InternatIonal MyeloMa FoundatIon
ASH 2008
Multiple Myeloma
Highlights
for Physicians
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 Multiple Myeloma Highlights for Physicians
Continuing Advances in Treatment
· Is early response to treatment an independent risk factor?
The 50th Annual Meeting of the American Society for Hematology
· Which patients become operationally "cured" and do these
(ASH) was held December 5 through 9, 2008 in San Francisco,
include 10-year survivors?
California. There were 8 simultaneous sessions that included oral
· What is the best method of risk stratification?
presentations of studies related to multiple myeloma, and over
the Genetic origin of Myeloma
8 poster groupings with presentations concerning myeloma, not
Dr. Leif Bergsagel, Mayo Clinic, Scottsdale Arizona, began this
including posters on transplantation. In addition, the Interna-
presentation with a review of the progression of plasma cell
tional Myeloma Foundation sponsored a Satellite Symposium on
neoplasia from a normal B cell to MGUS, SMM, intramedullary
December 5, Finding Your Way Through the Treatment Maze
myeloma, extramedullary myeloma, and finally a myeloma cell
Selecting the Best Treatment in the Era of Novel Agents. There
line. This progression is a multi-step process characterized by
was also an Education Program on Plasma Cell Disorders, as well
genetic events including somatic hypermutation, errors in isotype
as a session from the newly formed Ad Hoc Scientific Committee
switch recombination, changes in chromosome numbers, IgH
on Plasma Cell Biology: High-Risk Myeloma.
and other translocations, and dysregulation of cyclin and other
Multiple myeloma treatment continues to advance as research
genes. Early in disease progression, ras and myc may be dysregu-
results accumulate from trials of conventional, novel, and new
lated. Later events include deletions such as CDKN2C/p18, p53
therapies. Additional longer-term follow-up data are now avail-
deletion on 17p, deletion of the glucocorticoid receptor, which
able from phase III trials of combination therapies that include
may predict resistance to glucocorticoids, and mutations alter-
the novel agents bortezomib, lenalidomide, and thalidomide,
ing the expression of components of the NFkB pathway, TRAF3
and early results are promising for some even newer agents that
(low expression of which may be associated with resistance to
have entered phase I/II trials; additional agents are in develop-
dexamethasone and sensitivity to bortezomib), and others. The
ment and in early stage preclinical and clinical studies.
importance of some genetic alterations may decrease as newer
therapies overcome those associated with poor prognosis or
This write-up summarizes key presentations at the 2008 ASH
drug resistance. Bergsagel noted that interpretation of risk fac-
Annual Meeting, and includes some opinions of presenters and a
tors among patients who participated in clinical trials should
few comments made during the limited question and answer dis-
take into account the eligibility of patients with high- vs. low-risk
cussions. Key issues discussed during the meeting include those
disease.
that have been of continuing concern, as well as emerging issues,
such as the role of autologous stem cell transplant (ASCT) in the
Molecular Indicators of High-risk disease
era of novel therapies; whether the goal of treatment should be
In his presentation, Dr. John Shaughnessy, University of Arkansas
cure or management of myeloma as a chronic disease; the neces-
for Medical Sciences, Little Rock, Arkansas, noted that "genomic
sity for and type of maintenance therapy; and how best to assess
chaos" in myeloma has made molecular characterization diffi-
for and use information about risk factors.
cult. His group is asking if genomics can aid in risk assessment
Genetic Events in Relationship
and help guide therapy decisions, noting that the common his-
tology of myeloma is associated with variable outcomes. They
to Risk Profiling and Pathogenesis
are exploring the hypothesis that extremes of mRNA expression
High-Risk Myeloma
correlated with treatment failure may point to critical genomic
The Ad Hoc Scientific Committee Session on Plasma Cell Biol-
events that may provide insights into the pathogenic mecha-
ogy: High-Risk Myeloma was chaired by Dr. Raymond Powles,
nisms of therapy failure; these insights may be able to validate
Parkside Oncology Clinic, Wimbledon, UK. Dr. Powles pointed
prognostic predictive models to support risk-adapted therapy.
out that the High-Risk Multiple Myeloma Ad Hoc Scientific Com-
The 70-gene model from gene expression profiles (GEP) of
mittee was new to this annual meeting and will be probation-
patients treated with Total Therapy (TT) has been published
ary for three years. This committee was convened in part as a
and validated. Dr. Shaughnessy noted that different models have
response to myeloma being the single most frequently discussed
identified different sets of genes and gene signatures associated
disease at the last ASH Annual Meeting in 2007, and to the num-
with high risk, and correlating these different models remains a
ber of simultaneous sessions on myeloma.
problem to be resolved.
Dr. Powles emphasized there are many unanswered
Influence of Targeted Therapy in Redefining High-Risk
questions related to high-risk myeloma:
Myeloma
· Does early diagnosis alter risk?
Dr. William Dalton, Moffitt Cancer Center and Research Insti-
tute, Tampa, Florida, observed that a high-risk population can
· Which patients progress to bone disease, renal
involvement, amyloid, bone marrow failure, and/or clinical
be defined by response to therapy, progression to relapse, and
immune paresis?
genetic and epigenetic factors. Also of importance are microenvi-
· Which individual patients respond best to which drugs?
ronmental influences that include a network of survival signals,
3
which are difficult to characterize if myeloma cells are studied
these data for risk assessment. Groups with different prognoses
in isolation from the bone marrow microenvironment. Some
continue to be defined based on differences in up- and down-
of these influences include interaction with fibronectin, which
regulation of gene expression. However, the importance of
may be associated with resistance to treatment, and expression
genetic markers in defining risk has to be assessed in the context
of interleukin (IL)-6, a major growth factor constitutively acti-
of the particular agent used for treatment.
vated in patients with myeloma that in turn activates STAT3, a
In response to a question, Dr. Munshi said the best way to evalu-
signal transducer and transcription activator. STAT3 signaling in
ate CR was to perform protein electrophoresis and immunofix-
myeloma cells is also enhanced by adhesion mediated by beta-1
ation on both serum and urine, and determine the percentage
integrin. Questions that must be asked are how interaction with
of plasma cells in the bone marrow, with confirmation 6 weeks
the bone marrow microenvironment influences acquisition of
later. Dr. Barlogie suggested assessment should include MRI, and
mutations and/or transcription profiles; are there subpopula-
Dr. San Miguel added immunofixation of bone marrow and FLC,
tions of cells with specific mutations and/or transcription profiles
although he conceded that neither of these two tests nor MRI is
that interact differently with the microenvironment; and whether
yet an accepted measure of CR.
myeloma stem cells exist, and if so, how they might interact with
the microenvironment.
Staging
Dr. Dalton believes it is possible to target and redefine high-
Improved survival of patients with myeloma after introduc-
risk myeloma, e.g., by use of combinations of therapies acting
tion of novel agents and applicability of ISS: an analysis of
on different intracellular pathways. This will require strategic
the Greek myeloma study group (GMSG) (abstract #655)
development of combination therapies to improve outcomes.
Dr. Meletios Dimopoulos, Alexandra Hospital, Athens, Greece,
Furthermore, understanding of the precise mechanisms of action
presented this study on behalf of Dr. Efstathios Kastritis and col-
of novel target-based therapies will improve rational drug combi-
leagues. Most of the patients in this study were treated outside
nations. Models for drug development which include examining
of clinical trials. The aim was to assess applicability of ISS in the
the influence of the tumor microenvironment will yield addi-
era of novel agents because the ISS has not been validated as
tional new targets for therapy.
a prognostic tool in patients who have been treated up front
Diagnosis and Management
with novel agent-based therapies. Since 1985, 1376 patients with
newly diagnosed myeloma have been entered into the GMSG
Dr. Nikhil Munshi, Dana-Farber Cancer Institute, Harvard Medical
database, 859 before 1999 and 517 after January 1, 2000, when
School, Boston, Massachusetts, chaired the Plasma Cell Disorders
thalidomide (thal) became available in Greece.
Education Session. He reviewed diagnostic advances, including
the use of free light chain (FLC), fluorescent in situ hybridization
Patients in the more recent of the two cohorts were older, had a
(FISH), magnetic resonance imaging (MRI), and GEP, approaches
higher ISS stage and other negative prognostic factors, but also
that have moved from targeting myeloma tumor cells with mel-
had better response rates. After a multivariate analysis, age, diag-
phalan-prednisone (MP) to targeting myeloma cells along with
nosis before 2000, and ISS stage remained significant adverse
their bone marrow environment, and from palliation, to treat-
survival factors. The Kaplan-Meier survival curves by ISS stage
ment as a chronic illness, to nearing a cure. He then gave a talk
were clearly separated. Novel agents significantly improved
entitled Investigative Tools for Diagnosis and Management.
survival of patients treated outside tertiary centers, mainly for
younger patients in whom median survival doubled. Patients
Dr. Munshi noted that analysis of high levels of serum free light
with high ISS, renal disease, high LDH, anemia, and poor per-
chain has helped to predict a higher risk of progression in MGUS
formance status (PS) saw improved survival with novel agents;
and SMM, but that whether stringent complete response (CR)
however, median survival for patients with ISS stage III is still
with normal FLC is a predictor of overall survival needs to be
less than 3 years.
validated. Furthermore, although determination of FLC in urine
is not indicated, determination of Bence-Jones proteins in a
Response
24-hour urine sample is still important for staging and prognostic
Effect of pre- and post-transplant responses on outcome
work-up, as are albumin, lactic dehydrogenase (LDH), and beta-
of patients with myeloma: CR and nCR should not be
2-microglobulin levels, bone marrow cytogenetics, and FISH.
considered as equivalent prognostic markers: results of a
Dr. Munshi believes that the International Staging System (ISS)
PETHEMA/Gem prospective study (abstract #161)
is universally applicable, cytogenetics are informative in about
Dr. Joan Blade, Hospital Clinic, Barcelona, Spain, presented the
25% of patients, and the presence of an abnormal karyotype is an
results of a prospective analysis of the prognostic influence of
independent predictor of poor outcome. The addition of high-
response in patients in the GEM200 program on behalf of Dr.
density genomic arrays including RNA-based GEP, array com-
Juan Jose Laherta, University Hospital, Madrid, Spain, and col-
parative genomic hybridization (CGH), and single nucleotide
leagues. There were 632 patients evaluable after VBMCP/VBAD
polymorphism (SNP) DNA-based analyses, will improve prognos-
and BUMEL or MEL 200 ASCT. A median FU of 45 months was
tication. He noted that there are no genes in common between
available for 968 patients registered; 178 patients did not go on
the 70-gene Arkansas model and the 15-gene IFM model, agree-
to transplant; there was 2% transplant-related mortality; and 119
ing with Dr. Shaughnessy that this currently complicates using
patients who received a second transplant were excluded.
4
CR post-transplant was significantly correlated with response
diagnosed patients. Additional data are becoming available for
before transplant. Patients with conversion from partial response
the use of novel therapies in combination with each other as well
(PR) to near (n) CR or CR have significantly longer event-free sur-
as with conventional therapies for myeloma.
vival (EFS) and overall survival (OS) compared with patients who
remain in PR after transplant. Patients who converted to nCR
Induction Therapy
after transplant had significantly improved EFS and OS compared
During the Plasma Cell Disorders Education Session, Dr. Jean-
with those who had nCR both pre- and post-transplant. Patients
Luc Harousseau, University Hospital, Hotel-Dieu, Nantes, France,
with nCR and stable disease (SD) did better than patients with
reviewed induction therapy in multiple myeloma, which usually
PR post-transplant, as did patients younger than age 65 years.
means remission induction, in contrast to induction in acute leu-
Patients with SD may not have responded to initial therapy, but
kemias, where the goal is to achieve CR. He observed that until
also don't have progressive disease. Although they may be con-
recently, the choice of induction therapy was easy: VAD (vincris-
sidered to have chemoresistant disease, they may have indolent
tine adriamycin dex) followed by high-dose therapy (HDT) plus
disease. For non-responsive but non-progressive disease, trans-
autologous stem cell transplant (ASCT) for younger patients,
plantation may not add anything, and the good outcome may be
and melphalan prednisone (MP) for older patients. The advent
due to the indolent course of the myeloma.
of novel therapies has presented more choices of combination
therapy, many of which are still in clinical trials. In general, add-
90% sustained CR rate projected 4 years after onset of CR
ing a novel agent to MP improves response, e.g., MPT (MP plus
in GEP (abstract #162)
thal) is better than MP or Mel 100 for progression-free survival
Dr. Bart Barlogie, University of Arkansas Medical Center, Little
(PFS) and response rate, and in some trials for OS. VMP (MP plus
Rock, Arkansas, conveyed the message that a durable CR can be
bortezomib) results in better response and longer PFS and OS
achieved using current therapies. He described an extension of
than MP. MPR (MP plus lenalidomide) is still being studied, as are
Total Therapy 3 A (TT3A), n=303, the results of which are pub-
various other combinations of novel agents with corticosteroids
lished, with the TT3B cohort, n=177 for a total of 480 patients.
and/or alkylating agents.
TT3B involves VRD (bortezomib-lenalidomide-dexamethasone)
maintenance for 3 years vs. TT3A with VTD maintenance for 1
Dr. Harousseau emphasized that MP is no longer the standard
year and thal dex (TD) maintenance for 2 years. The group may
induction therapy for elderly patients, with either MPT or MPV
be considering extending maintenance with lenalidomide (len).
being a better choice. The combination of len dex is also attrac-
tive for this population, with reduced-dose dex offering better
A multivariate analysis of TT3A and TT2B by GEP was used to
tolerability. However, the best induction therapy for elderly
define a high-risk population in which cytogenetics and LDH
patients will be tested in upcoming IFM trials.
are still risk factors, and CR is also a highly significant favorable
feature of outcome. TT3A and TT3B vs. TT2 indicates that CR
For younger patients, CR/very good partial response (VGPR)
duration is the best surrogate for a "cure." TT3 is of benefit in
is achieved after HDT and ASCT. Btz dex prior to ASCT results
patients with low-risk disease but is of no benefit for those with
in better response rates across all cytogenetic risk groups than
high-risk disease.
VAD, which all randomized studies confirm should no longer be
used for induction therapy prior to ASCT. Studies are continu-
The addition of btz in TT3 results in translocation 4;14 no longer
ing to collect data for len dex and for three-drug combinations,
being an adverse feature, especially in otherwise low-risk disease.
e.g., two novel agents plus dex, or a novel agent with dex plus
A post-bortezomib (btz) pharmacogenomic 80-gene model has
an alkylating agent.
been tested and validated as having better prognostic value than
the Arkansas GEP 70 score to evaluate patient response to a test
Btz dox (Doxil; peg ylated doxorubicin) dex (PAD) as
dose of bortezomib. For the 85% of patients identified as having
induction prior to reduced intensity ASCT followed by
baseline low-risk disease, current therapy is difficult to improve
lenalidomide (len) prednisone (LP) for consolidation and
upon. A study for low-risk disease randomly assigns patients to
len as maintenance in elderly untreated myeloma patients
standard TT3 vs. "TT light," or TT4, which is expected to have
(abstract #159)
reduced toxicity and sustained efficacy; 20 patients have been
Dr. Antonio Palumbo, Ospedale San Giovanni Battista, Torino,
enrolled. For high-risk disease, TT5 is being tested in a phase II
Italy, presented the results of this study to determine if 4 cycles
study in which a dose dense but less dose intense treatment may
of PAD followed by mobilization with cyclophosphamide and
avoid host exhaustion. So far, there has been high compliance
G-CSF (granulocyte colony stimulating factor) then MEL 100
for performing GEP at baseline, 48 hours post btz, 48 hours post
reduced-intensity conditioning (RIC) for 2 cycles was feasible
MEL, and prior to both transplants 1 and 2 to evaluate the effect
in patients aged 65 to 75 years. LP consolidation was given for
of therapy.
4 cycles, then len alone was used for maintenance. All patients
have not yet been treated; responses for the first 77 enrolled
Front-Line Treatment of Myeloma
patients (per protocol not ITT population) are: 60% VGPR or
In the last few years the novel therapies (bortezomib, lenalido-
better after 4 cycles PAD, 87% VGPR or better with 13% CR after
mide, and thalidomide) moved from approval in the relapsed/
PAD Mel 100, CR rising to 59% after consolidation and 73% after
refractory setting, to late-phase trials in the front-line setting, to
maintenance. Median follow-up (FU) is 17.6 months; PFS pro-
approval for both thalidomide and bortezomib for use in newly
jected as 80% at 3 years, OS 90% at 2 years. Patients younger than
5
age 70 years are doing better, so the cut-off for this regimen is
between the two arms with a 5-year median OS for both groups.
probably age 70 years. PAD overcomes the prognostic factors of
A landmark analysis indicated that patients who had CR as the
elevated beta 2-microglobulin and abnormal cytogenetics. Grade
best response had the best prognosis, with 80% 5-year survival.
3 to 4 adverse events (AE) include 15% thrombocytopenia, 15%
Patients with ISS stage I disease at diagnosis had a 70% 5-year
peripheral neuropathy (PN), which may require adjustment of
survival. Patients who received thal maintenance had a reduced
the btz dose, and 15% infections.
OS at relapse compared with patients who didn't receive thal
Phase III Trials in Newly Diagnosed Myeloma
maintenance.
Superior CR rate and PFS after ASCT with up-front vel thal
Mel + pred vs Mel + pred + thal in induction therapy for
dex ( VTD) compared with thal dex (TD) in newly diag-
myeloma in elderly patients: final analysis of the Dutch
nosed myeloma (abstract #158)
cooperative group HOVON 49 study (abstract #649)
Dr. Michele Cavo, Istituto Seragnoli, Bologna, Italy, presented
Dr. Pierre Wijermans, Haga Hospital, The Hague, Netherlands,
preliminary results of a phase III randomized study of three
presented the results of this randomized, phase III study in
21-day cycles of induction therapy with btz thal dex compared
patients older than age 65 years. The target enrollment was 420
with thal dex followed by stem cell collection, cyclophosph-
patients but the study was stopped early at MP n=167 and MPT
amide, HD melphalan, and consolidation. 460 evaluable patients
n=165 because doctors in the Netherlands were convinced that
after at least ASCT were included in this analysis. The median
thalidomide should be given as frontline therapy for elderly
age was 56 years. Results for the ITT population so far are: VTD
patients. Toxicity was higher in the thal arm, mostly grade 2, with
n=226 with CR/nCR 32%; TD n=234 with 12% CR/nCR. At least
a low thrombosis rate because most patients received DVT pro-
VGPR was 62% vs. 29 %; PR or greater was 94% vs. 79%. VTD was
phylaxis, although it was not required. CR+VGPR was 29% for
superior, at least for the nCR rate, across subgroups including
MPT vs. 9% for MP. The quality of response increased with con-
poor prognostic factors such as deletion (del)13, translocation
tinued therapy. EFS was MPT 53% vs. 35% MP at 1 year, 33% vs.
4;14, and del 17. The response to the first ASCT was: VTD CR/
19% at 2 years, 9% vs. 3% at 4 years. There was no difference in
nCR 55% vs. TD 32%; CR 43% vs. 23%, at least VGPR 78% vs. 56%.
OS; most patients in the control arm got thal at relapse, and its
VTD also gave significantly better response rates than TD after
role as maintenance can't be ruled out.
the second ASCT and consolidation.
First analysis of HOVON-65/GMMG-HD4 randomized phase
Serious AE (SAE) that were higher with VTD included grade 3
III trial comparing btz, adriamycin, dex (PAD) vs. VAD
to 4 PN and skin rash; otherwise SAE were similar. Of patients
as induction treatment prior to HD mel in patients with
with grade 3 to 4 PN while on VTD as induction therapy, 95%
newly diagnosed myeloma (abstract #653)
remained on therapy with no effect on response rate compared
Dr. Pieter Sonneveld, University Hospital Rotterdam, Rotterdam,
with those with lower-grade or no PN. Discontinuations of induc-
Netherlands, presented results of the first interim analysis on ITT
tion therapy were higher for patients on TD than VTD, mostly
response data for the initial 300 of 825 patients (150 patients
due to disease progression. Estimated 2-year PFS is 90% for VTD
per arm) randomized to VAD vs. 3 cycles of PAD. Following ran-
vs. 80% for TD, which is significant; OS for VTD is 96% vs. 91%
domization, all patients received CAD, stem cell collection, and
for TD, which is not a significant difference.
HDM with autologous peripheral blood (PB) SCT. Patients then
received either thal or btz maintenance for 2 years. If patients
Dr. Cavo concluded that short-term induction with VTD results
had HLA identical siblings, they could have an allogeneic trans-
in significantly increased rates of at least nCR and VGPR, and
plant in lieu of an autologous transplant. Patients in the Nether-
overcomes adverse prognostic factors. The significantly increased
lands received 1 HDM/PBSCT vs. 2 for participating patients in
VGPR or greater rate is seen after both first and second ASCT and
Germany. CR/nCR was 5% for PAD (lower than expected) vs. 1%
consolidation, as is significantly improved time to progression
for VAD. VGPR was 42% for PAD, 15% for VAD. HDM and SCT
(TTP) and PFS. However, longer follow-up is needed for this
results were CR/nCR 23% for PAD vs. 9% for VAD.
trial, which closed this past April with a current median follow-
up of only 15 months. Less than half the patients have received
The only significant AE for PAD was 16% grade 3 to 4 PN, vs. 6%
their second ASCT, so even fewer have received consolidation
for VAD. Deep vein thrombosis (DVT) rates were similar for both
therapy.
arms with no prophylaxis. PAD overcomes the poor prognosis
associated with translocation 4;14 and del 13 but these poor-risk
Final analysis of HOVON-50 randomized phase III trial of
patients do not totally account for the improved responses with
thal adria dex (TAD) and HD mel (HDM) in patients with
PAD. Reponses continue to improve while patients are on btz
myeloma (abstract #157)
maintenance.
Dr. Henk Lokhorst, University Hospital Utrecht, Utrecht, Neth-
erlands, presented the results of the study of 556 patients ran-
Vel-mel-pred ( VMP) vs. vel-thal-pred ( VTP) in elderly
domized to VAD vs. TAD, followed by all patients receiving CAD
untreated patients with myeloma: which is the best partner
(cyclophosphamide adriamycin dex) and G-CSF. Patients then
for Velcade: an alkylating or an immunomodulator agent?
received RIC (n=109) or HDM followed by maintenance with
(abstract #651)
interferon (IFN) or thal. Although response rates, EFS, and PFS
Dr. Maria-Victoria Mateos, University Hospital of Salamanca,
were better in the TAD group, there was no difference in OS
Salamanca, Spain, presented the results of this phase III, ran-
6
domized trial in 260 newly diagnosed patients older than age
Data for the VISTA trial through April 25, 2008, was presented
65 years. Patients received VMP vs. VTP. The first 6-week cycle
by Dr. Jesus San Miguel, University Hospital of Salamanca, Sala-
was standard btz for both groups. Thereafter patients received
manca, Spain. This phase III trial, which included 682 patients
bortezomib once a week for 5 cycles plus either oral melphalan
who were not candidates for transplantation, was stopped at the
and prednisone or thalidomide at 100 mg daily plus prednisone.
third interim analysis with a median FU of 16 months. Current
For both groups, treatment continued for a maximum of 6 cycles
median FU is 25.9 months. M-protein determinations, which
(31 weeks) barring disease progression or unacceptable toxicity.
were done at a centralized lab, were stopped at study end.
The overall response rate (ORR) was 81% for each arm with 22%
There was a 36% reduced risk of death with VMP, although 43%
CR for VMP and 27% for VTP, nCR was 19% vs. 10%; PR 40% vs.
of patients receiving MP also received btz at relapse. There was
44%. Median FU is 16 months with the 2- year TTP estimated at
consistent efficacy in patients with poor prognostic characteris-
72% for VMP vs. 65% for VTP, and the OS estimated to be 88% vs.
tics, including high creatinine clearance (CrCl), or high-risk cyto-
93% at 2 years.
genetics, e.g., translocations 4;14 and 14;16. Of patients treated
There was more neutropenia, thrombocytopenia, and infection
with VMP, 38% vs. 57% of those treated with MP required sub-
with VMP and higher cardiologic toxicity with VTP. Thrombopro-
sequent therapy for progression. The response rate was higher
phylaxis was mandatory but DVT and TE (thromboembolism)
with btz as therapy for progressive disease (PD) in patients in the
was 4% in the VTP arm. SAE were significantly higher with VTP as
MP arm vs. patients in the VMP arm; responses to subsequent
was the discontinuation rate. There were 4% deaths in both arms.
therapy with thal or len were similar regardless of arm. Patients
ORR and IF- (immunofixation) negative CR rates were similar. Dr.
receiving VMP were not more resistant to subsequent therapy at
Mateos concluded that thal may not be the partner of choice with
relapse. Better survival was seen for patients who received VMP
btz for elderly patients and suggested that lenalidomide should
upfront than those who received MP and subsequent therapy at
be tested. During the discussion, suggestions included testing
relapse. CR was associated with longer TTP but not longer OS,
maintenance therapy due to a precipitous drop in EFS around
possibly due to the low number of events. Erthythropoietin stim-
20 months when effective therapy ended, as well as a less intense
ulating agent (ESA) use did not adversely affect long-term out-
regimen of VMP for more fragile patients.
comes with VMP or MP, although ESA use was higher with MP.
Prospective, randomized phase III study of btz, mel, pred,
There were no differences in hematologic AE between arms. VMP
and thal ( VMPT) vs. btz mel pred ( VMP) in elderly newly
was associated with higher gastrointestinal toxicity (19% vs. MP
diagnosed myeloma patients (abstract #652)
5%) and PN (13% vs. none). PN reversed in 79% of patients in
Dr. Antonio Palumbo presented the results of this GIMEMA trial
a median of 1.9 months and 60% of patients with PN eventu-
in 393 patients over age 65 years who were not eligible for trans-
ally completely recovered. The longer FU confirms a significant
plant and who received either VMP with no maintenance, or
benefit for VMP vs. MP, including time to next therapy, in all
VMPT and maintenance with btz and thal. The protocol started
patients, including those with high-risk cytogenetics, the elderly,
with a schedule similar to that used in the VISTA trial, which was
and those with renal impairment. Patients who receive VMP will
amended to weekly btz.
not progress to relapsed disease that is intrinsically more resis-
tant than those who receive MP.
VGPR or better was 55% for VMPT vs. 45% for VMP; CR for VMPT
was 39% and 21% for VMP. Time to PR for the majority of patients
Early Trials in Newly Diagnosed Patients
occurred in 1 to 2 cycles of treatment, but CR increased slowly
Dr. Sundar Jagannath, St. Vincent's Comprehensive Cancer Cen-
over time, suggesting lower intensity but longer treatment might
ter, New York, and Dr. Antonio Palumbo moderated a session in
result in more CR. There was no difference in OS projected at 3
which early phase trials of therapy of newly diagnosed patients
years between the two treatment arms.
were discussed. These results are summarized in the following
Hematologic AE are similar, but non-hematologic AE are signifi-
table:
cantly different. VMPT is associated with 13% sensory neuropa-
See chart "Summary of Early Trial Data in Newly Diagnosed
thy vs. 5% for VMP. Infections were higher with VMPT, 13% vs 9%.
Myeloma" on page 10
In a subgroup analysis, weekly vs. biweekly btz did not reduce
CR but did reduce PN from 24% to 6% for VMPT, and reduced CR
Relapsed and Refractory Myeloma
slightly and PN from 14% to 2% for VMP.
Combination of len, mel pred, and thal (RMPT)
Dr. Palumbo concluded that VMPT doubles the response rate of
in relapsed/refractory: results of a multicenter
VMP, and increases time to next therapy, but not OS. He sug-
phase II clinical trial (abstract #868)
gested longer FU (beyond the current 14 months) is needed to
Dr. Antonio Palumbo presented the results of a GIMEMA study.
assess PFS and OS. Because of the need for further investigation,
He noted that the CR rate with VMP is 21%, and with VMPT CR is
VMPT shouldn't be incorporated into the standard of care.
increased to 39%. This study included 44 patients, half receiving
Updated follow-up and results of subsequent therapy in
50 mg thal, the other half 100 mg thal, standard dose MP, and len
the phase III VISTA trial: btz plus mel-pred ( VMP) vs mel-
10 mg for 3 of every 4 weeks for 6 cycles of induction. Low-dose
pred (MP) in newly diagnosed myeloma (abstract #650)
ASA (100 mg) WHAT IS ASA? was mandated. The CR/nCR rate
7
was 13%, with 20% VGPR. This was a lower response rate than
tive than x-ray, and with the development of low-dose whole body
seen in historic controls treated with VMPT, and the hematologic
CT, this may become the new gold standard. MRI is also more
toxicity and infection rate was also greater. The OS projected at
sensitive than x-ray because it detects bone marrow involvement:
12 months was also lower that seen with VMP.
low T1- and high T2-weighted images are characteristic. MRI is
Maintenance Therapy
the choice to evaluate vertebral compression. Positron emission
tomography (PET)/CT is also more sensitive than x-ray, with the
Maintenance thal may improve progression-free but not
same sensitivity as MRI, although it may miss small lesions, and
overall survival: results from the Myeloma IX maintenance
false positives are seen with inflammatory disease. Another draw-
randomization (abstract #656)
back is that PET/CT is very expensive.
Dr. Gareth Morgan, Royal Marsden Hospital, Sutton, Surry, United
Treatments for myeloma bone disease include bisphosphonates,
Kingdom, presented preliminary results of a maintenance study
surgical procedures, e.g., vertebroplasty and balloon kypho-
randomizing patients to thalidomide or no maintenance. This
plasty, radiation, and, obviously, treatment of the underlying
study enrolled 1970 patients, including older, less fit patients
myeloma disease. Kyphoplasty offers good pain relief. Bispho-
treated with MP or CTD, and younger, fitter patients treated with
sphonates bind to bone, are taken up by osteoclasts, blocking
CTD or CVAD then HDM, with 820 randomized to maintenance.
their activity, and reduce skeletal-related events. However, they
The optimum induction regimen isn't known because the study
have no clear antitumor activity. AE associated with bisphos-
has not been completely unblinded.
phonates include an acute-phase inflammatory reaction with
CTD with no maintenance seems to be the optimum intensive
zoledronic acid requiring premedication, renal toxicity, a newly
regimen. For patients receiving non-intensive therapy, the OS
identified musculoskeletal pain syndrome, which can occur early
with CTD is 40 months vs. 29 months with MP. It appears that
or late in treatment, and osteonecrosis of the jaw (ONJ). The
the use of thal plus alkylating agent plus steroid as one treat-
mechanism behind ONJ is still unclear, with no direct cause and
ment is superior to alkylating agent plus steroid followed by thal
effect relationship with bisphosphonates. Risk factors include
maintenance.
invasive dental procedures, longer time from diagnosis, and
For patients with PR after intensive therapy, thal maintenance
infection with actinomycetes. If ONJ occurs, bisphosphonates
improves PFS but not OS, and there was no benefit beyond 6
should be discontinued until lesions heal. Management includes
months of maintenance. This may reflect a continuing therapy
dental evaluation prior to bisphosphonate use, empirical treat-
rather than maintenance benefit. Thal maintenance had no
ment with antibiotics and oral rinses, pain control, and limited
impact on OS of patients with chromosome 14 translocations
debridement. Dr. Roodman notes that hyperbaric oxygen is not
associated with poor prognosis, and was associated with reduced
effective. ASCO guidelines suggest bisphosphonates should be
PFS and OS for patients with deletion of 17p. Dr. Morgan con-
administered for two years, but there are no clinical data to
cluded that rather than defining a maintenance effect for thal,
support this, although two prospective studies are ongoing.
the results might reflect a consolidation effect for poor response
Withholding bisphosphonates for a short period of time before
after induction. He thinks CTD induction with no maintenance
dental procedures, as suggested in Canadian guidelines, makes
after HDM might be appropriate for younger patients, and sug-
no sense, Roodman explains, because the drugs can remain in
gested looking at len maintenance.
bone for a decade. He concludes that as signaling pathways and
factors involved in myeloma bone disease are identified, new
Skeletal-Related Events
and more effective targeted therapies may be developed.
Dr. G. David Roodman, Pittsburgh Healthcare System and Uni-
IMF Satellite Symposium
versity of Pittsburgh, Pennsylvania, presented Skeletal Imaging
and Management of Bone Disease during the Plasma Cell Disor-
Finding Your Way Through the Treatment Maze
ders Education Session. Myeloma is the most frequent tumor to
Selecting the Best Treatment in the Era
involve the skeleton. Dr. Roodman believes that if one were to
of Novel Agents
look closely enough, all patients with myeloma would be found
This program was facilitated by Dr. S. Vincent Rajkumar, Mayo
to have skeletal involvement. Fracture increases the risk of mor-
Clinic, Rochester, Minnesota, and featured discussions of case
tality. At diagnosis, 20% of patients have pathologic fractures,
studies by Dr. Rajkumar and faculty members Dr. Antonio
and up to 60% will have fractures over the course of their dis-
Palumbo, Dr. Philippe Moreau (IFM, Nantes, France), and Dr.
ease. In myeloma, bone remodeling absorption and formation
Jesus F. San Miguel. The audience's knowledge of treatment
are uncoupled.
options for each case patient was assessed before and after the
Dr. Roodman feels that bone scans can underestimate the degree
presentations and discussions.
of bone disease, and therefore the diagnostic gold standard
Case studies with suggested treatments included the following:
should be a metastatic bone survey of the skull, vertebrae, pelvis,
· a newly diagnosed patient with multiple myeloma who was
and extremities, although lesions will not be seen until there is a
ineligible for transplantation
30% loss of trabecular bone. This test is not useful for assessing
P-T (melphalan-prednisone-thalidomide) or MP-V (MP-
response to therapy, because in most patients these lesions do
bortezomib; btz) are good options; MP-lenalidomide
not heal. Computed tomography (CT) evaluation is more sensi-
(Revlimid; MPR) is still being investigated
8
thalidomide-dexamethasone (thal-dex) is not the stan-
New therapies in development to target different points in path-
dard of care because the results are not superior to those
ways thought to be important in the development of myeloma
obtained with MP
include monoclonal antibodies targeting receptors on the sur-
for patients over the age of 75 years, dose-reductions
face of myeloma cells and agents affecting intracellular signaling
should be considered to reduce toxicity
pathways such as:
· a newly diagnosed, transplantation-eligible patient with ISS
· new proteasome inhibitors
stage III multiple myeloma, who had normal cytogenetics and
· histone deacetylase inhibitors
translocation 4;14 by FISH
· heat shock protein (HSP) 90 inhibitors
alkylating agents, which interfere with the collection of
· new immunomodulatory drugs
stem cells, should not be used
thal-dex is FDA approved, but is associated with neuro-
The issue of maintenance therapy was discussed in the question
logic side effects
and answer period. Dr. Moreau felt that maintenance with thali-
btz-dex, VTD (btz-thal-dex), and VRD [btz- Revlimid
domide was beneficial mainly in patients who had a response of
(lenalidomide)-dex] are being studied
less than VGPR. Dr. San Miguel noted that thalidomide was not
choices include the oral regimen lenalidomide+low-dose
approved for this purpose. Dr. Palumbo said there was no role
dex (Rd) for a patient with low-risk disease; a btz-based
for maintenance, but adding a third drug for consolidation after
regimen for a patient with high-risk disease; and VTD for a
a sub-optimal response was appropriate. Ongoing trials may
patient with acute renal failure, to control disease rapidly
clarify the role of maintenance therapy.
there were suggestions to add a third drug, e.g., cyclo-
New Treatments in Early Stage Development
phosphamide or Doxil (pegylated doxorubicin), which
As the natural history of myeloma is better understood, new ther-
needs to be tested in trials, or to use two drugs and save
the third one for relapse
apies are being developed to target specific pathways involved
in the disease. Targets include the interaction of myeloma cells
· a patient age 64 years, with ISS stage II myeloma, normal cyto-
with the bone marrow microenvironment, cell surface proteins
genetics, t(4;14) by FISH, for whom transplantation eligibility
and receptors on myeloma and bone marrow stromal cells,
is uncertain, due to a partial response after 4 cycles of induc-
tion therapy
and intracellular molecules in pathways involved in myeloma
pathogenesis.
for younger patients not being treated in a clinical trials,
induction therapy, possibly with a btz-dex-based regimen
Progress is being made in developing therapies targeted to spe-
followed by ASCT prepared by Mel 200, with post-ASCT
cific growth factors and other molecules essential for the devel-
maintenance with thal (or maybe lenalidomide) for one
opment and progression of myeloma. Because many of these
year would be a reasonable regimen
therapies have limited activity as single agents, they will likely
ongoing studies are addressing whether ASCT is needed
be used in combinations, particularly with the novel therapies
in the era of novel therapies
bortezomib, lenalidomide, and thalidomide. Combining agents
· a patient with multiple myeloma who relapsed multiple times
with different mechanisms of action may increase their activity
after multiple treatments following induction therapy
while reducing the likelihood of side effects.
IMiDs (thal, len, and presumably pomalidomide which is
Interesting clinical trial results are summarized in the table
in development) with btz should be restricted to well-
"Clinical Trial Results New Therapies" on page 11
controlled trials to preserve future options for patients
young patients with early relapse (less than one year post-
Future Directions
ASCT), intermediate relapse (1 to 3 years post ASCT), and
New therapies that are targeted to specific pathways in myeloma
late relapse (more than 3 years) should be distinguished:
development continue to enter clinical trials. The novel thera-
early relapse: therapy should address overcoming drug
pies bortezomib and thalidomide have moved from the relapsed,
resistance with combinations or alternating non-cross-
refractory setting to the frontline setting, and lenalidomide
resistant agents
may be expected to do the same. The trend of combining these
intermediate relapse: therapy should prolong survival
therapies with conventional chemotherapies, each other, and/or
with sequential novel agent combinations until cura-
and targeted therapies is continuing, expanding the treatment
tive treatments are developed
options for patients with multiple myeloma. Multiple myeloma
late relapse: re-induction and a second ASCT
is becoming more like a chronic, long-term disease as new treat-
for elderly patients, their general condition should be
ment options continue to become available.
taken into account, using a different drug than that used
Lynne Lederman, PhD, is a medical writer based in Mamaroneck, New York
for induction followed by enrollment in a trial for active
treatment, and oral cyclophosphamide plus prednisone
for patients not candidates for active treatment
9
Summary of Early Trial Data in Newly Diagnosed Myeloma
treatment
First Author (abstract)
Study Design
Results and Conclusions
RCd: lenalidomide (len)
Shaji Kumar (#91)
Phase II feasibility; patients
VGPR+CR 32%, may increase
with cyclophosphamide
could go on to ASCT; n=34,
with time for patients not going to
(cyclo) and low-dose dex-
then cyclophosphamide dose
transplant and still on study; most
amethasone (dex)
lowered and 19 additional
AE were hematologic; 20 patients
patients enrolled
completed therapy, 2 died, 11 PD;
median time on study 4.8 months,
median FU 12.3 months; 30 patients
collected stem cells, 8 failed, 3 sal-
vaged with AMD3100, 1 with cyclo
Len, bortezomib (btz),
Paul Richardson (#92)
Phase I/II to define maximum
46 patients completed 8 cycles,
dex: btz standard dose and
tolerated dose (MTD) of combi-
15 went to ASCT. Most common AE:
schedule; len maintenance
nation and response; n=66
manageable myelosuppression; 3%
after 8 cycles; dex reduced
TE; low rate PN. 26% CR, 18% nCR,
during study
36% PR. Further phase III studies
in progress or planned.
Btz, dex, cyclo, and len
Shaji Kumar (#93)
Phase I/II multicenter EVOLU-
Most common AE: PN, cytopenias
(VDCR): standard btz, dex
TION; n=25, MTD not reached,
(not cumulative), no TE. Best
weekly
2 dose-limiting toxicities (DLT).
unconfirmed response preliminary
Phase II recruiting and random-
phase I: 36% CR (20% stringent CR),
izing to 3 arms: VDR, VDC, and
68% VGPR or better. 11 patients
VDCR induction up to 8 cycles,
have collected stem cells.
then btz maintenance weekly
Btz, cyclo, thal, and dex
William Bensinger (#94)
Phase II; btz cyclo dex cycles 1
Best response: 26% CR, 9% nCR,
to 3; btz, thal, dex cycles 4 to 6;
21% VGPR; OS n=43 86%
n=44
(12-month estimate); 22 patients
transplanted; 11 patients grade
3 to 4 AE requiring dose reduction,
10 patients discontinued; 8 deaths
including 4 disease related
Consecutive patients
Prashant Kapoor (#95)
100 patients classified mSMART
Median estimated FU 46 months.
receiving len dex as initial
model as high risk (n=16) or
Similar responses high and standard
therapy, could pursue
standard risk (n=84)
risk, median OS similar at 2 years:
ASCT at end of 4th cycle
92% alive, at 3 years: 84% vs. 77%.
TTP and PFS high risk inferior to
standard risk.
Btz and HD mel (HDM)
Murielle Rousell (#160)
Phase II, open label, multicenter Btz HDM might be superior to
before ASCT
study, 2 cycles btz before and
HDM alone after VAD induction.
2 after HDT; n=54; choice of
A phase III study was planned.
induction therapy not specified
10
Clinical Trial Results New Therapies
treatment
First author
Study Design
Results and Conclusions
(abstract)
Perifosine (alkylphospholipid oral AKT inhibitor)
Perifosine
Paul Richardson Phase I/II multicenter trial in patients
GI toxicity, diarrhea manageable with dose reduction. Manageable
(KRX-0401)
(#870)
with relapsed/refractory myeloma
hyponatremia, hyperglycemia with dex. Best response in 72 evalu-
+ btz
including btz; btz standard schedule,
able patients CR 3%, nCR 4%, ORR 38%; dex did contribute to ORR;
at progression add dex; n=84
median TTR: 5 cycles; TTR btz refractory: 6 cycles, TTP (n=72):
6.3 months; in those MR or better 9.4 months; ORR 38%, btz
refractory 31%
Randomized phase III trial peri + bz+dex vs. bz+dex+ placebo
in relapsed/refractory myeloma planned or ongoing
Vorinostat [Histone Deacetylase (HDAC) Inhibitor]
Vorinostat
Donna Weber
14-day vorinostat dose, from bid to qd
DLT: 1 transient AST grade (gr) 3, thrombocytopenia gr 4; thrombo-
plus btz
(#871)
schedule; btz dose lower, escalated to
cytopenia, fatigue common; SAE 29%; PR 38%;
standard dose; EBMT response criteria;
DOR 5.3 months
n=34, median age 64 years
Vorinostat
Donna Weber
Vorinostat days 4 to 11, dose escalated;
DLT: prolonged QT and fatigue gr 4; increased myelosuppression
plus btz
(#871)
btz dose started higher, reduced to
with increasing cycles; VGPR 10%, PR 33%; DOR not available
standard dose; IMWG response criteria;
n=23, median age 54 years
Monoclonal Antibodies (mAb)
CNTO 328
Jean-Francois
Phase II study in btz- naïve, relapsed/
Part 1: median TTP 8.7 mo, CR 3 patients, VGPR 3 patients,
(anti-IL-6
Rossi
refractory myeloma, part 1: n=21;
PR 6 patients; CR+VGPR 29%, ORR 57%; hematologic toxicity
mAb) plus btz
(#867)
part 2: n=270
as expected with btz, mostly neutropenia; 5 patients gr 3 to 4
infections; part 2 ongoing
Pomalidomide [Thalidomide analog (IMiD) CC4047]
Pomalidomide
Martha Lacy
Phase II relapsed myeloma; n=60,
Hematologic toxicity gr 2 neutropenia prominent, non-hematologic
plus
(#866)
starting dose 2 mg PO daily, dex 40 mg
toxicity gr 3 fatigue 28%, 1 death neutropenia/pneumonia. No gr 3
low-dose dex
once a week, mandated ASA for DVT
to 4 PN, no DVT/PE. Dose reduction pomalidomide 13%, dex 32%.
prophylaxis
66% MR or better; best response median FU 4 months: ORR 58%,
CR+VGPR 25%.
Future phase II trial of pom dex for len-refractory and
btz- refractory myeloma.
Carfilzomib (Proteasome Inhibitor PR-171)
Carfilzomib
Sundar
PX-171-003, open label, single-arm,
39 evaluable patients, PR 13%, MR 13%, SD 41%, PD 28%;
(PR-171; CFZ)
Jagannath
phase II study in patients with relapsed
5 btz-refractory pts had MR or better; median DOR: 7 months.
(#864)
and refractory myeloma with at least
Hematologic toxicity primarily anemia and thrombocytopenia, cycli-
2 prior therapies that included btz,
cal as for btz, not as much neutropenia. Non-hematologic toxicity
thal or len; CFZ 20 mg I.V. push 2
gr 3 to 4 events in 3 patients, e.g., fatigue. Creatinine changes gener-
consecutive days 3 weeks on, one week
ally transient and non-cumulative; 4 patients with acute renal failure,
off for maximum 12 cycles; trial is
1 died pneumonia and septic shock. All renal failure reversible off
ongoing; n=46
drug. Well tolerated for up to a year, no painful PN. Next stepped up
dose escalation from cycle 2, study expanded to n=250, treatment
extended beyond a year, potential for accelerated approval within a
year as a drug for unmet need.
Carfilzomib
Ravi Vij
PX-171-004, open label, single-arm,
ORR: 35%, CR 3%, VGPR 6.5%, PR 26%; btz-exposed ORR 18%, btz-
(PR-171; CFZ)
(#865)
phase II study in patients with relapsed
naïve ORR 57%; 90% response by cycle 4. TTP btz-naïve median FU
myeloma; 12 cycles; dex 4 mg PO first
108 days no progression, btz- exposed median FU 113 days some
cycle only as premed to reduce cytokine progression. Don't have DOR yet. AE hematologic gr 3 to 4 10%
release seen in phase I studies as
or less ; non-hematologic toxicity 2 gr 3 dyspnea, overall fatigue,
low-grade fever; results for n=31
nausea/vomiting; 2 cases tumor lysis syndrome in btz- naïve patients,
reported here
1 possible, 1 documented. Prophylaxis amendment to protocol
instituted hydration, allopurinol, no additional instances in next 80
patients. Will extend phase II studies.
11
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