- Email: [email protected]
Treatment Options for Triple-class Refractory Multiple Myeloma
Journal Pre-proof Treatment Options for Triple-Class Refractory Multiple Myeloma Joseph Mikhael, MD PII:
S2152-2650(19)32008-7
DOI:
https://doi.org/10.1016/j.clml.2019.09.621
Reference:
CLML 1438
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 7 June 2019 Revised Date:
5 August 2019
Accepted Date: 29 September 2019
Please cite this article as: Mikhael J, Treatment Options for Triple-Class Refractory Multiple Myeloma, Clinical Lymphoma, Myeloma and Leukemia (2019), doi: https://doi.org/10.1016/j.clml.2019.09.621. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 The Author(s). Published by Elsevier Inc.
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Treatment Options for Triple-Class Refractory Multiple
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Myeloma
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Joseph Mikhael, MD
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Applied Cancer Research and Drug Discovery, Translational Genomics Research
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Institute (TGen), City of Hope Cancer Center, Phoenix, AZ
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Word count (2000–10,000 words): 4108
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Address for correspondence: Dr. Joseph Mikhael, Translational Genomics Research
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Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004
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E-mail contact: [email protected]
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Mikhael
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Abstract (178/250)
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The advent of new, more effective, and less toxic therapies has revolutionized the
13
management of multiple myeloma in the past decade. Despite the availability of new
14
treatments, the majority of patients with multiple myeloma will become refractory to
15
the therapies that currently comprise the hematologic standard of care for the
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malignancy: proteasome inhibitors, immunomodulatory agents, and monoclonal
17
antibodies. Moreover, in recent years, a new subset of patients refractory to all 3 of
18
these agents has emerged. This population, in which a clear treatment paradigm
19
remains undefined, is characterized by poor survival outcomes. Current approaches
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to the treatment of triple-class refractory disease are limited, and include
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conventional chemotherapy, salvage autologous stem cell transplantation, and
22
recycling prior regimens, each of which have generally short-lived efficacy. It is
23
anticipated that additional agents will be available for triple refractory disease in the
24
near future, namely selinexor, chimeric antigen receptor T cell therapy, and next-
25
generation monoclonal antibodies. The development and further refinement of novel
26
treatments for this subset of patients in the coming years should be considered a key
27
clinical and research priority.
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Key words: Multiple myeloma, Refractory, Autologous stem cell
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transplantation, Selinexor, Monoclonal antibodies
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Introduction
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Multiple myeloma (MM), characterized by the expansion of malignant plasma cells in
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the bone marrow,1 accounts for approximately 1% of all malignancies and 10% of
33
hematologic malignancies.2 In the past decades, the advent of new, more effective,
34
and less toxic therapies has revolutionized the management of MM.3, 4 The ever-
35
expanding treatment landscape parallels substantial improvements in our
36
understanding of the biology of MM, optimized supportive care strategies, and the
37
refinement of combination treatment regimens.2, 3, 5
38
There are currently 3 drug classes available for the treatment of MM that have
39
shifted treatment paradigms and considerably improved outcomes for patients:
40
proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal
41
antibodies.6, 7 Various approaches to treatment using these agents have been
42
developed and these are widely used in the treatment of MM, often in triplet
43
combinations that involve 2 novel agents plus a steroid; a combination treatment
44
strategy has been adopted that uses a number of different therapies with distinct
45
mechanisms of action.8
46
The use of combination treatments has been a cornerstone of the therapeutic
47
management of MM for decades, but the agents included in these regimens have
48
been refined and have evolved considerably in recent years. For example, although
49
melphalan has served as the backbone for several PI and IMiD combinations for
50
more than 30 years, other agents have replaced alkylating agents as first-choice
51
treatment options for MM. However, melphalan remains commonly used as part of
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the conditioning regimen in autologous stem cell transplant (ASCT)-eligible patients,9
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and has recently been validated in a large phase III trial of bortezomib, lenalidomide, Page 3
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and dexamethasone (RVD) with and without ASCT, demonstrating an improved
55
progression-free survival (PFS) in the transplant arm after high-dose melphalan and
56
2 cycles of RVD.10
57 58
The advent of novel therapeutic strategies, and their inclusion in initial therapeutic
59
regimens,11 has resulted in significant improvements in patient outcomes. A real-
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world evidence study by Fonseca et al12 found that the percentage of patients with
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MM receiving novel therapy continuously increased from 8.7% in 2000 to 61.3% in
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2014. Patients with MM diagnosed after 2010 had better survival outcomes.12 Those
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diagnosed in 2012 were 1.25 times more likely to survive for 2 years than those
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diagnosed in 2006.12 Over the 14-year study period, patients with MM showed
65
improved OS, with the 2-year survival gap decreasing at a rate of 3% per year
66
between patients with MM and matched controls.12
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Despite these advances, the majority of patients with MM will become refractory to
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PIs, IMiDs, and monoclonal antibodies.13 This can leave clinicians unsure of how to
69
proceed, as fewer therapeutic options remain for heavily pretreated patients who
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develop more aggressive disease, resulting in poorer outcomes for this patient
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population.14 A multicenter study enrolled 543 patients with triple-class exposed,
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IMiD- and PI-refractory MM, who had also been treated with an alkylating agent. The
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median OS was 13 (95% confidence interval [CI] 11–15) months.15 In a 2016
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retrospective analysis investigating outcomes in a similar patient population, OS was
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poor despite the availability of newer agents, with a median OS of approximately
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8 months.14 Furthermore, a 2018 retrospective analysis demonstrated that patients
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who were penta-refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, Page 4
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and daratumumab had a median OS of only 5.6 months.16 The identification of more
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effective therapeutic interventions for this patient population has therefore emerged
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as a key priority for MM research.
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Defining a Treatment Paradigm for Triple-Class
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Refractory MM
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Although there is no current standard of care for the treatment of patients with
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relapsed and/or refractory MM (RRMM),17 combination regimens are generally
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preferred to monotherapy. This is because combination treatments enable multiple
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pathways to be targeted to induce prolonged durable responses in patients with
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MM.18
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However, once patients with MM have become triple-class refractory, there is even
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less consensus on what can be defined as a preferred approach to therapy. Reusing
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or recycling prior treatments to which a patient was previously refractory may be
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considered, in light of synergistic effects of drug combinations, or due to the
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presence of clonal evolution that may signify renewed drug sensitivity in later
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disease.19 Although this option may be considered for patients who had previously
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exhibited a sufficiently durable response (of at least 6 months) to a given regimen,19
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this would generally yield low response rates with limited PFS in patients with a
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short-term remission duration or progression following initial treatment, so other
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strategies are required.20
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These key alternative approaches include conventional chemotherapy, salvage
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ASCT, the novel nuclear export inhibitor, selinexor, along with other novel
100
approaches, such as treatment with chimeric antigen receptor (CAR) T cell therapy,
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and next-generation antibodies and bispecific T cell engager technology.
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Conventional Chemotherapy
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Although not used routinely, conventional chemotherapy can elicit a good (albeit Page 6
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short-lived) response in patients with RRMM.
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D(T)-PACE (dexamethasone ± thalidomide, cisplatin, doxorubicin,
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cyclophosphamide, and etoposide) is a chemotherapeutic regimen that has been
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evaluated in cases of RRMM, with studies reporting response rates of approximately
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50%. However, because its toxicity is common and PFS is short, D(T)-PACE is
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generally considered most effective when used as a bridge to other MM treatment
110
interventions.21
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Similarly, high-dose cyclophosphamide has shown value as a potential bridge to
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novel therapies in refractory MM. When used in combination with dexamethasone,
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high-dose cyclophosphamide was shown to be an efficient rescue regimen in
114
double-refractory MM, with an overall response rate (ORR) of 55%, with 3 patients
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(15%) achieving complete response (CR). Twelve patients (67%) were treated with
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further therapies after achieving at least stable disease. The median PFS and OS
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were 6 and 12 months, respectively.22
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Bendamustine, a bifunctional alkylating agent, has demonstrated efficacy at different
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stages of MM, including patients with more advanced disease. In a retrospective
120
analysis of individuals with heavily pretreated RRMM, 39 patients received a median
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of 3 cycles of bendamustine, either as monotherapy or concomitantly with
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corticosteroids. The results found bendamustine to be effective in these patients,
123
with 3% achieving a very good partial response, 33% partial response, 18% minor
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response, 26% stable disease, and 20% progressive disease; the median event-free
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survival and OS were 7 and 17 months, respectively 23 In triple-refractory (100%)
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and penta-refractory (40%, defined as refractory to one monoclonal antibody, two
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PIs and two IMiDs) patients refractory to CD38 monoclonal antibodies, those who
128
received bendamustine (n = 15) as their next line of therapy had a median PFS and
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OS of 3.2 and 9.3 months, respectively.24
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Doxorubicin, cisplatin, and etoposide are 3 further chemotherapeutic agents that
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have been evaluated in RRMM. Although the depth and duration of responses to
132
these treatments can be poor when used alone, use of these agents in combination
133
can elicit highly active, durable responses, especially when used in synergistic
134
combinations that also reduce toxicity risk.25
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In combination with more conventional chemotherapy regimens, histone deacetylase
136
(HDAC) inhibitors have shown promise as a treatment option for patients with
137
triple-class refractory MM. HDACs deacetylate the lysine residues of both histones
138
and non-histone proteins, resulting in histone hyperacetylation and alterations in
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chromatin structure that cause growth cycle arrest and apoptosis in tumor cells.26
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Preclinical studies investigating HDAC inhibitors and PIs in MM demonstrated a
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synergistic effect on tumor cells, which leads to the accumulation of polyubiquitinated
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proteins and activation of apoptosis.27 In the phase III PANORAMA1 trial in patients
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with RRMM who had received 1 to 3 previous lines of therapy, patients treated with
144
the HDAC inhibitor panobinostat plus bortezomib and dexamethasone showed
145
significantly longer median PFS than those receiving placebo plus bortezomib and
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dexamethasone (11.99 months [95% CI 10.33–12.94] vs. 8.08 months [7.56–9.23];
147
hazard ratio 0.63, 95% CI 0.52–0.76; P < .0001).28 Similar effects were observed in
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subgroup analysis of patients who had previously received an IMiD, bortezomib plus
149
an IMiD, or at least 2 lines of treatment including bortezomib and an IMiD.29, 30
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Panobinostat plus bortezomib and dexamethasone had a tolerable safety profile,
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with the most frequent grade 3–4 adverse events (AEs) being myelosuppression,
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diarrhea, asthenia or fatigue, peripheral neuropathy, and pneumonia.28-30 Analysis of
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patients with RRMM who had experienced a failure with daratumumab (n = 354)
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showed that patients who switched to chemotherapy (P = .0208) or panobinostat (P
155
= .0298) had received a greater number of therapies than those who switched to
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elotuzumab-based regimens.31
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Salvage ASCT
158
ASCT was first used in combination with melphalan in patients with MM in the 1980s.
159
Its success in clinical trials meant that the procedure was soon considered an
160
important component of the standard of care for newly diagnosed patients with MM
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aged up to 65–70 years without significant comorbidities.32
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A study comparing conventional treatments (8 cycles of RVD, plus stem cell
163
mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating
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factor after 3 cycles of RVD) with RVD treatment and ASCT (3 induction cycles of
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RVD, followed by stem cell collection, and then ASCT with melphalan, followed by Page 9
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2 cycles of RVD) reported a median PFS of 50 months in the transplant arm,
167
compared with 36 months in the RVD arm.10 The upfront trial of RVD versus RVD
168
plus ASCT demonstrated the continued value of ASCT in frontline therapy.33
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However, it also speaks to the value of ASCT in relapsed disease, as 79% of
170
patients in the RVD alone arm had ASCT at first relapse.10 Salvage ASCT has now
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been employed in later relapse, as a number of retrospective studies have also
172
demonstrated the efficacy of salvage ASCT following reinduction therapy in patients
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with MM who have relapsed after a prior ASCT. The most important factor predicting
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PFS after salvage ASCT is the duration of remission after initial ASCT, with those
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patients with PFS of ≥ 18 months after their first autotransplant most likely to
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benefit.34 Although recent guidelines from the International Myeloma Working Group
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recommend that salvage ASCT is considered for all eligible patients,35 the procedure
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is an option suitable only for a small minority. Many patients with MM are not
179
considered candidates due to their age and weakened state, arising as a
180
consequence of comorbidities, organ dysfunctions, and limitations in mental/mobility
181
functions, which would not enable them to withstand the procedure.20
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Selinexor
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Selinexor is a first-in-class selective inhibitor of nuclear export36 that provides an
184
additional therapeutic option for those with triple refractory disease; indeed, it has
185
been studied in patients with ‘quad- and penta-refractory disease’ by virtue of their
186
exposure to and becoming refractory to the 5 key agents used in this patient
187
population (bortezomib, lenalidomide, carfilzomib, pomalidomide, and
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daratumumab). Selinexor is currently being evaluated as a component of
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combination regimens in a number of phase II and III clinical trials in patients with
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RRMM.36 In the STORM (Selinexor Treatment of Refractory Myeloma) study
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(NCT02336815), selinexor is being used in combination with low-dose
192
dexamethasone. The first part of this phase II trial evaluated selinexor and
193
dexamethasone in patients with MM refractory to bortezomib, carfilzomib,
194
lenalidomide, and pomalidomide, along with a small subset of patients with penta-
195
refractory disease, who were also refractory to an anti-CD38 antibody; indeed, this
196
was a very heavily pretreated population of patients with a median of 7 prior lines of
197
therapy.37 The ORR was 21% in patients with quad-refractory MM, and 20% for
198
patients with penta-refractory MM. Of note, the ORR was 35% among patients with
199
high-risk cytogenetics, including t(4;14), t(14;16), and del(17p). The median duration
200
of response was 5 months, and 65% of responding patients were alive at 12 months.
201
The most common grade ≥ 3 AEs were thrombocytopenia, anemia, neutropenia,
202
hyponatremia, leukopenia, and fatigue. Dose interruptions for AEs occurred in
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41 patients, dose reductions occurred in 29 patients, and treatment discontinuation
204
occurred in 14 patients.37
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Part 2 of STORM focused specifically on patients with penta-refractory MM, and
206
included many patients with rapidly progressive disease, with nearly 50% having
207
high-risk myeloma.38 In this context, selinexor in combination with low-dose
208
dexamethasone was highly active in this population, with an ORR of 26.2%.38
209
Treatment responses showed depth with a fast onset of action (within the first cycle
210
in most patients), with 2 patients achieving stringent CRs, both of whom were
211
minimal residual disease (MRD) negative.38, 39 Median OS was 8.6 months.38, 39 No
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major organ toxicity was observed, and AEs were typically transient and
213
reversible.38, 39 Supportive care was important in reducing the severity of these
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toxicities.38 In July 2019, selinexor was granted accelerated approval by the FDA for Page 11
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adult patients with RRMM who have received at least four prior therapies and whose
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disease is refractory to at least two proteasome inhibitors, at least two
217
immunomodulatory agents, and an anti-CD38 monoclonal antibody.40
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The ongoing phase Ib/II STOMP (Selinexor and backbone Treatments Of Multiple
219
myeloma Patients) studies are evaluating selinexor and low-dose dexamethasone in
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combination with a number of standard approved therapies including lenalidomide,
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pomalidomide, bortezomib, carfilzomib, and daratumumab, and have generated
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promising findings to date.41-43
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Other Novel Approaches
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Key clinical trial data for novel therapies are summarized in Table 1.
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CAR T Cell Therapy
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T cells can be genetically modified to express CARs, which are fusion proteins that
227
have an antigen recognition region and a co-stimulation domain.44 In MM, CAR T cell
228
therapies have shown clinical activity of up to 90–100% with a manageable safety
229
profile.44 Of note, bb2121 has shown promising efficacy at dose levels of
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≥ 150×106 CAR T cells in 33 patients with RRMM who had received at least 3 prior
231
lines of therapy, including a proteasome inhibitor and an immunomodulatory agent,45
232
with a median PFS of 11.8 months. In total, 15 patients had a CR (45%)45 and
233
25 patients (76%) had cytokine release syndrome, which was of grade 3 in 2 patients
234
(6%).45 Cytokine release syndrome is the common toxicity associated with CAR T
235
cells, and is caused by the release of cytokines by the infused T cells.46 Built along
236
the bb2121 platform is bb21217, intended to have improved cell persistence. Early
237
efficacy results show 6 of 7 patients (median of 9 prior lines of therapy) Page 12
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demonstrating clinical responses at a dose of 150x106 CAR T cells.47
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In a heavily pretreated MM patient population that had failed IMiDs, proteasome
240
inhibitors and daratumumab, an overall response rate of 83% (5/6 patients) was
241
shown with P-BCMA-1.48 Only 1 patient developed cytokine release syndrome, of
242
limited severity (grade 2).48 The lack of significant toxicity observed with P-BCMA-1
243
is favorable compared to other CAR T cell therapies.48
244
Venetoclax
245
Venetoclax is a potent, selective, orally bioavailable small-molecule inhibitor of B cell
246
lymphoma (BCL)-2.36 Venetoclax has been investigated alone and in combination
247
with other therapies for the treatment of RRMM.49-51 Venetoclax monotherapy has an
248
acceptable safety profile and clear anti-myeloma activity in patients with RRMM,
249
primarily with t(11;14) having high BCL-2, low BCL-extra large, and low myeloid
250
leukemia cell differentiation protein-1 expression levels.49, 50 As part of a combination
251
regimen with bortezomib and dexamethasone, venetoclax has also demonstrated
252
efficacy in RRMM in a randomized phase III trial of venetoclax-bortezomib-
253
dexamethasone versus bortezomib-dexamethasone. Results revealed an improved
254
ORR of 82% and 68% and prolonged PFS of 22.4 months and 11.5 months,
255
respectively.52 However, there was a concerning safety signal with increased deaths
256
in the venetoclax-bortezomib-dexamethasone arm due to infections.52 The U.S. Food
257
and Drug Administration (FDA) placed a partial hold on trials with this agent in
258
myeloma and recommended that all patients with MM on this agent must be on
259
antibiotic prophylaxis. Subsequently, this partial hold has been lifted upon revisions
260
to the study protocol. It remains unclear what role this agent may play in myeloma,
261
but venetoclax could be a niche agent for patients with t(11;14) mutations, providing Page 13
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clinicians with a means to identify patients likely to respond to certain treatments.52
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This is important in the context of triple-class RRMM, as clinicians can be unsure as
264
to which therapies are the most appropriate for such a heavily pretreated population
265
that have failed standard MM therapies.
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Programmed Cell Death Protein-1 Antibodies
267
Upregulation of the programmed cell death protein 1 (PD-1) pathway in MM prevents
268
the activation of antitumour T cell populations and can contribute to immune escape
269
by the tumour, enabling its proliferation.53 Pembrolizumab is an antibody that targets
270
PD-1, restoring the capacity of the immune system to perform cytotoxic T cell killing
271
of malignant plasma cells.53 Interim analysis from a phase III trial of pomalidomide
272
and dexamethasone with or without pembrolizumab in 249 RRMM patients with ≥2
273
prior lines of therapy showed an unfavourable benefit–risk profile for the triple
274
combination.54Median PFS was 5.6 months in the pembrolizumab plus
275
pomalidomide and dexamethasone group and 8.4 months in the pomalidomide and
276
dexamethasone-only group.54 Serious AEs (SAEs) occurred in 46% (56/121) of
277
patients in the pomalidomide and dexamethasone group, compared with 63%
278
(75/120) in the pembrolizumab plus pomalidomide and dexamethasone group.54
279
There were 4 (3%) treatment-related deaths with pembrolizumab plus pomalidomide
280
and dexamethasone.54 In the pomalidomide and dexamethasone-only group, no
281
treatment-related deaths were reported.54 Although these patients were not an
282
exclusively triple-class population, this study suggests that pembrolizumab does not
283
confer a survival benefit in RRMM.
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B Cell Maturation Antigen Antibodies
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B cell maturation antigen (BCMA) is a cell surface receptor in the tumor necrosis
286
factor superfamily.44 Expression of BCMA is limited to B cells in advanced stages of
287
differentiation, and is required for the survival of long-lived plasma cells.44 Because
288
BCMA is expressed at significantly higher levels in all of the patient’s MM cells but
289
not on other normal tissues except normal plasma cells,44 it was identified as a target
290
for MM treatment. GSK2857916 is a humanized immunoglobulin G1 monoclonal
291
antibody with high affinity to BCMA conjugated to a microtubule-disrupting toxin
292
(monomethyl auristatin F). A phase I trial investigating monotherapy with the
293
antibody demonstrated a 38.5%% ORR and a median PFS of 6.2 months in those
294
who were refractory to daratumumab, a proteasome inhibitor and an
295
immunomodulator.55
296
Treatments Utilizing Bispecific T-cell Engager Technology
297
Bispecific T-cell Engagers (‘bispecifics’) contain 2 single-chain variable fragments
298
that are connected by a linker molecule. To redirect anticancer immunity, bispecifics
299
bind a T cell-specific antigen, often CD3, with 1 fragment, and a cancer-specific
300
epitope with the other, thus providing a platform to facilitate interaction between
301
effector and cancer cells.56 These may be particularly useful as the same product
302
can be given to all patients, whereas CAR T cell therapy is based on the patients’
303
own cells.57 The CD3-CD19 bispecific blinatumomab was granted FDA approval
304
based on the results of a phase II study that reported a 43% CR in patients with
305
relapsed or refractory B-cell precursor acute lymphoblastic leukemia.58 In RRMM,
306
preliminary results from the first-in-human study, in patients who had progression
307
after ≥2 lines of therapy (PI and IMiD), of the bispecific antibody construct AMG 420
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showed promising evidence of activity, with 13/42 responders.59 Of these, 3 were
309
CRs and 2 were PRs.59 The median time to any response was 1 month.59 Safety
310
was comparable to other immunotherapies, with SAEs in 50% of patients.59
311
Treatment-related SAEs included grade 3 polyneuropathies (n = 2) and edema (n =
312
1), both requiring hospitalization.59 Five MRD-negative stringent CRs were observed
313
in patients receiving AMG 420 400 µg/day.59
314
Other molecules are also being evaluated in RRMM, including inhibitors of murine
315
double minute 2 (MDM2), kinase, or bromodomain, along with other drug classes
316
that can induce apoptosis in MM cells.36
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Table 1. Novel approaches to triple-class RRMM
Name of agent 45
bb2121
bb21217
47
48
P-BCMA-101
Mechanism of action
Stage of development
Study number
Study population
Key efficacy results
Key safety results
CAR T cell
Phase I
NCT02658929
≥3 prior lines of therapy, including a PI and an IMiD, N = 33
ORR was 85%, CR in 15/33 (45%) of which 6 have since relapsed. Median PFS was 11.8 months (95% CI 6.2–17.8)
25/33 (76%) developed cytokine release syndrome, neurologic toxic effects in 14/33 (42%)
CAR T cell
Phase I
NCT03274219
≥3 prior lines of therapy, including a PI and an IMiD, N=8
6/7 demonstrated clinical response (1 sCR, 3 VGPR, 2 PR)
5/8 developed cytokine release syndrome
CAR T cell
Phase I
NCT03288493
≥3 prior lines of therapy, including a PI and an IMiD, N = 12
ORR was 83%
One patient has developed cytokine release syndrome (8%), most comment SAEs were cytopenia and febrile neutropenia
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Venetoclax (with bortezomib and 52 dexamethasone)
BCL-2 inhibitor
Phase III
NCT02755597
1–3 prior lines of therapy, N = 291
Mean PFS in the ventoclax arm was 22.4 months versus 11.5 months in the placebo arm, ORR was 82% vs 68%
41/194 (21.1%) deaths in the venetoclax arm, 11/97 (11.3%) in the placebo arm, severe, grade 3–5 toxicity and SAE rate were similar between the two arms.
Pembrolizumab (with pomalidomide and 54 dexamethasone)
Anti-PD-1 antibody
Phase III
NCT02576977
≥2 prior lines of therapy, N = 249
Median PFS in pembrolizumab arm was 5.6 months versus 8.4 months in the pomalidomide and dexamethasoneonly arm
4 deaths (3%) in the pembrolizumab arm. SAEs occurred in 75/120 (63%) in the pembrolizumab arm versus 56/121 (46%) in the pomalidomide and dexamethasone-only arm
BCMA
Phase I
NCT02064387
Prior therapy with an alkylator, PI and IMiD, N = 35
21/35 (60%) achieved a PR or better, including 2 sCR, and 3 CR. Median PFS was 12 months
Most commonly reported AEs were cough, increased aspartate aminotransferase and nausea (all grade 1 or 2). Corneal events and thrombocytopenia were manageable
Bispecific T-cell engager
Phase I
NCT02514239
Progression after ≥2 lines (incl PI and IMiD), N=42
13/42 responders including 6 sCRs, 3 CRs, 2 VGPR, 2 PRs. Median time to any response was 1 month
Treatment-related SAEs included 2 grade 3 polyneuropathy and 1 edema. Grade 2–3 cytokine release syndrome seen in 3 patients
GSK2857916
59
AMG 420
55
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BCL-2, B cell lymphoma 2; CAR, chimeric antigen receptor; CI, confidence interval; CR, complete response; IMiD, immunomodulatory agent; ORR, objective response rate;
319
PD-1, programmed cell death protein-1; PFS, progression-free survival; PI, proteasome inhibitor; PR, partial response; SAE, serious adverse event; sCR, stringent complete
320
response; VGPR, very good partial response
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Conclusion and Recommendations
322
In 2015, therapeutic options for MM expanded further when daratumumab and
323
elotuzumab were approved by the FDA for MM. Although monoclonal antibodies are
324
now of paramount importance in the context of MM care, their growing prominence is
325
coupled with the emergence of a new subset of patients who are refractory to
326
monoclonal antibodies, PIs, and IMiDs. The development and further refinement of
327
novel treatments for this subset of patients in the coming years should be considered
328
a key priority in myeloma. Current approaches to the treatment of triple-refractory
329
disease include conventional chemotherapy and salvage ASCT. It is anticipated that
330
in the near future, additional agents will be available for triple refractory disease,
331
namely selinexor, CAR T cell therapy, and next-generation monoclonal antibodies.
332
Therapeutic interventions for MM must be considered in the context of a supportive
333
care strategy that looks to improve patients’ quality of life and to help achieve better
334
treatment outcomes.60 Patients with RRMM are particularly vulnerable due to prior
335
exposure to chemotherapy, myelosuppression, long-term exposure to
336
corticosteroids, and impaired organ function.13 Supportive care must encompass
337
strategies to manage broader elements of MM, such as bone disease and spinal
338
cord compression, anemia, bone marrow failure and infections, and renal failure,33, 60
339
as well as management of treatment-related AEs.61
340
An understanding of disease-related factors, such as cytogenic abnormalities and
341
prognostic markers (eg, MRD),62, 63 and patient-related factors, such as renal
342
insufficiency, hepatic impairment, and comorbidities,62 is critical for evaluating
343
appropriate therapeutic options for patients with triple-class refractory MM.
344
Treatment-related factors, including prior drug exposures, longevity of remission, and Page 20
Mikhael
345
treatment-related toxicities,62 must also be considered. Further research is required
346
as part of continued efforts to identify and validate predictive biomarkers in MM that
347
can be used to guide treatment selection and to evaluate the efficacy of novel
348
therapies.64
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Disclosure
350
J.M. has acted as a consultant for AbbVie, Amgen, Celgene, Karyopharm
351
Therapeutics, Sanofi and Takeda. He has also received research funding from
352
AbbVie, Celgene, and Sanofi.
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Acknowledgments
354
The author acknowledges Hannah Burke, BSc (Core, London) for providing medical
355
writing support, and Rachael Cazaly, BSc (Core, London) for providing editorial
356
support, which was funded by Karyopharm Therapeutics and complied with Good
357
Publication Practice guidelines (Link). Karyopharm Therapeutics reviewed the
358
manuscript. However, the author is fully responsible for the opinions, conclusions,
359
and data interpretation presented in this manuscript.
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360
References
361
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Noll JE, Williams SA, Tong CM, et al. Myeloma plasma cells alter the bone
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responses with oral selinexor plus low dose dexamethasone in patients with
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S2152-2650(19)32008-7
DOI:
https://doi.org/10.1016/j.clml.2019.09.621
Reference:
CLML 1438
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 7 June 2019 Revised Date:
5 August 2019
Accepted Date: 29 September 2019
Please cite this article as: Mikhael J, Treatment Options for Triple-Class Refractory Multiple Myeloma, Clinical Lymphoma, Myeloma and Leukemia (2019), doi: https://doi.org/10.1016/j.clml.2019.09.621. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 The Author(s). Published by Elsevier Inc.
1
Treatment Options for Triple-Class Refractory Multiple
2
Myeloma
3
Joseph Mikhael, MD
4
Applied Cancer Research and Drug Discovery, Translational Genomics Research
5
Institute (TGen), City of Hope Cancer Center, Phoenix, AZ
6
Word count (2000–10,000 words): 4108
7
Address for correspondence: Dr. Joseph Mikhael, Translational Genomics Research
8
Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004
9
E-mail contact: [email protected]
10
Mikhael
11
Abstract (178/250)
12
The advent of new, more effective, and less toxic therapies has revolutionized the
13
management of multiple myeloma in the past decade. Despite the availability of new
14
treatments, the majority of patients with multiple myeloma will become refractory to
15
the therapies that currently comprise the hematologic standard of care for the
16
malignancy: proteasome inhibitors, immunomodulatory agents, and monoclonal
17
antibodies. Moreover, in recent years, a new subset of patients refractory to all 3 of
18
these agents has emerged. This population, in which a clear treatment paradigm
19
remains undefined, is characterized by poor survival outcomes. Current approaches
20
to the treatment of triple-class refractory disease are limited, and include
21
conventional chemotherapy, salvage autologous stem cell transplantation, and
22
recycling prior regimens, each of which have generally short-lived efficacy. It is
23
anticipated that additional agents will be available for triple refractory disease in the
24
near future, namely selinexor, chimeric antigen receptor T cell therapy, and next-
25
generation monoclonal antibodies. The development and further refinement of novel
26
treatments for this subset of patients in the coming years should be considered a key
27
clinical and research priority.
28
Key words: Multiple myeloma, Refractory, Autologous stem cell
29
transplantation, Selinexor, Monoclonal antibodies
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Mikhael
30
Introduction
31
Multiple myeloma (MM), characterized by the expansion of malignant plasma cells in
32
the bone marrow,1 accounts for approximately 1% of all malignancies and 10% of
33
hematologic malignancies.2 In the past decades, the advent of new, more effective,
34
and less toxic therapies has revolutionized the management of MM.3, 4 The ever-
35
expanding treatment landscape parallels substantial improvements in our
36
understanding of the biology of MM, optimized supportive care strategies, and the
37
refinement of combination treatment regimens.2, 3, 5
38
There are currently 3 drug classes available for the treatment of MM that have
39
shifted treatment paradigms and considerably improved outcomes for patients:
40
proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal
41
antibodies.6, 7 Various approaches to treatment using these agents have been
42
developed and these are widely used in the treatment of MM, often in triplet
43
combinations that involve 2 novel agents plus a steroid; a combination treatment
44
strategy has been adopted that uses a number of different therapies with distinct
45
mechanisms of action.8
46
The use of combination treatments has been a cornerstone of the therapeutic
47
management of MM for decades, but the agents included in these regimens have
48
been refined and have evolved considerably in recent years. For example, although
49
melphalan has served as the backbone for several PI and IMiD combinations for
50
more than 30 years, other agents have replaced alkylating agents as first-choice
51
treatment options for MM. However, melphalan remains commonly used as part of
52
the conditioning regimen in autologous stem cell transplant (ASCT)-eligible patients,9
53
and has recently been validated in a large phase III trial of bortezomib, lenalidomide, Page 3
Mikhael
54
and dexamethasone (RVD) with and without ASCT, demonstrating an improved
55
progression-free survival (PFS) in the transplant arm after high-dose melphalan and
56
2 cycles of RVD.10
57 58
The advent of novel therapeutic strategies, and their inclusion in initial therapeutic
59
regimens,11 has resulted in significant improvements in patient outcomes. A real-
60
world evidence study by Fonseca et al12 found that the percentage of patients with
61
MM receiving novel therapy continuously increased from 8.7% in 2000 to 61.3% in
62
2014. Patients with MM diagnosed after 2010 had better survival outcomes.12 Those
63
diagnosed in 2012 were 1.25 times more likely to survive for 2 years than those
64
diagnosed in 2006.12 Over the 14-year study period, patients with MM showed
65
improved OS, with the 2-year survival gap decreasing at a rate of 3% per year
66
between patients with MM and matched controls.12
67
Despite these advances, the majority of patients with MM will become refractory to
68
PIs, IMiDs, and monoclonal antibodies.13 This can leave clinicians unsure of how to
69
proceed, as fewer therapeutic options remain for heavily pretreated patients who
70
develop more aggressive disease, resulting in poorer outcomes for this patient
71
population.14 A multicenter study enrolled 543 patients with triple-class exposed,
72
IMiD- and PI-refractory MM, who had also been treated with an alkylating agent. The
73
median OS was 13 (95% confidence interval [CI] 11–15) months.15 In a 2016
74
retrospective analysis investigating outcomes in a similar patient population, OS was
75
poor despite the availability of newer agents, with a median OS of approximately
76
8 months.14 Furthermore, a 2018 retrospective analysis demonstrated that patients
77
who were penta-refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, Page 4
Mikhael
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and daratumumab had a median OS of only 5.6 months.16 The identification of more
79
effective therapeutic interventions for this patient population has therefore emerged
80
as a key priority for MM research.
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Defining a Treatment Paradigm for Triple-Class
82
Refractory MM
83
Although there is no current standard of care for the treatment of patients with
84
relapsed and/or refractory MM (RRMM),17 combination regimens are generally
85
preferred to monotherapy. This is because combination treatments enable multiple
86
pathways to be targeted to induce prolonged durable responses in patients with
87
MM.18
88
However, once patients with MM have become triple-class refractory, there is even
89
less consensus on what can be defined as a preferred approach to therapy. Reusing
90
or recycling prior treatments to which a patient was previously refractory may be
91
considered, in light of synergistic effects of drug combinations, or due to the
92
presence of clonal evolution that may signify renewed drug sensitivity in later
93
disease.19 Although this option may be considered for patients who had previously
94
exhibited a sufficiently durable response (of at least 6 months) to a given regimen,19
95
this would generally yield low response rates with limited PFS in patients with a
96
short-term remission duration or progression following initial treatment, so other
97
strategies are required.20
98
These key alternative approaches include conventional chemotherapy, salvage
99
ASCT, the novel nuclear export inhibitor, selinexor, along with other novel
100
approaches, such as treatment with chimeric antigen receptor (CAR) T cell therapy,
101
and next-generation antibodies and bispecific T cell engager technology.
102
Conventional Chemotherapy
103
Although not used routinely, conventional chemotherapy can elicit a good (albeit Page 6
Mikhael
104
short-lived) response in patients with RRMM.
105
D(T)-PACE (dexamethasone ± thalidomide, cisplatin, doxorubicin,
106
cyclophosphamide, and etoposide) is a chemotherapeutic regimen that has been
107
evaluated in cases of RRMM, with studies reporting response rates of approximately
108
50%. However, because its toxicity is common and PFS is short, D(T)-PACE is
109
generally considered most effective when used as a bridge to other MM treatment
110
interventions.21
111
Similarly, high-dose cyclophosphamide has shown value as a potential bridge to
112
novel therapies in refractory MM. When used in combination with dexamethasone,
113
high-dose cyclophosphamide was shown to be an efficient rescue regimen in
114
double-refractory MM, with an overall response rate (ORR) of 55%, with 3 patients
115
(15%) achieving complete response (CR). Twelve patients (67%) were treated with
116
further therapies after achieving at least stable disease. The median PFS and OS
117
were 6 and 12 months, respectively.22
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118
Bendamustine, a bifunctional alkylating agent, has demonstrated efficacy at different
119
stages of MM, including patients with more advanced disease. In a retrospective
120
analysis of individuals with heavily pretreated RRMM, 39 patients received a median
121
of 3 cycles of bendamustine, either as monotherapy or concomitantly with
122
corticosteroids. The results found bendamustine to be effective in these patients,
123
with 3% achieving a very good partial response, 33% partial response, 18% minor
124
response, 26% stable disease, and 20% progressive disease; the median event-free
125
survival and OS were 7 and 17 months, respectively 23 In triple-refractory (100%)
126
and penta-refractory (40%, defined as refractory to one monoclonal antibody, two
127
PIs and two IMiDs) patients refractory to CD38 monoclonal antibodies, those who
128
received bendamustine (n = 15) as their next line of therapy had a median PFS and
129
OS of 3.2 and 9.3 months, respectively.24
130
Doxorubicin, cisplatin, and etoposide are 3 further chemotherapeutic agents that
131
have been evaluated in RRMM. Although the depth and duration of responses to
132
these treatments can be poor when used alone, use of these agents in combination
133
can elicit highly active, durable responses, especially when used in synergistic
134
combinations that also reduce toxicity risk.25
135
In combination with more conventional chemotherapy regimens, histone deacetylase
136
(HDAC) inhibitors have shown promise as a treatment option for patients with
137
triple-class refractory MM. HDACs deacetylate the lysine residues of both histones
138
and non-histone proteins, resulting in histone hyperacetylation and alterations in
139
chromatin structure that cause growth cycle arrest and apoptosis in tumor cells.26
140
Preclinical studies investigating HDAC inhibitors and PIs in MM demonstrated a
141
synergistic effect on tumor cells, which leads to the accumulation of polyubiquitinated
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proteins and activation of apoptosis.27 In the phase III PANORAMA1 trial in patients
143
with RRMM who had received 1 to 3 previous lines of therapy, patients treated with
144
the HDAC inhibitor panobinostat plus bortezomib and dexamethasone showed
145
significantly longer median PFS than those receiving placebo plus bortezomib and
146
dexamethasone (11.99 months [95% CI 10.33–12.94] vs. 8.08 months [7.56–9.23];
147
hazard ratio 0.63, 95% CI 0.52–0.76; P < .0001).28 Similar effects were observed in
148
subgroup analysis of patients who had previously received an IMiD, bortezomib plus
149
an IMiD, or at least 2 lines of treatment including bortezomib and an IMiD.29, 30
150
Panobinostat plus bortezomib and dexamethasone had a tolerable safety profile,
151
with the most frequent grade 3–4 adverse events (AEs) being myelosuppression,
152
diarrhea, asthenia or fatigue, peripheral neuropathy, and pneumonia.28-30 Analysis of
153
patients with RRMM who had experienced a failure with daratumumab (n = 354)
154
showed that patients who switched to chemotherapy (P = .0208) or panobinostat (P
155
= .0298) had received a greater number of therapies than those who switched to
156
elotuzumab-based regimens.31
157
Salvage ASCT
158
ASCT was first used in combination with melphalan in patients with MM in the 1980s.
159
Its success in clinical trials meant that the procedure was soon considered an
160
important component of the standard of care for newly diagnosed patients with MM
161
aged up to 65–70 years without significant comorbidities.32
162
A study comparing conventional treatments (8 cycles of RVD, plus stem cell
163
mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating
164
factor after 3 cycles of RVD) with RVD treatment and ASCT (3 induction cycles of
165
RVD, followed by stem cell collection, and then ASCT with melphalan, followed by Page 9
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2 cycles of RVD) reported a median PFS of 50 months in the transplant arm,
167
compared with 36 months in the RVD arm.10 The upfront trial of RVD versus RVD
168
plus ASCT demonstrated the continued value of ASCT in frontline therapy.33
169
However, it also speaks to the value of ASCT in relapsed disease, as 79% of
170
patients in the RVD alone arm had ASCT at first relapse.10 Salvage ASCT has now
171
been employed in later relapse, as a number of retrospective studies have also
172
demonstrated the efficacy of salvage ASCT following reinduction therapy in patients
173
with MM who have relapsed after a prior ASCT. The most important factor predicting
174
PFS after salvage ASCT is the duration of remission after initial ASCT, with those
175
patients with PFS of ≥ 18 months after their first autotransplant most likely to
176
benefit.34 Although recent guidelines from the International Myeloma Working Group
177
recommend that salvage ASCT is considered for all eligible patients,35 the procedure
178
is an option suitable only for a small minority. Many patients with MM are not
179
considered candidates due to their age and weakened state, arising as a
180
consequence of comorbidities, organ dysfunctions, and limitations in mental/mobility
181
functions, which would not enable them to withstand the procedure.20
182
Selinexor
183
Selinexor is a first-in-class selective inhibitor of nuclear export36 that provides an
184
additional therapeutic option for those with triple refractory disease; indeed, it has
185
been studied in patients with ‘quad- and penta-refractory disease’ by virtue of their
186
exposure to and becoming refractory to the 5 key agents used in this patient
187
population (bortezomib, lenalidomide, carfilzomib, pomalidomide, and
188
daratumumab). Selinexor is currently being evaluated as a component of
189
combination regimens in a number of phase II and III clinical trials in patients with
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RRMM.36 In the STORM (Selinexor Treatment of Refractory Myeloma) study
191
(NCT02336815), selinexor is being used in combination with low-dose
192
dexamethasone. The first part of this phase II trial evaluated selinexor and
193
dexamethasone in patients with MM refractory to bortezomib, carfilzomib,
194
lenalidomide, and pomalidomide, along with a small subset of patients with penta-
195
refractory disease, who were also refractory to an anti-CD38 antibody; indeed, this
196
was a very heavily pretreated population of patients with a median of 7 prior lines of
197
therapy.37 The ORR was 21% in patients with quad-refractory MM, and 20% for
198
patients with penta-refractory MM. Of note, the ORR was 35% among patients with
199
high-risk cytogenetics, including t(4;14), t(14;16), and del(17p). The median duration
200
of response was 5 months, and 65% of responding patients were alive at 12 months.
201
The most common grade ≥ 3 AEs were thrombocytopenia, anemia, neutropenia,
202
hyponatremia, leukopenia, and fatigue. Dose interruptions for AEs occurred in
203
41 patients, dose reductions occurred in 29 patients, and treatment discontinuation
204
occurred in 14 patients.37
205
Part 2 of STORM focused specifically on patients with penta-refractory MM, and
206
included many patients with rapidly progressive disease, with nearly 50% having
207
high-risk myeloma.38 In this context, selinexor in combination with low-dose
208
dexamethasone was highly active in this population, with an ORR of 26.2%.38
209
Treatment responses showed depth with a fast onset of action (within the first cycle
210
in most patients), with 2 patients achieving stringent CRs, both of whom were
211
minimal residual disease (MRD) negative.38, 39 Median OS was 8.6 months.38, 39 No
212
major organ toxicity was observed, and AEs were typically transient and
213
reversible.38, 39 Supportive care was important in reducing the severity of these
214
toxicities.38 In July 2019, selinexor was granted accelerated approval by the FDA for Page 11
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adult patients with RRMM who have received at least four prior therapies and whose
216
disease is refractory to at least two proteasome inhibitors, at least two
217
immunomodulatory agents, and an anti-CD38 monoclonal antibody.40
218
The ongoing phase Ib/II STOMP (Selinexor and backbone Treatments Of Multiple
219
myeloma Patients) studies are evaluating selinexor and low-dose dexamethasone in
220
combination with a number of standard approved therapies including lenalidomide,
221
pomalidomide, bortezomib, carfilzomib, and daratumumab, and have generated
222
promising findings to date.41-43
223
Other Novel Approaches
224
Key clinical trial data for novel therapies are summarized in Table 1.
225
CAR T Cell Therapy
226
T cells can be genetically modified to express CARs, which are fusion proteins that
227
have an antigen recognition region and a co-stimulation domain.44 In MM, CAR T cell
228
therapies have shown clinical activity of up to 90–100% with a manageable safety
229
profile.44 Of note, bb2121 has shown promising efficacy at dose levels of
230
≥ 150×106 CAR T cells in 33 patients with RRMM who had received at least 3 prior
231
lines of therapy, including a proteasome inhibitor and an immunomodulatory agent,45
232
with a median PFS of 11.8 months. In total, 15 patients had a CR (45%)45 and
233
25 patients (76%) had cytokine release syndrome, which was of grade 3 in 2 patients
234
(6%).45 Cytokine release syndrome is the common toxicity associated with CAR T
235
cells, and is caused by the release of cytokines by the infused T cells.46 Built along
236
the bb2121 platform is bb21217, intended to have improved cell persistence. Early
237
efficacy results show 6 of 7 patients (median of 9 prior lines of therapy) Page 12
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demonstrating clinical responses at a dose of 150x106 CAR T cells.47
239
In a heavily pretreated MM patient population that had failed IMiDs, proteasome
240
inhibitors and daratumumab, an overall response rate of 83% (5/6 patients) was
241
shown with P-BCMA-1.48 Only 1 patient developed cytokine release syndrome, of
242
limited severity (grade 2).48 The lack of significant toxicity observed with P-BCMA-1
243
is favorable compared to other CAR T cell therapies.48
244
Venetoclax
245
Venetoclax is a potent, selective, orally bioavailable small-molecule inhibitor of B cell
246
lymphoma (BCL)-2.36 Venetoclax has been investigated alone and in combination
247
with other therapies for the treatment of RRMM.49-51 Venetoclax monotherapy has an
248
acceptable safety profile and clear anti-myeloma activity in patients with RRMM,
249
primarily with t(11;14) having high BCL-2, low BCL-extra large, and low myeloid
250
leukemia cell differentiation protein-1 expression levels.49, 50 As part of a combination
251
regimen with bortezomib and dexamethasone, venetoclax has also demonstrated
252
efficacy in RRMM in a randomized phase III trial of venetoclax-bortezomib-
253
dexamethasone versus bortezomib-dexamethasone. Results revealed an improved
254
ORR of 82% and 68% and prolonged PFS of 22.4 months and 11.5 months,
255
respectively.52 However, there was a concerning safety signal with increased deaths
256
in the venetoclax-bortezomib-dexamethasone arm due to infections.52 The U.S. Food
257
and Drug Administration (FDA) placed a partial hold on trials with this agent in
258
myeloma and recommended that all patients with MM on this agent must be on
259
antibiotic prophylaxis. Subsequently, this partial hold has been lifted upon revisions
260
to the study protocol. It remains unclear what role this agent may play in myeloma,
261
but venetoclax could be a niche agent for patients with t(11;14) mutations, providing Page 13
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clinicians with a means to identify patients likely to respond to certain treatments.52
263
This is important in the context of triple-class RRMM, as clinicians can be unsure as
264
to which therapies are the most appropriate for such a heavily pretreated population
265
that have failed standard MM therapies.
266
Programmed Cell Death Protein-1 Antibodies
267
Upregulation of the programmed cell death protein 1 (PD-1) pathway in MM prevents
268
the activation of antitumour T cell populations and can contribute to immune escape
269
by the tumour, enabling its proliferation.53 Pembrolizumab is an antibody that targets
270
PD-1, restoring the capacity of the immune system to perform cytotoxic T cell killing
271
of malignant plasma cells.53 Interim analysis from a phase III trial of pomalidomide
272
and dexamethasone with or without pembrolizumab in 249 RRMM patients with ≥2
273
prior lines of therapy showed an unfavourable benefit–risk profile for the triple
274
combination.54Median PFS was 5.6 months in the pembrolizumab plus
275
pomalidomide and dexamethasone group and 8.4 months in the pomalidomide and
276
dexamethasone-only group.54 Serious AEs (SAEs) occurred in 46% (56/121) of
277
patients in the pomalidomide and dexamethasone group, compared with 63%
278
(75/120) in the pembrolizumab plus pomalidomide and dexamethasone group.54
279
There were 4 (3%) treatment-related deaths with pembrolizumab plus pomalidomide
280
and dexamethasone.54 In the pomalidomide and dexamethasone-only group, no
281
treatment-related deaths were reported.54 Although these patients were not an
282
exclusively triple-class population, this study suggests that pembrolizumab does not
283
confer a survival benefit in RRMM.
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B Cell Maturation Antigen Antibodies
285
B cell maturation antigen (BCMA) is a cell surface receptor in the tumor necrosis
286
factor superfamily.44 Expression of BCMA is limited to B cells in advanced stages of
287
differentiation, and is required for the survival of long-lived plasma cells.44 Because
288
BCMA is expressed at significantly higher levels in all of the patient’s MM cells but
289
not on other normal tissues except normal plasma cells,44 it was identified as a target
290
for MM treatment. GSK2857916 is a humanized immunoglobulin G1 monoclonal
291
antibody with high affinity to BCMA conjugated to a microtubule-disrupting toxin
292
(monomethyl auristatin F). A phase I trial investigating monotherapy with the
293
antibody demonstrated a 38.5%% ORR and a median PFS of 6.2 months in those
294
who were refractory to daratumumab, a proteasome inhibitor and an
295
immunomodulator.55
296
Treatments Utilizing Bispecific T-cell Engager Technology
297
Bispecific T-cell Engagers (‘bispecifics’) contain 2 single-chain variable fragments
298
that are connected by a linker molecule. To redirect anticancer immunity, bispecifics
299
bind a T cell-specific antigen, often CD3, with 1 fragment, and a cancer-specific
300
epitope with the other, thus providing a platform to facilitate interaction between
301
effector and cancer cells.56 These may be particularly useful as the same product
302
can be given to all patients, whereas CAR T cell therapy is based on the patients’
303
own cells.57 The CD3-CD19 bispecific blinatumomab was granted FDA approval
304
based on the results of a phase II study that reported a 43% CR in patients with
305
relapsed or refractory B-cell precursor acute lymphoblastic leukemia.58 In RRMM,
306
preliminary results from the first-in-human study, in patients who had progression
307
after ≥2 lines of therapy (PI and IMiD), of the bispecific antibody construct AMG 420
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showed promising evidence of activity, with 13/42 responders.59 Of these, 3 were
309
CRs and 2 were PRs.59 The median time to any response was 1 month.59 Safety
310
was comparable to other immunotherapies, with SAEs in 50% of patients.59
311
Treatment-related SAEs included grade 3 polyneuropathies (n = 2) and edema (n =
312
1), both requiring hospitalization.59 Five MRD-negative stringent CRs were observed
313
in patients receiving AMG 420 400 µg/day.59
314
Other molecules are also being evaluated in RRMM, including inhibitors of murine
315
double minute 2 (MDM2), kinase, or bromodomain, along with other drug classes
316
that can induce apoptosis in MM cells.36
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Table 1. Novel approaches to triple-class RRMM
Name of agent 45
bb2121
bb21217
47
48
P-BCMA-101
Mechanism of action
Stage of development
Study number
Study population
Key efficacy results
Key safety results
CAR T cell
Phase I
NCT02658929
≥3 prior lines of therapy, including a PI and an IMiD, N = 33
ORR was 85%, CR in 15/33 (45%) of which 6 have since relapsed. Median PFS was 11.8 months (95% CI 6.2–17.8)
25/33 (76%) developed cytokine release syndrome, neurologic toxic effects in 14/33 (42%)
CAR T cell
Phase I
NCT03274219
≥3 prior lines of therapy, including a PI and an IMiD, N=8
6/7 demonstrated clinical response (1 sCR, 3 VGPR, 2 PR)
5/8 developed cytokine release syndrome
CAR T cell
Phase I
NCT03288493
≥3 prior lines of therapy, including a PI and an IMiD, N = 12
ORR was 83%
One patient has developed cytokine release syndrome (8%), most comment SAEs were cytopenia and febrile neutropenia
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Venetoclax (with bortezomib and 52 dexamethasone)
BCL-2 inhibitor
Phase III
NCT02755597
1–3 prior lines of therapy, N = 291
Mean PFS in the ventoclax arm was 22.4 months versus 11.5 months in the placebo arm, ORR was 82% vs 68%
41/194 (21.1%) deaths in the venetoclax arm, 11/97 (11.3%) in the placebo arm, severe, grade 3–5 toxicity and SAE rate were similar between the two arms.
Pembrolizumab (with pomalidomide and 54 dexamethasone)
Anti-PD-1 antibody
Phase III
NCT02576977
≥2 prior lines of therapy, N = 249
Median PFS in pembrolizumab arm was 5.6 months versus 8.4 months in the pomalidomide and dexamethasoneonly arm
4 deaths (3%) in the pembrolizumab arm. SAEs occurred in 75/120 (63%) in the pembrolizumab arm versus 56/121 (46%) in the pomalidomide and dexamethasone-only arm
BCMA
Phase I
NCT02064387
Prior therapy with an alkylator, PI and IMiD, N = 35
21/35 (60%) achieved a PR or better, including 2 sCR, and 3 CR. Median PFS was 12 months
Most commonly reported AEs were cough, increased aspartate aminotransferase and nausea (all grade 1 or 2). Corneal events and thrombocytopenia were manageable
Bispecific T-cell engager
Phase I
NCT02514239
Progression after ≥2 lines (incl PI and IMiD), N=42
13/42 responders including 6 sCRs, 3 CRs, 2 VGPR, 2 PRs. Median time to any response was 1 month
Treatment-related SAEs included 2 grade 3 polyneuropathy and 1 edema. Grade 2–3 cytokine release syndrome seen in 3 patients
GSK2857916
59
AMG 420
55
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BCL-2, B cell lymphoma 2; CAR, chimeric antigen receptor; CI, confidence interval; CR, complete response; IMiD, immunomodulatory agent; ORR, objective response rate;
319
PD-1, programmed cell death protein-1; PFS, progression-free survival; PI, proteasome inhibitor; PR, partial response; SAE, serious adverse event; sCR, stringent complete
320
response; VGPR, very good partial response
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Conclusion and Recommendations
322
In 2015, therapeutic options for MM expanded further when daratumumab and
323
elotuzumab were approved by the FDA for MM. Although monoclonal antibodies are
324
now of paramount importance in the context of MM care, their growing prominence is
325
coupled with the emergence of a new subset of patients who are refractory to
326
monoclonal antibodies, PIs, and IMiDs. The development and further refinement of
327
novel treatments for this subset of patients in the coming years should be considered
328
a key priority in myeloma. Current approaches to the treatment of triple-refractory
329
disease include conventional chemotherapy and salvage ASCT. It is anticipated that
330
in the near future, additional agents will be available for triple refractory disease,
331
namely selinexor, CAR T cell therapy, and next-generation monoclonal antibodies.
332
Therapeutic interventions for MM must be considered in the context of a supportive
333
care strategy that looks to improve patients’ quality of life and to help achieve better
334
treatment outcomes.60 Patients with RRMM are particularly vulnerable due to prior
335
exposure to chemotherapy, myelosuppression, long-term exposure to
336
corticosteroids, and impaired organ function.13 Supportive care must encompass
337
strategies to manage broader elements of MM, such as bone disease and spinal
338
cord compression, anemia, bone marrow failure and infections, and renal failure,33, 60
339
as well as management of treatment-related AEs.61
340
An understanding of disease-related factors, such as cytogenic abnormalities and
341
prognostic markers (eg, MRD),62, 63 and patient-related factors, such as renal
342
insufficiency, hepatic impairment, and comorbidities,62 is critical for evaluating
343
appropriate therapeutic options for patients with triple-class refractory MM.
344
Treatment-related factors, including prior drug exposures, longevity of remission, and Page 20
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treatment-related toxicities,62 must also be considered. Further research is required
346
as part of continued efforts to identify and validate predictive biomarkers in MM that
347
can be used to guide treatment selection and to evaluate the efficacy of novel
348
therapies.64
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Disclosure
350
J.M. has acted as a consultant for AbbVie, Amgen, Celgene, Karyopharm
351
Therapeutics, Sanofi and Takeda. He has also received research funding from
352
AbbVie, Celgene, and Sanofi.
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Acknowledgments
354
The author acknowledges Hannah Burke, BSc (Core, London) for providing medical
355
writing support, and Rachael Cazaly, BSc (Core, London) for providing editorial
356
support, which was funded by Karyopharm Therapeutics and complied with Good
357
Publication Practice guidelines (Link). Karyopharm Therapeutics reviewed the
358
manuscript. However, the author is fully responsible for the opinions, conclusions,
359
and data interpretation presented in this manuscript.
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