Addressing THe CUrrenT CHALLenges OF mULTipLe myeLOmA TreATmenT Introduction

Addressing THE
CURRENT CHALLENGES OF
multiple myeloma TREATMENT
This CME-certified activity is
based on information presented
at a satellite symposium held
on December 7, 2012,
in Atlanta, Georgia.
Faculty
Paul G. Richardson, MD—
Program Chair
Faith Davies, MBBCh, MRCP, MD,
FRCPath
Johannes Drach, MD
Andrzej Jakubowiak, MD, PhD
María-Victoria Mateos, MD, PhD
Author
Lynne Lederman, PhD
Release date: March 13, 2013
Expiration date: March 13, 2014
Estimated time to complete activity: 1 hour
Jointly sponsored by
Multiple Myeloma
Research Foundation
Support for this activity has been provided
through educational grants from Amgen,
Bristol-Myers Squibb, Celgene Corporation,
Merck Sharp & Dohme Corporation,
Millennium: The Takeda Oncology Company,
and Onyx Pharmaceuticals.
Introduction
The past several years have seen significant advances in the management of multiple myeloma. This
has been due in large part to a better understanding of the biology of the disease and the development of several highly effective therapies. Current approaches to improving response rates and,
ultimately, overall survival focus on taking an individualized approach to treatment, since multiple
myeloma is a heterogeneous disease. Patients with multiple myeloma can have different clinical
outcomes and responses to treatment based on underlying genomics. To better understand the
correlation between genetic factors and mechanisms of disease, drug response, and patient relapse, research is under way to identify molecular and genomic markers important in multiple
myeloma pathogenesis. In particular, the Multiple Myeloma Research Foundation (MMRF) has
launched a landmark study, CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment
of Genetic Profile), to identify the molecular profiles and clinical characteristics that define certain
subsets of myeloma patients. These profiles will provide a better understanding of multiple myeloma
pathology and further facilitate the development of new therapeutic agents and strategies for individualizing patient care.
To achieve optimal results, oncologists must be adept at individualizing patient-management strategies, including stratifying patients based on risk and maximizing the depth and duration of treatment response. Physicians must consider an individualized approach in the context of both newly
diagnosed and relapsed and relapsed/refractory disease, and they must have a high degree of familiarity with current novel therapies and next-generation agents, either of which may be useful for
patients who become resistant to regimens used in the frontline setting.
Addressing the current challenges of myeloma treatment was the goal of a symposium held December 7, 2012, in Atlanta, Georgia, prior to the American Society of Hematology Annual Meeting. Paul
G. Richardson, MD, served as Program Chair and led a panel of experts, including Johannes Drach,
MD; María-Victoria Mateos, MD, PhD; Andrzej Jakubowiak, MD, PhD; and Faith Davies, MBBCh,
MRCP, MD, FRCPath, in discussions that covered recent clinical data and the latest advances in
multiple myeloma therapy.
Activity Overview
To achieve optimal results, oncologists who treat multiple myeloma must
be adept in individualizing patient management strategies, which includes
stratifying patients based on risk and maximizing the depth and duration
of treatment response. Oncologists also need to be aware of these
approaches in the context of relapsed or refractory disease and the next
generation of agents that may be useful for patients that become resistant
to current regimens.
Target Audience
Accreditation Statement
This activity has been planned and implemented in accordance with the
Essential Areas and Policies of the Accreditation Council for Continuing
Medical Education (ACCME) through the joint sponsorship of Penn State
College of Medicine, Curatio CME Institute, and the Multiple Myeloma
Research Foundation. Penn State College of Medicine is accredited by the
ACCME to provide continuing medical education for physicians.
Credit Designation
This activity has been designed to meet the educational needs of
hematologist-oncologists and medical oncologists involved in the care of
patients with multiple myeloma.
Penn State College of Medicine designates this enduring material for a
maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim
only the credit commensurate with the extent of their participation in the
activity.
Learning Objectives
Method of Participation
Faulty
Disclosure
Upon completion of this activity, participants should be able to:
•Use cytogenetics, fluorescence in situ hybridization (FISH), and gene
expression profiling to define patient prognosis and risk stratification
•Outline a treatment plan to achieve the desired response while balancing
the risk for toxicities in high-risk and standard-risk myeloma patients
•Implement evidence-based strategies to prolong the duration of response
in multiple myeloma patients
•Incorporate current consensus recommendations, guidelines, and the
latest clinical evidence in the management of multiple myeloma
•Evaluate clinical data regarding the use of new agents in patients who
develop resistance to or relapse from their initial therapy
Paul G. Richardson, MD—Program Chair
RJ Corman Associate Professor of Medicine
Harvard Medical School
Clinical Director, Jerome Lipper Center for Multiple Myeloma
Dana-Farber Cancer Institute
Boston, Massachusetts
Faith Davies, MBBCh, MRCP, MD, FRCPath
Cancer Research UK Senior Cancer Fellow
Consultant Hematologist
Royal Marsden Hospital
Institute of Cancer Research
London, United Kingdom
Johannes Drach, MD
Professor of Medicine, Hematology and Oncology
Program Director, Multiple Myeloma and Malignant Lymphoma
Medical University of Vienna
Department of Medicine I/Clinical Division of Oncology
Vienna, Austria
Andrzej Jakubowiak, MD, PhD
Professor of Medicine
Director, Myeloma Program
The University of Chicago
Chicago, Illinois
María-Victoria Mateos, MD, PhD
Consultant Physician
University Hospital of Salamanca
Salamanca, Spain
2 u March 2013
There are no fees for participation in this CME activity. To receive credit
during the period March 13, 2013 to March 13, 2014, participants must
(1) read the learning objectives and disclosure statements, (2) study the
educational activity, and (3) complete the posttest and activity evaluation,
including the certificate information section.
The posttest and evaluation can be accessed at the end of the activity
OR completed online at:
http://www.curatiocme.com/posttest/AddressingMM. Please e-mail
any questions to [email protected]. For questions about CME credit
for this activity, contact Penn State at [email protected] or (717)
531-6483. Reference course # G5308-13-R
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amount occurring in the last 12 months with a commercial interest whose
products or services are discussed in the CME activity content over which
the individual has control. Relationship information appears below:
Faith Davies, MBBCh, MRCP, MD, FRCPath, has disclosed the following
relevant financial relationships:
Speaker and Celgene, Janssen, Lilly, Merck Sharp & Dohme
Advisory Board: Corporation, Millennium: The Takeda Oncology
Company, Novartis
Dr. Davies discusses the unlabeled or investigational use of a commercial
product.
Johannes Drach, MD, has disclosed the following relevant financial
relationships:
Consultant/Speaker: Celgene, Janssen
Investigator: Roche, Mundipharma
Dr. Drach discusses the unlabeled or investigational use of a commercial
product.
Andrzej Jakubowiak, MD, PhD, has disclosed the following relevant
financial relationships:
Advisory Board: Bristol-Myers Squibb, Celgene, Millennium: The
Takeda Oncology Company, Onyx
Consultant: Bristol-Myers Squibb, Celgene, Millennium: The
Takeda Oncology Company, Onyx
Speaker: Celgene
Dr. Jakubowiak discusses the unlabeled or investigational use of a
commercial product.
María-Victoria Mateos, MD, PhD, has disclosed the following relevant
financial relationships:
Consultant: Bristol-Myers Squibb, Celgene, Janssen, Millennium:
The Takeda Oncology Company, Mundipharma, Onyx
Dr. Mateos discusses the unlabeled or investigational use of a commercial
product.
Paul G. Richardson, MD, has disclosed the following relevant financial
relationships:
Advisory Board: Bristol-Myers Squibb, Celgene, Johnson & Johnson,
Millennium: The Takeda Oncology Company, Novartis
Dr. Richardson discusses the unlabeled or investigational use of a
commercial product.
Curatio CME Institute
Denise C. LaTemple, PhD, President, Curatio CME Institute, has disclosed
no relevant financial relationships.
Jonathan S. Simmons, ELS, Senior Managing Editor, has disclosed no
relevant financial relationships.
Multiple Myeloma Research Foundation
Anne Quinn Young, MPH, Vice President, Communications, has disclosed
no relevant financial relationships.
Penn State College of Medicine
Faculty and staff involved in the planning and review of this activity have
nothing to disclose.
Core Principle Solutions, LLC
Dana Delibovi, copy editor, has disclosed no relevant financial relationships.
Lynne Lederman, PhD, medical writer, has disclosed the following financial
relationships:
Consultant:Infinity Discovery, Inc., a division of Infinity
Pharmaceuticals and Oncology Business Review
Ms Lederman discusses the unlabeled or investigational use of a commercial
product.
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This educational activity may contain discussion of published and/or
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Takeda Oncology Company, and Onyx Pharmaceuticals do not recommend
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Pharmaceuticals. Please refer to the official prescribing information for each
product for discussion of approved indications, contraindications, and warnings.
Generic Name
Trade Name
Approved Use (if any)
Unapproved/Investigational Use
Bortezomib
Velcade
Treatment of patients with multiple myeloma (MM)
Maintenance therapy
Carfilzomib
Kyprolis
Treatment of patients with MM who have received at least two prior therapies including bortezomib
and an immunomodulatory agent and have demonstrated disease progression on or within 60 days
of completion of the last therapy
Frontline therapy
Ixazomib
NA
NA
Treatment of MM
Lenalidomide
Revlimid
Treatment of MM, in combination with dexamethasone, in patients who have received at least one
prior therapy
Frontline therapy; maintenance therapy
Pomalidomide
Pomalyst
Treatment of patients with MM who have received at least two prior therapies including
lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of
completion of the last therapy
Frontline therapy
Thalidomide
Thalomid
Treatment of patients with newly diagnosed MM in combination with dexamethasone
Relapsed/refractory MM; frontline therapy in
combination with melphalan-prednisone;
maintenance therapy
Vorinostat
Zolinza
Treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have
progressive, persistent, or recurrent disease on or following two systemic therapies
Treatment of MM
Addressing the Current Challenges of Multiple Myeloma Treatment u 3
Cytogenetics and Risk Stratification
The International Staging System (ISS)1 based on serum β2-microglobulin and serum albumin—though prognostic for survival—classically does not take molecular or genetic information into account. Dividing myeloma into hyperdiploid or nonhyperdiploid groups using
metaphase karyotyping adds substantial prognostic value.2 Nonhyperdiploidy includes a high frequency of 14q translocations and 13q deletions and is associated with a poorer prognosis.3 Fluorescence in
situ hybridization (FISH) analysis may be a more informative method
of stratifying risk, with t(4;14), t(14;16), and del(17p) associated with
poor prognosis, del(13q) associated with intermediate prognosis, and
all other abnormalities associated with more favorable prognosis after
conventional therapy, recognizing that myeloma remains incurable in
the longer term.4,5
The International Myeloma Working Group (IMWG) has proposed a
new multiple myeloma risk-stratification schema that combines FISH
data with ISS staging to improve risk assessment.6 Advanced testing
via gene expression profiling (GEP)7,8 and single-nucleotide polymorphism array9 also holds promise, and the Mayo Clinic mSMART risk
classification system incorporates plasma cell FISH, metaphase cytogenetics, and plasma cell labeling index (PCLI) in its risk classification
approach.10 A summary of current risk categories used in multiple
myeloma is shown in Table 1.2,11-13
Research to determine whether novel therapies can overcome highrisk cytogenetics in multiple myeloma is ongoing. Several trials have
assessed the efficacy of thalidomide in patients with adverse cyto­
genetic profiles but have generally failed to show that this drug can
overcome cytogenetic risk.14-16 For example, the Medical Research
Council (MRC) Myeloma IX trial recently reported that thalidomide-­
based maintenance therapy did not yield a survival benefit in patients
with adverse findings on FISH testing.15
In contrast, lenalidomide and bortezomib may overcome unfavorable
cytogenetics and lead to good outcomes.17-23 One study of lenalidomide
plus dexamethasone in the relapsed/refractory setting showed that
treatment with this regimen overcame the negative prognostic effect of
del(13q) and t(4;14) but not del(17p).17 Another study of initial therapy
found that, across high-risk groups of patients whose cytogenetic abnormalities were treated with lenalidomide and dexamethasone, overall
survival (OS) did not differ significantly from the standard risk group.18
In an analysis of relapsed and refractory patients, however, OS was
significantly shorter among patients with del(13q) and t(4;14) who received this regimen compared with patients who did not have these
cytogenetic abnormalities.24 Bortezomib has demonstrated the ability
to overcome adverse cytogenetics, including del(17p). A recent report
4 u March 2013
Table 1. Multiple myeloma: risk categories summary.2,11-13
Standard Risk
(Expected OS: 6–7 Yrs)
High Risk
(Expected OS: 2–3 Yrs)
t(11;14)
t(6;14)
del(17p)
t(4;14)*
t(14;16)
Hyperdiploidy
Nonhyperdiploidy
del(13q)
β2M*
Low (<3.5 mg/L)
High (≥5.5 mg/L)
PCLI
<3%
High (≥3%)
—
IgA
Good risk
High risk
Risk Factors
FISH
Cytogenetics
Isotype
GEP
*Patients with t(4;14), β2M <4 mg/L, and Hb ≥10 g/dL may have
intermediate-risk disease.
β2M, β2 microglobulin; FISH, fluorescence in situ hybridization; GEP, gene
expression profile; Hb, hemoglobin; IgA, immunoglobulin A; OS, overall
survival; PCLI, plasma cell labelling index.
Table 2. Median survival in patients with del(17p) in the phase 3 HOVON-65/
GMMG-HD4 trial.21
VAD → ASCT → PAD → ASCT →
T Maintenance P Maintenance
Patients (n)
40
25
Median PFS
(months)
12
22
Median OS
(months)
24
Statistical
Significance
HR, 0.47
95% CI, 0.26–0.86
P=0.01
Not reached at 55
HR, 0.36
months
95% CI, 0.18–0.74
P=0.003
CI, confidence interval; ASCT, autologous stem cell transplantation; HR,
hazard ratio; OS, overall survival; PAD, bortezomib, doxorubicin,
dexamethasone; PFS, progression-free survival; VAD, vincristine,
doxorubicin, dexamethasone; T, thalidomide.
from the HOVON trial observed a survival benefit in patients with this
chromosomal abnormality who were treated initially with bortezomib-based therapy (Table 2).21 Five-year data from the VISTA trial
showed that bortezomib-based initial therapy in a transplant-ineligible
population resulted in improved OS compared with conventional chemotherapy, regardless of cytogenetic risk group.23 However, in earlier
investigations by the Intergroupe Francophone du Myelome (IFM), OS
benefit was observed for del(13q) and t(4;14) but not for del(17p), although this is likely due to the shorter bortezomib exposure seen in
these studies compared to both VISTA and HOVON.20
Based on available evidence, the most recent consensus by the International Myeloma Workshop Consensus Panel 2 is that bortezomib and
lenalidomide may be able to overcome some high-risk features of
multiple myeloma and help achieve greater clinical benefit.11 However,
the IMWG asserts that it is still too early to mandate definitive treatment
decisions based solely on cytogenetics and recommends further clinical trials based on risk stratification that includes not only cytogenetic
risk but other risk categories.11
Current Approaches to Newly
Diagnosed Patients
Complete response (CR) is an important treatment goal in multiple
myeloma. Patients who achieve CR—particularly CR that is confirmed
by immunophenotypic testing or positron emission tomography/
computed tomography (PET/CT)—often experience superior progression-free survival (PFS) and OS.25-27 Although achievement of
high-quality, sustained CR is important, it should be balanced with
acceptable treatment-related toxicity.
New multidrug regimens based on novel, molecularly targeted agents
are replacing conventional chemotherapy for newly diagnosed multiple
myeloma patients and are increasing the likelihood of CR. In a phase 1/2
study examining both transplant-eligible and transplant-ineligible patients, initial therapy with a combination of lenalidomide, bortezomib,
and dexamethasone (RVD) produced a 100% response rate, with 29%
patients attaining CR and 67% attainting at least a very good partial
response (VGPR) overall28; similar results were achieved in a second
study evaluating the efficacy of RVD as part of a large, randomized
phase 2 trial.29 Transplant-eligible patients treated initially with bortezomib, thalidomide, and dexamethasone (VTD) also achieved a higher rate
of CR than did patients treated with TD alone (31% vs 11%, P<0.0001)
as part of a landmark phase 3 trial confirming the superiority of a threedrug combination over a two-drug regimen in this setting.19
Not only are novel drugs now a mainstay of induction regimens, but
they are finding their way into pretransplant conditioning. The addition
of bortezomib30 or busulfan31 may improve conditioning with high-dose
melphalan prior to autologous stem cell transplantation (ASCT). Consolidation and maintenance with novel drugs29 are now being used
more frequently posttransplantation to reduce the risk of relapse and
prolong PFS and OS. Maintenance with novel agents has in fact replaced interferon maintenance, which is no longer the standard because of its significant toxicity, with lenalidomide and bortezomib currently the preferred novel agents for maintenance therapy. Specifically,
in the IFM 2005-02 and CALGB 100104 studies, use of maintenance
lenalidomide post-ASCT improved CR/VGPR and duplicate PFS compared with placebo32,33; an OS benefit was also observed in the CALGB
trial.33 However, some concern arose in these studies over the potential
for secondary malignancies in the lenalidomide maintenance arm, but
these appear rarely, are primarily driven by genotoxic chemotherapy,
and appear not to affect overall clinical benefit. Maintenance with
Table 3. VISTA: Key end points, VMP versus MP at 5-year follow-up.23
VMP
(n=344)
MP
(n=338)
P Value
Median OS (mo)
56.4
43.1
0.0004
5-year OS (%)
46.0
34.4
NR
Median time to next
treatment (mo)
27.0
19.2
<0.0001
Median treatment-free
interval (mo)
16.6
8.3
<0.0001
End Point
MP, melphalan plus prednisone; NR, not reported; OS, overall survival;
VMP, bortezomib, melphalan, and prednisone.
bortezomib was a key part of the HOVON trial, in which treatment with
bortezomib-based induction followed by ASCT and bortezomib maintenance resulted in greater posttransplant CR and OS than was seen in
patients receiving conventional chemotherapy followed by thalidomide
maintenance.21 In another study, the addition of bortezomib to thalidomide maintenance improved both CR and PFS relative to single-agent
maintenance with thalidomide or interferon.34 It should be noted that
thalidomide may not be an optimal choice for maintenance, because of
the potential for deleterious effect on survival seen after relapse35 and
reduced quality of life due to cumulative toxicity.36
Because novel-agent induction has been shown to achieve good rates
of CR and VGPR, researchers are investigating the potential benefits of
delaying ASCT until the time of relapse; however, until results of these
trials are available, induction with novel agents and ASCT up front remains the preferred strategy.
Older patients who are not eligible for ASCT now have treatment choi­
ces that are more effective than melphalan plus prednisone (MP), the
older standard of care.23,37-43 Several newer regimens retain melphalan
while incorporating a novel agent; these combinations have yielded
significant benefit in terms of PFS and OS. For example, in the phase
3 VISTA trial, after a median follow-up of 5 years, the median OS for
patients receiving bortezomib, melphalan, and prednisone (VMP) is
approximately 60 months (Table 3).23 Other melphalan-based regimens showing favorable outcomes in clinical trials include melphalan,
prednisone, and thalidomide (MPT); bortezomib, melphalan, prednisone, and thalidomide (VMPT) followed by bortezomib and thalidomide
maintenance (VT); and melphalan, prednisone, and lenalidomide
(MPR) followed by lenalidomide maintenance (R).38,40,44 The MPR-R
regimen, for example, showed significantly greater response rate and
median PFS than did MPR or MP.40 It is noteworthy that several of these
trials included a maintenance phase—a harbinger of a trend toward
providing novel-agent maintenance in the population of multiple myeloma patients who cannot receive ASCT. Other regimens that incorporate
Addressing the Current Challenges of Multiple Myeloma Treatment u 5
Figure 1. Nonhematologic adverse events significantly greater with RD versus Rd in the phase 3 E4A03 trial.43
From Lancet Oncology 11(1), Rajkumar SV, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma:
an open-label randomised controlled trial, 29–37. Copyright 2012, with permission from Elsevier.
60
P=0.001
52
50
Patients, %
40
30
35
P=0.0003
26
P=0.04
16
20
12
10
RD (n=223)
Rd (n=220)*
9
0
P=0.01
11
4
P=0.003
5
0.5
DVT/PE
Infection/pneumonia
Nonneuropathic weakness
Any ≥grade 3 AE in
Early mortality first 4 months (first 4 months)
*Data unavailable for 2 patients.
DVT/PE, deep vein thrombosis/pulmonary embolism; RD, lenalidomide and high-dose dexamethasone; Rd, lenalidomide and low-dose dexamethasone.
novel agents are cyclophosphamide plus bortezomib or thalidomide
and lenalidomide plus dexamethasone.
In selecting a therapeutic regimen, clinicians must consider toxicities
related to the use of novel agents and combinations, especially nonhematologic adverse events (AEs) such as the venous thromboembolism
associated with thalidomide and lenalidomide. Tailoring treatment can
be an effective strategy for reducing the incidence and severity of
certain AEs. For example, lenalidomide should be administered with
low-dose rather than high-dose dexamethasone, especially in older
patients, since data show that toxicity from high-dose dexamethasone
reduces survival benefit when this combination is used (Figure 1).43
When bortezomib is used, reducing the intravenous (IV) dosing schedule from twice weekly to once weekly45 (in multidrug combination
therapy) or using a subcutaneous (SC) route of administration twice
weekly46 has proven to be effective for reducing the frequency and
severity of some AEs, including neurotoxicity. SC bortezomib has yielded comparable efficacy to the IV form while reducing the incidence of
peripheral neuropathy (PN) of any grade from 53% to 38%.46
Advances in Relapsed/Refractory Myeloma
There are numerous strategies available for the treatment of relapsed/
refractory multiple myeloma, including cytotoxic drugs, novel agents,
and new combination regimens. Several factors may affect treatment
choice, including age, prognostic factors, comorbidities, the quality and
duration of response to prior therapy, and the number of relapses that
6 u March 2013
have occurred. Disease progression during treatment with a specific
combination does not preclude a patient’s response to another combination containing one of the same drugs, but overcoming resistance
remains a challenge.
Data suggest that multidrug combinations appear to be more effective
and result in high overall response rates (ORRs) and response rates.
Novel molecularly targeted agents are used increasingly in combination
therapies for patients with relapsed and/or refractory disease. Regimens incorporating bortezomib or lenalidomide with dexamethasone
have consistently proved superior to the previous standard, dexamethasone monotherapy.47-50 These two-drug regimens are now important
options in the relapsed/refractory setting, but data continue to accrue
in support of three-drug regimens that contain two novel agents.
Three-drug combinations have the potential to protect against resistance to a drug in the regimen by providing coverage via multiple molecular pathways; efficacy results have been favorable with the RVD
regimen in the relapsed and refractory setting.51,52 The VTD regimen
has been shown to be superior to TD alone in both response rate and
PFS, though not in OS.53
The next-generation proteasome inhibitor carfilzomib is now approved
for the management of patients with relapsed/refractory myeloma who
have received at least two prior therapies including bortezomib and an
immunomodulator.54 A phase 2 clinical trial reported a 23.7% ORR with
a median duration of response of 7.8 months when carfilzomib was
used as a single agent with low-dose dexamethasone as premedication
in patients with relapsed and refractory multiple myeloma who had a
median of five prior therapies, including bortezomib.55 The incidence of
PN in this trial was 12.4% (mainly grades 1 and 2), and other toxicities
proved manageable, though less common AEs included renal, cardiac,
and pulmonary dysfunction, as well as hypertensive episodes. Another
phase 2 trial in relapsed and refractory patients reported an ORR of
17.1% and a median duration of response >10.6 months. No exacerbation of baseline PN occurred in this trial.56 Carfilzomib is currently
being studied in combination with lenalidomide and dexamethasone, as
well as other agents, including thalidomide and cyclophosphamide, for
the treatment of newly diagnosed patients.
With the great need for novel therapies, the number of new agents in
various stages of development (e.g., oral proteasome inhibitors, histone
deacetylase [HDAC] inhibitors, monoclonal antibodies) is encouraging
and are discussed in more detail below.
Managing Disease- and
Treatment-Related Toxicities
Myeloma-related bone disease, neuropathy, and venous thromboembolic events (VTEs) are significant challenges confronting the clinicians
who manage patients with multiple myeloma. Bone disease, in particular, remains a significant problem. Approximately 70% of patients with
multiple myeloma present with a lytic bone lesion in their axial skeleton
at the time of diagnosis.57 Accurately identifying bone disease is essential, and techniques to accomplish this are continuing to evolve. Although skeletal surveys remain the standard for identifying myeloma-related bone disease newer techniques, such as CT scans and
PET/CT scans, may be more sensitive and are being implemented
more frequently.
The IV bisphosphonates zoledronic acid and pamidronate are the current standard of care for preventing and minimizing myeloma-related
bone disease due to their proven efficacy. The Medical Research
Council (MRC) Myeloma IX trial, which compared IV zoledronic acid to
the oral bisphosphonate clodronic acid, reported that zoledronic acid
was associated with a lower incidence of skeletal-related events at a
median follow-up of 3.7 years (Table 4). Zoledronic acid was associated with increased survival, independent of reduction of skeletal-­
related events, suggesting an antimyeloma effect.58
The optimal duration of bisphosphonate therapy is still unknown. The
results of the MRC trial, which continued therapy at least until relapse,
led to changes in some guidelines; those predating publication of this
study suggested giving bisphosphonates for up to 2 years. The 2012
National Comprehensive Cancer Network guidelines recommend bisphosphonates for patients with multiple myeloma until disease progres-
Table 4. Outcomes in multiple myeloma patients treated with zoledronic acid
vs clodronic acid in the Medical Research Council (MRC) Myeloma IX Study.58
Zoledronic
Acid
(n=981)
Clodronic
Acid
(n=979)
P Value
27
35
0.0004
S REs in subset of patients with
bone lesions at baseline (%)
35
43
0.0038
S REs in subset of patients
without bone lesions at
baseline (%)
10
17
0.0068
Vertebral fractures (%)
5
9
0.0008
Other fractures (%)
5
7
0.04
New osteolytic lesions (%)
5
10
<0.0001
Outcome Variable
SREs (%)
SRE, skeletal-related events.
Data reported at a median of 3.7 years of follow-up.
sion.59 The 2011 British Committee for Standards in Haematology/
United Kingdom Myeloma Forum guidelines state that although there are
no definitive data on the optimal duration of bisphosphonate therapy,
clinicians should take into account individual factors such as remission
status, extent of skeletal disease, renal function, patient preference,
and the occurrence of AEs, such as osteonecrosis of the jaw.60
To preserve quality of life, it is important for clinicians to assess
myeloma patients for signs and symptoms of peripheral neuropathy
(PN) before initiating neurotoxic drugs, such as thalidomide and
bortezomib. Once PN develops, interrupting the drug regimen or
modifying the dose, along with controlling symptoms, must be a
priority to avoid compromising future therapy. Thalidomide-based PN
is typically sensory, often limits dose and duration of treatment, and
may be irreversible if not addressed promptly. Bortezomib-related
PN, which tends to be based more in the legs, is predominately
sensory, often reversible, and can typically be managed with dose
reduction.61 Reducing the dosing schedule of IV bortezomib from
twice weekly to once weekly has been shown to deliver the same
dose intensity with a lower incidence of PN.44,45,62,63 This strategy
may actually improve the efficacy of the regimen because patients
are often able to remain on therapy longer. Changing the mode of
administration of bortezomib is another effective approach. In a recent study, SC administration of bortezomib was shown to reduce PN
significantly, without any reduction in efficacy, compared with the
same dose administered IV. In addition, the time to the development
of neuropathy was also delayed.46 In some cases, it may be necessary to switch to another agent, such as lenalidomide or carfilzomib,
both of which are associated with much less neurotoxicity, if patients
still experience significant PN with bortezomib use.
Addressing the Current Challenges of Multiple Myeloma Treatment u 7
Figure 2. IMWG consensus opinion on VTE prophylaxis.66
Prior to therapy with IMiDs
Risk factors?
0–1
risk
factors
ASA
100
mg/day
>1
risk
factors
or
High-dose dexamethasone (≥480 mg/cycle)
or
Doxorubicin therapy or combination chemotherapy
LMWH (equivalent to dalteparin
5,000 IU/day, enoxaparin 40 mg/day,
fondaparinux 2.5 mg/day)
At least 4–6 months, if necessary, continuing
thrombosis prophylaxis if risk factors remain or
new risk factors are encountered
ASA, acetylsalicylic acid; IMiD, immunomodulatory drug, LMWH, low-molecular-weight heparin; VTE, venous
thromboembolism.
Patients with multiple myeloma may be at risk for VTEs due to the
disease itself, age, comorbidities, or specific agents.64,65 Proper assessment is critical prior to and during therapy, especially when agents
such as lenalidomide or thalidomide are used. Medications used to
prevent thromboembolism include aspirin, warfarin, and low-molecular-weight heparin. The IMWG has developed a consensus on VTE
prophylaxis,66 which is summarized in Figure 2. If a patient develops a
VTE while on antimyeloma therapy, it is usually possible to continue
with antimyeloma treatment once adequate anticoagulant control has
been achieved.
Future Directions in Multiple Myeloma
Clinical Research
Prior to 2003, it had been 30 years since the approval of any new therapy
for multiple myeloma, but in the last 10 years, six agents have been approved. There are currently many more drugs under investigation, some
of which are close to receiving approval (Table 5). These include agents
that target the myeloma cell itself, some that target the bone marrow
microenvironment, and some that are aimed at both targets.67
The challenge remains for these agents to proceed through the approval process and rapidly emerge into the clinic once efficacy is shown;
toxicity profiles will be an especially important consideration, as the
ability to continue therapy in myeloma is especially important. Specifically, some of the second- and third-generation drugs appear to be
8 u March 2013
more tolerable, and novel oral agents may allow increased adherence
to and persistence with therapy. For example, ixazomib, a proteasome
inhibitor currently in later-phase development, has shown clinical activity in relapsed and refractory multiple myeloma, with an 11% incidence
of PN, all grades 1 and 2.68 Several trials have shown that a next-generation immunomodulator, pomalidomide, is active in multiple myeloma, with an ORR up to 43% when combined with dexamethasone in a
relapsed/refractory setting.69-71 Most recently, as of February 2013,
pomalidomide was approved by the US Food and Drug Administration
(FDA) for patients who have received at least two prior therapies of
established benefit, which included both bortezomib and lenalidomide,
and who have demonstrated disease progression on the last therapy.
Some agents, such as HDAC inhibitors, have been disappointing as
monotherapy but may be more active in combination with other novel
drugs. These agents can be rationally combined to target different
disease pathways in myeloma.72 Combining vorinostat with bortezomib
has been shown to reduce the risk of disease progression in relapsed/
refractory patients, but side effects constrained the overall clinical
benefit. The hope is that other agents such as panobinostat, romidepsin, and the HDAC6 selective inhibitor ACY-1215, all now under study,
prove more effective.72,73 This therapeutic approach of rational combinations should improve response and survival while reducing toxicity
and allowing prolonged treatment. Other important advances include
the development of highly active monoclonal antibody therapy for mul-
tiple myeloma, other small-molecule inhibitors (such as perifosine, a
potent modulator of AKt, JNK, and NFκB), specific agents addressing
targets in myeloma-related bone disease pathways, and personalized
therapy based on genomic profiling.72,74
The Multiple Myeloma Research Consortium (MMRC) has played a
significant role in the ongoing efforts to augment the therapeutic armamentarium for multiple myeloma. Focusing on phase 1 and 2 clinical
trials with associated correlative science studies, the MMRC has facilitated the launch of more than 30 clinical trials of novel compounds and
combination approaches. The efforts of the MMRC and its partners
have contributed to the FDA approval of four new treatments for multiple myeloma in just 4 years. However, substantial challenges remain,
such as identifying effective ways to treat patients who have del(17p)
and/or extramedullary disease.
Table 5. Selected novel drugs being explored in multiple myeloma.
Second-/thirdgeneration
agents
Novel classes
Proteasome inhibitors
Carfilzomib,* ixazomib
(MLN9708),† marizomib
(NPI-0052), oprozomib
IMiDs
Pomalidomide*
HDAC inhibitors
Vorinostat,† panobinostat,†
romidepsin, rocilinostat
(ACY-1215)
Akt/PI3K/mTOR
inhibitors
Perifosine,† everolimus,
temsirolimus
Aurora kinase inhibitors TAK-901, MLN8237
FGFR3 inhibitors
Dovitinib (TKI258),
MFGR1877S
CDK inhibitors
PD 0332991, dinaciclib
(SCH 727965), AT7519
Bcl inhibitor
Navitoclax (ABT-263)
Summary and Conclusion
Hsp90 inhibitor
Ganetespib (STA-9090)
Recent advances in the management of multiple myeloma include new
criteria for risk assessment, novel agents, and combination regimens for
newly diagnosed and relapsed/refractory disease, and improved strategies for preventing and minimizing AEs. Efforts are under way to improve
upon the existing methods for determining prognosis in myeloma, including a new risk-stratification schema that will combine FISH data with ISS
staging, GEP, and single-nucleotide polymorphism array. Although treatment regimens incorporating novel agents such as bortezomib and
lenalidomide are showing promising results in patients with certain
chromosomal abnormalities, additional studies are necessary, especially
in patients with del(17p), which is associated with a poor prognosis.
BTK inhibitors
Ibrutinib (PCI-32765),
AVL-292
Monoclonal antibodies
Elotuzumab,† siltuximab
(CNTO 328; anti–IL-6),
daratumumab (anti-CD38),
BHQ880 (anti-DKK1)
Achieving durable CR remains a critical goal for all patients with multiple myeloma. For young, fit patients, ASCT remains the standard of
care, with induction, consolidation, and maintenance therapies utilizing
novel agents leading to better outcomes. For older or frail patients who
cannot tolerate ASCT, melphalan and prednisone combined with a
novel agent, or other novel combination therapies, are recommended.
Dose adjustments should be considered based on age and comorbidities to enable optimal delivery of effective therapy.
IMiD, immunomodulatory drug; HDAC, histone deacetylase.
*Recently approved.
†
Phase 3 trials ongoing or planned.
tients with multiple myeloma, as these can lead to increased morbidity
and mortality, as well as decreased quality of life. Prompt management
of these events is critical to avoid negative outcomes. Dose reductions of
novel agents may often be used to prevent exacerbation of symptoms
while ensuring that patients can still reap the benefits of therapy.
It is important to consider disease- and treatment-related AEs in all pa-
Future directions in the management of multiple myeloma include the
development of personalized medicine, immune (vaccine) therapies,
and novel agents that target the tumor cell in its microenvironment. In
this respect, HDAC inhibitors, other small-molecule inhibitors, monoclonal antibodies, and next-generation proteasome inhibitors and immunomodulatory drugs show great promise and continue to be evaluated in ongoing clinical trials.
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Addressing the Current Challenges of Multiple Myeloma Treatment u 13
Addressing THE CURRENT CHALLENGES OF
multiple myeloma TREATMENT
Please note your answers on the Posttest Answer Sheet on the following page.
Posttest
1. Nonhyperdiploidy is associated with a
patients with multiple myeloma (MM).
a. Poor
b. Good
prognosis in
2.A new risk-stratification schema proposed by the International
Myeloma Working Group (IMWG) would combine which of the
following to more accurately determine prognosis in MM?
a. International Staging System (ISS) and fluorescence in situ
hybridization (FISH) data
b. Metaphase karyotyping and ISS data
c. Gene expression profiling (GEP) and FISH data
d. ISS and GEP data
3.In the VISTA trial, bortezomib-based initial therapy resulted in
improved overall survival (OS) compared with conventional
chemotherapy, regardless of patients’ cytogenetic risk.
a. True
b. False
4.In a recent trial of transplant-eligible patients with MM, initial
therapy with a regimen of lenalidomide/bortezomib/
dexamethasone produced a
response rate.
a. 50%
b. 75%
c. 89%
d. 100%
5.In the CALGB 100104 study, maintenance with which of the
following agents improved response rates and OS compared
with placebo?
a. Lenalidomide
b. Carfilzomib
c. Bortezomib
d. Thalidomide
14 u March 2013
6.Carfilzomib is currently approved for the treatment of patients
with MM who:
a. Are newly diagnosed.
b. Have received one prior therapy with any agent.
c. Have received at least two prior therapies including bortezomib.
d. Have received at least two prior therapies including bortezomib and
an immunomodulatory drug.
7.Less than 70% of patients with MM present with a lytic bone
lesion in their axial skeleton at the time of diagnosis.
a. True
b. False
8.In the Medical Research Council Myeloma IX trial, zoledronic acid
was associated with a
incidence of skeletal-related
events compared with clodronic acid.
a. Higher
b. Lower
9.According to IMWG guidelines, which of the following would NOT
be appropriate venous thromboembolism prophylaxis for patients
with >1 risk factor?
a. Dalteparin 5,000 IE/day
b. Aspirin 100 mg/day
c. Enoxaparin 40 mg/day
d. Fondaparinux 2.5 mg/day
10.Pomalidomide is a(n)
being explored in clinical trials for
the treatment of MM.
a. Proteasome inhibitor
b. Immunomodulator
c. Histone deacetylase (HDAC) inhibitor
d. Monoclonal antibody
Addressing THE CURRENT CHALLENGES OF
multiple myeloma TREATMENT
Number of credits: 1.0 AMA PRA Category 1 Credit ™ • Release date: March 13, 2013 • Expiration date: March 13, 2014
Participants requesting credit must read the CME activity. A certificate will be issued only upon receipt of a completed activity posttest with a score of 70% or
better, along with a completed evaluation and certificate information form. Participants requesting CME credit can submit their posttest, evaluation, and
certificate information form in any of the following ways:
Mail
Penn State College of Medicine
44 East Granada Ave, Room 1108
PO Box 851
Hershey, Pennsylvania 17033
Fax
(717) 531-5604
If you mail or fax your completed posttest, evaluation, and certificate information form,
your certificate will be sent to you in
approximately 4 to 6 weeks.
Online
Access the posttest and evaluation on the
Curatio CME Institute Web site:
http://www.curatiocme.com/posttest/AddressingMM
For questions about CME credit for this activity, contact Penn State College of Medicine at [email protected] or (717) 531-6483 and reference
Course # G5308-13-R.
CERTIFICATE INFORMATION
Please complete to receive credit for this program. PLEASE PRINT CLEARLY.
First Name
Middle Initial
Last Name
Title/Position
Affiliation
Degree
Specialty
Business Address
City
State
Business Telephone (
)
-
Business Fax (
)
ZIP
-
E-mail Address
Please choose one:
q Physician
I claim (choose one): q .5
q Non-Physician
q .75
q 1.0 AMA PRA Category 1 Credit ™
Signature________________________________________________________________________________________________________________________
q I do not want to receive information about future CME activities.
POSTTEST ANSWER SHEET
Circle only one answer per question.
1. a
b
2. a
b
c
d
3. a
b
4. abcd
5. a
b
c
d
6. a
b
c
d
7. a
b
8. a
b
9.
abcd
10. a
b
c
d
Addressing the Current Challenges of Multiple Myeloma Treatment u 15
EVALUATION FORM
Name
1. Rate the extent to which you agree or disagree.
Strongly Strongly
Agree
Disagree
• The format for this activity was appropriate for the content presented.
5
4
3
2
1
• Participation in this activity changed my knowledge/attitudes.
5
4
3
2
1
• I will make a change in my practice as a result of my participation in this activity.
5
4
3
2
1
2. Commercial bias is defined as information that attempts to sway participant opinion in favor of a
commercial product/device with the objective of furthering a commercial entity’s business initiatives.
Using this definition, please rate the extent to which you agree or disagree with the following:
Strongly Strongly
Agree
Disagree
• The therapeutic recommendations presented in this activity did not encourage inappropriate or excessive
use of products/devices.
5
4
3
2
1
• The information presented in this activity did not serve to advance a proprietary interest of any commercial entity.
5
4
3
2
1
If you felt the activity was biased, please explain:____________________________________________________________________________
_______________________________________________________________________________________________________________
3. This activity helped me to achieve the following objectives:
Strongly Strongly
Agree
Disagree
• Use cytogenetics, fluorescence in situ hybridization (FISH), and gene expression profiling to define patient
prognosis and risk stratification
5
4
3
2
1
• Outline a treatment plan to achieve the desired response while balancing the risk for toxicities in high-risk and
standard-risk myeloma patients
5
4
3
2
1
• Implement evidence-based strategies to prolong the duration of response in multiple myeloma patients 5
4
3
2
1
• Incorporate current consensus recommendations, guidelines, and the latest clinical evidence in the
management of multiple myeloma
5
4
3
2
1
• Evaluate clinical data regarding the use of new agents in patients who develop resistance to or relapse from
their initial therapy
5
4
3
2
1
If you felt the learning objectives were not met, please explain:___________________________________________________________________
_______________________________________________________________________________________________________________
4. Based on this activity, how committed are you to making the following changes?
Very
Not
Committed
Committed
• Use the International Staging System (ISS) and cytogenetic information to define patient prognosis and
risk stratification
5
4
3
2
1
• Develop treatment plans that incorporate new and emerging therapies to achieve the maximum treatment
response in the context of minimizing toxicity for patients with multiple myeloma
5
4
3
2
1
• Monitor patients to adjust dosing to avoid disabling toxicities
5
4
3
2
1
If there are any other changes you plan to make in your practice based on this activity, please list them here.__________________________________
_______________________________________________________________________________________________________________
5. Are there any barriers or problems that might prevent you from implementing changes in your practice? (Please select all that apply.)
q Cost
q Insurance coverage for medications
q Lack of patient insurance
q Patient adherence
q Limited time
q Increased workload
q Other____________________________________________________
6. Questions or comments regarding this activity __________________________________________________________________________
________________________________________________________________________________________________________________
Thank you for taking time to complete this evaluation.
16 u March 2013