HDT) and ASCT. Bort-
ment may avoid "exhausting" the patients. These studies
ezomib plus dexamethasone before ASCT results in better
require taking bone marrow samples for gene expression
response rates across all risk groups based on cytogenetics
profiles at diagnosis, 48 hours after bortezomib treatment,
than does thearapy with VAD. All randomized studies con-
48 hours after high- dose chemotherapy, and before each
firm VAD should no longer be used for induction therapy
of two transplants, to evaluate the effect of therapy. So far,
before ASCT. Studies are continuing to collect data for
patients on these studies have been willing to undergo
lenalidomide plus dexamethasone and for three-drug com-
these tests.
binations, e.g., two novel agents plus dexamethasone, or a
novel agent with dexamethasone plus an alkylating agent.
Front-Line Treatment of Myeloma
Btz (bortezomib) dox (doxil; peg ylated doxorubicin)
In the last few years the novel therapies (bortezomib, lenali-
dex (Pad) as induction prior to reduced intensity
domide, and thalidomide) moved from approval in patients
aSCt followed by lenalidomide (len) prednisone (lP)
with relapsed or refractory myeloma, to late-phase clini-
for consolidation and len as maintenance in elderly
cal studies in the front-line setting (in patients with newly
untreated myeloma patients (abstract #159)
diagnosed myeloma), to approval for both thalidomide and
Dr. Antonio Palumbo, Ospedale San Giovanni Battista,
bortezomib for use in newly diagnosed patients. Additional
Torino, Italy, presented the results of this study to deter-
results are becoming available for the use of novel therapies
mine if 4 cycles of PAD followed by stem cell collection with
in combination with each other as well as with conventional
cyclophosphamide and G-CSF (granulocyte colony stimu-
therapies for myeloma.
lating factor) then MEL 100 reduced-intensity condition-
ing (RIC) for 2 cycles was feasible in patients aged 65 to 75
Induction Therapy
years. LP consolidation was given for 4 cycles, then lenali-
During the Plasma Cell Disorders Education Session, Dr.
domide alone was used for maintenance. Treatment has not
Jean-Luc Harousseau, University Hospital, Hotel-Dieu,
been given yet to all patients in the study, so preliminary
Nantes, France, reviewed induction therapy in multiple
results were presented. Patients younger than age 70 years
myeloma, which usually means remission induction. He
are doing better, so the cut-off for this regimen is probably
observed that until recently, the choice of induction ther-
age 70 years. PAD overcomes the poor outcome associated
apy was easy: VAD (vincristine adriamycin dexamethasone)
with high beta 2-microglobulin levels and abnormal cytoge-
followed by high-dose therapy (HDT) plus autologous
netics. Important side effects include 15% abnormally low
stem cell transplant (ASCT) for younger patients, and mel-
numbers of platelets (thrombocytopenia), the elements in
phalan-prednisone (MP) for older patients. The advent of
the blood responsible for clotting, 15% peripheral neuropa-
novel therapies has presented more choices of combination
thy (PN), which may require adjustment of the bortezomib
therapies, many of which are still in clinical studies. In gen-
dose, and 15% infections.
eral, adding a novel agent to MP improves response, e.g.,
MPT (MP plus thalidomide) is better than MP or Mel 100
Phase III Trials in Newly Diagnosed Myeloma
(reduced-dose melphalan) for progression-free survival and
Superior Cr rate and PFS after aSCt with up-front Vel
response rate, and in some trials for overall survival. VMP
thal dex ( Vtd) compared with thal dex (td) in newly
(MP plus bortezomib) results in better response and lon-
diagnosed myeloma (abstract #158)
ger progression-free survival and overall survival than MP.
Dr. Michele Cavo, Istituto Seragnoli, Bologna, Italy, pre-
MPR (MP plus lenalidomide) is still being studied, as are
sented preliminary results of a phase III randomized study
various other combinations of novel agents with corticoster-
of three 21-day cycles of induction therapy with VTD com-
oids (like dexamethasone or prednisone) and/or alkylating
pared with TD followed by stem cell collection, cyclophos-
agents (like melphalan or cyclophosphamide).
phamide, HD melphalan, and consolidation. This analysis
included 460 patients who were evaluable after at least
Dr. Harousseau emphasized that MP is no longer the stan-
ASCT. The median age was 56 years. Results so far indicate
dard induction therapy for elderly patients, with either MPT
that VTD is superior, at least for the nCR rate, across sub-
or MPV being a better choice. The combination of lenali-
groups including patients with factors associated with poor
domide plus dexamethasone is also attractive for older
outcome, such as missing parts (deletions) of chromosome
patients, with reduced-dose dexamethasone being more
13 and/or 17 and translocation 4;14. VTD produced better
tolerable. However, the best induction therapy for elderly
response rates than TD after the first and second ASCT and
patients will be tested in upcoming IFM trials.
consolidation.
6
Serious side effects that were higher with VTD included PN
First analysis of HoVon-65/GMMG-Hd4 randomized
and skin rash; otherwise serious side effects were similar
phase III trial comparing btz, adriamycin, dex (Pad)
with both treatments. Of patients with serious PN while on
vs. Vad as induction treatment prior to Hd mel in
VTD as induction therapy, 95% remained on therapy with
patients with newly diagnosed myeloma (abstract
no effect on response rate compared with patients with less
#653)
severe or no PN. Discontinuations of induction therapy were
Dr. Pieter Sonneveld, University Hospital Rotterdam, Rot-
higher for patients on TD than VTD, mostly due to disease
terdam, Netherlands, presented early results for the first
progression. The estimated 2-year progression-free survival
300 patients of an expected 825 patients randomly assigned
is longer for VTD, but there is no difference in overall sur-
to either VAD or 3 cycles of PAD, followed by CAD, stem
vival between treatments. However, the follow-up period is
cell collection, and HDM with autologous peripheral blood
very short, and fewer than half the patients have received
their second ASCT.
SCT. Patients then received either thalidomide or bort-
ezomib maintenance for 2 years. Those patients who had
Final analysis of HoVon-50 randomized phase III trial
a brother or sister with a matching white blood cell type
of thal adria dex (tad) and Hd mel (HdM) in patients
could receive stem cells from their sibling instead of their
with myeloma (abstract #157)
own stem cells. In this study, patients from the Netherlands
Dr. Henk Lokhorst, University Hospital Utrecht, Utrecht,
received one SCT, whereas patients from Germany received
Netherlands, presented the results of the study of 556
two transplants.
patients randomized to VAD vs. TAD, followed by all patients
receiving CAD (cyclophosphamide Adriamycin dexametha-
The CR/nCR for PAD was lower than expected, although
sone) and G-CSF. Patients then received reduced-intensity
response rates for PAD were higher than those for VAD. The
conditioning (n=109) or HDM followed by maintenance
only significant side effect for PAD was peripheral neuropa-
with interferon (IFN) or thalidomide.
thy, which was 16%, vs. 6% for VAD. Patients receiving bort-
ezomib maintenance therapy continue to have improved
As in other studies, although the patients receiving a novel
responses.
therapy-containing regimen, in this case TAD, had better
response rates, event-free survival, and progression-free sur-
Vel-mel-pred ( VMP) vs. Vel-thal-pred ( VtP) in elderly
vival, overall survival was the same in both treatment groups
untreated patients with myeloma: which is the best
(VAD vs. TAD). The best outcomes were seen for patients
partner for Velcade: an alkylating or an immunomodu-
who had CR as their best response; patients with ISS stage
lator agent? (abstract #651)
I disease at diagnosis also had better survival. However, in
Dr. Maria-Victoria Mateos, University Hospital of Salamanca,
this study, patients who received thalidomide maintenance
Salamanca, Spain, presented the results of this phase III,
therapy had a reduced overall survival at relapse.
randomized clinical study in 260 newly diagnosed patients
older than age 65 years. In this study, patients received the
Mel + pred (MP) vs mel + pred + thal (MPt) in
standard dose of bortezomib for one cycle, then received
induction therapy for myeloma in elderly patients:
weekly bortezomib for 5 cycles along with prednisone, and
final analysis of the Dutch cooperative group HOVON
either thalidomide (VTP group) or melphalan (VMP group),
49 study (abstract #649)
to determine which drug was best to add to bortezomib
Dr. Pierre Wijermans, Haga Hospital, The Hague, Nether-
therapy. The follow-up time is 16 months. The response
lands, presented the results of this randomized, phase III
rates and survival for both groups are good, and appear
study in patients older than age 65 years. The planned
about the same. VMP was associated with more side effects,
enrollment was 420 patients, but the study was stopped
including infection and reduced levels of white blood cells
early when 332 patients had been enrolled because doctors
and platelets. VTP was associated with side effects affecting
in the Netherlands were convinced that thalidomide should
the heart, and with a higher rate of serious side effects and
be given to newly diagnosed, elderly patients. Although
discontinuation rates. Dr. Mateos concluded that thalido-
side effects were greater in patients who received MPT, the
mide may not be the partner of choice with bortezomib for
CR plus VGPR rate and event-free survival were also higher
elderly patients and suggested that lenalidomide should be
with MPT. In this study, as in others, the overall survival for
tested. During the discussion, there were suggestions to test
patients receiving a combination containing a novel agent,
in this case MPT, was not different from those receiving
maintenance therapy because event-free survival decreased
MP. However, because most patients who received MP also
sharply when the study treatment ended, and to test a less
received thalidomide at relapse, thalidomide in this study
intense regimen of VMP for more fragile patients.
might have acted as maintenance therapy.
7
Prospective, randomized phase III study of btz, mel,
relapse. VMP was effective for patients with high-risk factors
pred, and thal ( VMPt) vs. btz mel pred ( VMP)
for poor outcome, including decreased kidney function or
in elderly newly diagnosed myeloma patients
high-risk cytogenetics, e.g., translocations 4;14 and 14;16.
(abstract #652)
Fewer patients who received VMP required further therapy
Dr. Antonio Palumbo presented the results of this GIMEMA
for progressive disease. Patients who were treated first with
trial in 393 patients over age 65 years who were not eli-
VMP had a higher response rate to bortezomib for progres-
gible for transplant and who received either VMP with no
sive disease than did patients who had first received MP.
maintenance, or VMPT and maintenance with bortezomib
However, response to thalidomide or lenalidomide after
and thalidomide. Although the study began with the stan-
progressive disease was the same whether or not patients
dard bortezomib schedule, it was changed to weekly bort-
had first received VMP or MP. Patients receiving VMP did not
ezomib. VMPT, that is, the combination that included both
have myeloma that was more resistant to further therapy at
bortezomib and thalidomide, resulted in better responses.
relapse. Better survival was seen for patients who received
The time to PR for the majority of patients occurred in 1 to
VMP up front than those who received MP and further ther-
2 cycles of treatment, but CR rates increased slowly over
apy at relapse. Patients who had CR had a longer time to
time, suggesting that a lower intensity but longer treatment
disease progression but not a longer overall survival, pos-
might result in more CR. There was no difference in overall
sibly due to the low number of events.
survival estimated at 3 years between the two treatments
(VMPT vs. VMP).
There were no differences between treatments in causing
side effects involving the blood. VMP was associated with
Side effects involving the blood were similar between the
more side effects affecting the digestive system and with
two treatments. VMPT is associated with a higher rate of
peripheral neuropathy (PN). PN was reversible in most
sensory neuropathy and infections. The switch from twice
patients. This longer follow-up confirms that VMP offers sig-
weekly to once weekly bortezomib did not result in a
nificant benefits over MP, including time to next therapy,
lower CR rate, but did reduce the rate of peripheral neu-
for all patients, including those with high-risk cytogenetics,
ropathy for patients receiving VMPT. For patients receiv-
the elderly, and those with poor kidney function. Patients
ing VMP, the less frequent dosing of bortezomib decreased
who receive VMP will not progress to relapsed disease
the rate of peripheral neuropathy, but also decreased the
that is more resistant to futher therapy than those who
CR rate slightly.
receive MP.
Dr. Palumbo concluded that VMPT doubles the response
Early Clinical Studies in Newly Diagnosed
rate of VMP, and increases time to next therapy, but not
Myeloma
overall survival. He said that a longer follow-up beyond the
Dr. Sundar Jagannath, St. Vincent's Comprehensive Cancer
current 14 months is needed to measure the progression-
Center, New York, and Dr. Antonio Palumbo moderated a
free survival and overall survival. Because of the need for
session in which early-phase clinical studies of therapy of
further investigation, VMPT shouldn't be incorporated into
newly diagnosed patients were discussed. The studies that
the standard of care at this time.
appear promising, and are being expanded or are leading to
further studies, include the following:
updated follow-up and results of subsequent therapy
in the phase III VISta trial: btz plus mel-pred ( VMP) vs
· RCd: lenalidomide with cyclophosphamide and low-dose
mel-pred (MP) in newly diagnosed myeloma (abstract
dexamethasone
#650)
· Lenalidomide, bortezomib, dexamethasone (the dexame-
Data for the VISTA trial through April 25, 2008, was pre-
thasone dose was reduced during study based on results
sented by Dr. Jesus San Miguel, University Hospital of
of a study of lenalidomide with either high- or reduced-
Salamanca, Salamanca, Spain. This phase III trial, which
dose dexamethasone)
included 682 patients who were not candidates for trans-
plantation, was stopped at the third interim analysis with a
· Bortezomib, dexamethasone, cyclophosphamide,
median follow-up of 16 months. Current median follow-up
lenalidomide (VDCR)
is 25.9 months.
· Bortezomib and high-dose melphalan before ASCT
There was a 36% reduced risk of death with VMP, although
43% of patients receiving MP also received bortezomib at
8
Relapsed and Refractory Myeloma
For patients with PR after intensive therapy, thalidomide
maintenance improves progression-free survival but not
Combination of lenalidomide, melphalan,
overall survival. There was no benefit in continuing main-
prednisone, and thalidomide (RMPT) in
tenance therapy beyond 6 months. This may be because
relapsed/refractory multiple myeloma:
the thalidomide given as maintenance therapy may actually
results of a multicenter phase II clinical trial
be acting as continuing therapy. Thalidomide maintenance
(abstract #868)
had no effect on overall survival of patients with chromo-
some 14 translocations (a marker of poor outcome), and
Dr. Antonio Palumbo presented the results of a GIMEMA
was associated with reduced progression-free survival and
study of lenalidomide, melphalan, prednisone, and thalido-
overall survival for patients with deletion of chromosome
mide (RMPT) in patients with relapsed, refractory myeloma.
17p. Dr. Morgan concluded that rather than defining a
(He said that the CR rate with VMP is 21%, and with VMPT
maintenance effect for thalidomide, the results might reflect
the CR rate is increased to 39%. Were these numbers borne
a consolidation effect for poor response after induction
out in this study? If not, delete the preceeding sentence.)
therapy. He thinks CTD induction therapy and no mainte-
This study included 44 patients: half received 50 mg thalido-
nance therapy after HDM might be appropriate for younger
mide, the other half received 100 mg thalidomide, standard
patients, and suggested looking at lenalidomide for mainte-
dose MP, and lenalidomide 10 mg for 3 of every 4 weeks
nance therapy.
for 6 cycles of induction. Low-dose aspirin (100 mg) was
required to reduce the chance of blood clots. The CR/nCR
Skeletal-Related Events
rate was 13%, with 20% VGPR. This was a lower response
rate than seen in patients who had received VMPT in other
Dr. G. David Roodman, Pittsburgh Healthcare System and
studies. The rate of side effects on blood counts and the
University of Pittsburgh, Pennsylvania, presented "Skeletal
infection rate was also higher. The 12-month estimated
Imaging and Management of Bone Disease" during the
overall survival was also lower than that seen with VMP.
Plasma Cell Disorders Education Session. Myeloma is the
most frequent tumor to involve the skeleton. Dr. Roodman
Maintenance Therapy
believes looking closely enough will show that the bones
Maintenance thalidomide may improve progression-
of all patients with myeloma are involved. In patients with
free but not overall survival: results from the Myeloma
myeloma, bone fracture increases the risk of death. At diag-
IX maintenance randomization (abstract #656)
nosis, 20% of patients have myeloma-related fractures, and
up to 60% of patients will have fractures over the course of
Dr. Gareth Morgan, Royal Marsden Hospital, Sutton, Surry,
their disease. In myeloma, the normal events of bone forma-
United Kingdom, presented early results of a maintenance
tion and remodeling are no longer properly controlled.
study randomly assigning patients to thalidomide main-
tenance or to no maintenance. This study enrolled 1970
Dr. Roodman thinks that bone scans can underestimate the
patients, including older, less fit patients treated with mel-
degree of bone disease, and therefore the gold standard for
phalan prednisone (MP) or cyclophosphamide, thalido-
detecting bone disease should be a bone survey (x-rays) of
mide, dexamethasone (CTD) (non-intensive therapy), and
the skull, spine, hip, arms, and legs to look for the spread
younger, fitter patients treated with CTD or CVAD and then
of myeloma in the bones. It takes a loss of 30% of the bone
high-dose melphalan (HDM) (intensive therapy). There
to be detectable on x-ray. This test is not useful for look-
were 820 patients randomly assigned to maintenance ther-
ing at the response to therapy, because in most patients
apy. The best induction regimen isn't known because which
the bone loss does not heal. Computed tomography (CT)
patients received which treatment has not yet been made
is more sensitive than x-ray, and with the development of
known completely.
low-dose whole body CT, it may become the new gold stan-
dard. Magnetic resonance imaging (MRI) is also more sensi-
CTD plus HDM with no maintenance seems to be the best
tive than x-ray because it detects bone marrow involvement.
intensive therapy. For patients receiving non-intensive
MRI is the choice to evaluate collapse of bones in the spine.
therapy, the overall survival with CTD is 40 months vs. 29
Positron emission tomography (PET)/CT is also more sensi-
months with MP. It appears that the use of thalidomide plus
tive than x-ray, with the same sensitivity as MRI, although
alkylating agent (melphalan or cyclophosphamide) plus ste-
it may miss small lesions, and false positives are seen with
roid (prednisone or dexamethasone) as one combination
inflammatory disease. Another drawback is that PET/CT is
treatment is superior to alkylating agent plus steroid fol-
very expensive.
lowed by thalidomide maintenance.
9
Treatments for myeloma bone disease include bisphos-
Case studies with suggested treatments included the
phonates, surgical procedures, radiation, and, obviously,
following:
treatment of the underlying myeloma disease. Kyphop-
· a newly diagnosed patient with multiple myeloma who
lasty, a surgical procedure to repair collapsed bones in the
was ineligible for transplantation
spine, offers good pain relief. Bisphosphonates bind to
bone and are taken up by cells that break down the struc-
MP-T (melphalan-prednisone-thalidomide) or
ture of bone. The activity of these cells is blocked, reduc-
MP-V (MP-bortezomib; btz) are good options;
ing skeletal-related events. However, bisphosphonates have
MP-lenalidomide (Revlimid; MPR) is still being
no clear effect on myeloma tumors. Side effects associated
investigated
with bisphosphonates include an acute reaction with zole-
thalidomide-dexamethasone (thal-dex) is not the
dronic acid; medication to prevent the reaction is therefore
standard of care because the results are not superior
given before the zoledronic acid infusion. Zoledronic acid
to those obtained with MP
can also have undesirable effects on the kidneys, cause
for patients over the age of 75 years, dose-reductions
pain in muscles and bones, and cause osteonecrosis of the
should be considered to reduce toxicity
jaw (ONJ), a condition in which tissue in the jaw breaks
· a newly diagnosed, transplantation-eligible patient with
down, exposing the bone. ONJ may not heal, and we do
ISS stage III multiple myeloma, who had normal cytogenet-
not fully understand how it develops. Risk factors for ONJ
ics and translocation 4;14 by FISH
include invasive dental procedures (e.g., tooth extractions),
alkylating agents, which interfere with the collection
longer time from diagnosis of myeloma, and infection with
of stem cells, should not be used
certain bacteria. If ONJ occurs, bisphosphonates should be
discontinued until ONJ heals. Management includes a den-
thal-dex is FDA approved, but is associated with
tal exam before bisphosphonate use, treatment with anti-
neurologic side effects
biotics and oral rinses, pain control, and limited surgical
VD (btz-dex), VTD (btz-thal-dex), and VRD
treatment of the lesions. Dr. Roodman notes that hyperbaric
[btz- Revlimid (lenalidomide)-dex] are being studied
oxygen (oxygen under increased pressure) is not effective.
Guidelines from the American Society of Clinical Oncology
choices include the oral regimen lenalidomide+low-
(ASCO) suggest bisphosphonates should be given for two
dose dex (Rd) for a patient with low-risk disease; a
years only, but there are no clinical results to support this
btz-based regimen for a patient with high-risk disease;
policy, although two clincal studies are ongoing. Stopping
and VTD for a patient with acute renal failure, to
bisphosphonates for a short period of time before dental
control disease rapidly
work, as suggested in Canadian guidelines, makes no sense,
there were suggestions to add a third drug,
Dr. Roodman explains, because these drugs can remain in
e.g., cyclophosphamide or Doxil (pegylated doxorubi-
bone for a decade. He concludes that as the factors involved
cin), which needs to be tested in trials, or to use two
in the development of myeloma bone disease are identi-
drugs and save the third one for relapse
fied, new and more effective targeted therapies may be
· a patient age 64 years, with ISS stage II myeloma, normal
developed.
cytogenetics, t(4;14) by FISH, for whom transplantation
IMF Satellite Symposium
eligibility is uncertain, due to a partial response after 4
cycles of induction therapy
Finding Your Way Through the Treatment Maze
for younger patients not being treated in clinical tri-
Selecting the Best Treatment in the Era of Novel
als, induction therapy, possibly with a btz-dex-based
Agents
regimen followed by ASCT prepared by mel 200, with
post-ASCT maintenance with thal (or maybe lenalido-
This program was facilitated by Dr. S. Vincent Rajkumar,
mide) for one year would be a reasonable regimen
Mayo Clinic, Rochester, Minnesota, and featured discus-
sions of case studies by Dr. Rajkumar and faculty members
on-going studies are addressing whether ASCT is
Dr. Antonio Palumbo, Dr. Philippe Moreau (IFM, Nantes,
needed in the era of novel therapies
France), and Dr. Jesus F. San Miguel. The audience's knowl-
· a patient with multiple myeloma who relapsed multi-
edge of treatment options for each case patient was mea-
ple times after multiple treatments following induction
sured before and after the presentations and discussions.
therapy
IMiDs (thal, len, and presumably pomalidomide
10
which is in development) with btz should be
bone marrow cells, and molecules within cells involved in
restricted to well-controlled trials to preserve future
the development of myeloma.
options for patients
young patients with early relapse (less than one year
Progress is being made in developing therapies targeted to
post-ASCT), intermediate relapse (1 to 3 years post
specific growth factors and other molecules essential for the
ASCT), and late relapse (more than 3 years) should
development and progression of myeloma. Because many
be distinguished:
of these therapies have limited activity as single agents, they
will likely be used in combinations, particularly with the
early relapse: therapy should address
novel therapies bortezomib, lenalidomide, and thalidomide.
overcoming drug resistance with combinations
Combining agents with different mechanisms of action
or alternating non-cross-resistant agents
may increase their activity while reducing the likelihood
intermediate relapse: therapy should prolong
of side effects.
survival with sequential novel agent combinations
until curative treatments are developed
These targeted agents that are showing promise in early
clinical studies include the following:
late relapse: re-induction and a second ASCT
· Perifosine(KRX-0401,alkylphospholipidoralAKTinhibitor)
for elderly patients, their general condition should be
in combination with bortezomib; a randomized phase III
taken into account, using a different drug than that
used for induction followed by enrollment in
clinical study of perifosine + borteomib+dexamethasone
a trial for active treatment, and oral cyclophosph-
vs. bortezomib+dexexamethasone in relapsed/refractory
amide plus prednisone for patients not candidates
myeloma is planned or ongoing
for active treatment
· Vorinostat [histone deacetylase (HDAC) inhibitor]
New therapies in development to target different points in
plus bortezomib
pathways thought to be important in the development of
· CNTO 328 [anti-interleukin-6 (myeloma growth factor)
myeloma include monoclonal antibodies targeting recep-
monoclonal antibody] plus bortezomib
tors on the surface of myeloma cells and agents affecting
intracellular signaling pathways such as:
· Pomalidomide (thalidomide analog CC-4047) plus
low-dose dexamethasone
· new proteasome inhibitors
· Carfilzomib (proteasome inhibitor PR-171); Dr. Sundar
· histone deacetylase (HDAC) inhibitors
Jagannath suggested that this drug has the potential for
· heat shock protein (HSP) 90 inhibitors
accelerated approval within a year as a treatment for the
· new immunomodulatory drugs
unmet needs of patients with relapsed and refractory
myeloma with at least 2 prior therapies that included
Maintenance therapy was discussed in the question and
bortezomib, thalidomide, or lenalidomide.
answer period. Dr. Moreau felt that maintenance with
thalidomide was beneficial mainly for patients who had a
Future Directions
response of less than VGPR. Dr. San Miguel noted that tha-
lidomide was not approved for this purpose. Dr. Palumbo
New therapies that are targeted to specific pathways in
said there was no role for maintenance, but adding a third
myeloma development continue to enter clinical trials. The
drug for consolidation after a sub-optimal response was
novel therapies bortezomib and thalidomide have moved
appropriate. Ongoing trials may clarify the role of mainte-
from the relapsed, refractory setting to the frontline set-
nance therapy.
ting, and lenalidomide may be expected to do the same.
The trend of combining these therapies with conventional
New Treatments in Early Stage
chemotherapies, each other, and/or with targeted therapies
Development
is continuing, expanding the treatment options for patients
with multiple myeloma. Multiple myeloma is becoming
As the natural history of myeloma is better understood, new
more like a chronic, long-term disease as new treatment
therapies are being developed to target specific pathways
options continue to become available.
involved in the development of myeloma. Targets include
the interaction of myeloma cells with the bone marrow
microenvironment, proteins and receptors on myeloma and
Lynne Lederman, PhD, is a medical writer based in Mamaroneck, New York
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE (2873)
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
www.myeloma.org