THE CASE

A 57-year-old man with no significant prior medical history presented with left hip pain and was found to have a proximal femoral fracture. Workup of etiology led to the diagnosis of κ light chain multiple myeloma (MM), revised international staging system (R-ISS) II, and presence of chromosome 1q gain by fluorescence in situ hybridization (FISH). He was treated with bortezomib, lenalidomide, and dexamethasone (VRD) for four cycles and achieved a very good partial response (VGPR) by International Myeloma Working Group (IMWG) criteria. The patient underwent autologous stem cell transplantation (ASCT) with high-dose melphalan (200 mg/m2) and achieved complete remission. After three years of lenalidomide maintenance, the patient was found to have increasing light chains and new bone pain consistent with disease relapse.

THE QUESTION

What is your approach in the management of relapsed and/or refractory MM (RRMM)?

THE RESPONSE

RRMM comprises three distinct patient populations defined according to IMWG criteria.1  These include: 1) primary refractory disease, 2) relapsed but not refractory, and 3) relapsed and refractory. After confirming the nature of relapse, several factors influence treatment decisions, including patient age, comorbidities, and performance status; nature of the relapse (biochemical, indolent, or aggressive clinical relapse); timing of the relapse (early vs. late); and lastly, residual toxicities and response to prior treatments. There is no clear evidence regarding the best timing of treatment in patients with biochemical relapse, but in patients with high-risk disease, rapid doubling of the paraprotein as well as patient preferences all play an important role in treatment decisions. In the previous decade, treatment of MM witnessed numerous breakthroughs with regulatory approvals of several drugs and regimens such as second- and third-generation proteasome inhibitors (PIs; carfilzomib and ixazomib, respectively)2,3 ; second-generation immunomodulators (ImIDs; pomalidomide)4 ; monoclonal antibodies such as elotuzumab5  (a monoclonal antibody targeting the signaling lymphocyte activation molecule SLAMF7), and daratumumab and isatuximab6,7  (monoclonal antibodies targeting CD38); panobinostat (histone deacetylase inhibitor)8 ; selinexor9  (an inhibitor of exportin, XPO1); and more recently, the first antibody drug conjugate against B-cell maturation antigen (BCMA), belantamab mafadotin.10  Soon this therapeutic armamentarium will be bolstered by other active and passive immunotherapeutic options such as chimeric antigen receptor T-cell (CAR-T) therapy,11  antibody drug conjugates,10  and T-cell engagers.12  These exciting developments are encouraging for patients, but the rapid paces of these advances have also added complexity without a clear comparative paradigm for an informed practice. Based on the number of prior lines of therapy and the number of approved agents, two groups of patients can be identified.

Early Relapse (1-3 lines)

Table 1 shows the selected regimens approved by the U.S. Food and Drug Administration (FDA) for patients with MM and one to three lines of prior treatment. Based on these data, triplet regimens are preferred based on their superior efficacy over doublets, if patients can tolerate them. However, in the absence of head-to-head comparisons among these novel regimens, it is difficult to make definite decisions on clinical practice. All of these regimens are active in MM, and given the chronic relapsing nature of the disease, most of them will be used in a patient’s lifetime. Studies looking at the sequencing of these regimens are needed to guide informed decisions. Another problem is the limited applicability of lenalidomide-based triplets in the United States given that most patients would receive maintenance lenalidomide. Prior exposure to lenalidomide varies from as low as 6 percent in TOURMALINE3  to 20 percent in ASPIRE,2  and does not really represent the U.S. clinical practice pattern. Thus, either bortezomib-based or pomalidomide-based triplets are reasonable in such settings. Because of the absolute magnitude of benefits, daratumumab followed by carfilzomib-based combinations emerge as the most efficacious regimens and preferred initial options in patients with early relapse. The choice of treatment, however, is individualized. For example, frail patients or those with indolent relapse can be considered for an elotuzumab- or ixazomib-based triplet depending on their safety profile, or in some cases, doublets as well.

Selected Approved Regimens for Early Relapse

Prior Therapy/TrialRegimensMedian Progression-Free SurvivalHazard Ratio for Progression or Death (95% CI)
One to three lines 
ASPIRE2  Carfilzomib/R/D vs. R/D 26.3 vs. 17.6 mo. 0.69 (0.57-0.83) 
POLLUX6  Daratumumab/R/D vs. R/D NR vs. 18.4 mo. 0.37 (0.27-0.52) 
CASTOR14  Daratumumab/bortezomib/D vs. bortezomib/D NR vs. 7.4 mo. 0.39 (0.28-0.53) 
ELOQUENT-25  Elotuzumab/R/D vs. R/D 19.4 vs. 14.9 mo. 0.70 (0.57-0.84) 
TOURMALINE3  Ixazomib/R/D vs. R/D 20.6 vs. 14.7 mo. 0.74 (0.59-0.94) 
More than two lines 
ELOQUENT-315  Elotuzumab/P/D vs. P/D 10.3 vs. 4.7 mo. 0.54 (0.34-0.86) 
ICARIA7  Isatuximab/P/D vs. P/D 11.5 vs. 6.5 mo. 0.59 (0.44-0.81) 
EQUULEUS4  Daratumumab/P/D 8.8 mo. NA 
Prior Therapy/TrialRegimensMedian Progression-Free SurvivalHazard Ratio for Progression or Death (95% CI)
One to three lines 
ASPIRE2  Carfilzomib/R/D vs. R/D 26.3 vs. 17.6 mo. 0.69 (0.57-0.83) 
POLLUX6  Daratumumab/R/D vs. R/D NR vs. 18.4 mo. 0.37 (0.27-0.52) 
CASTOR14  Daratumumab/bortezomib/D vs. bortezomib/D NR vs. 7.4 mo. 0.39 (0.28-0.53) 
ELOQUENT-25  Elotuzumab/R/D vs. R/D 19.4 vs. 14.9 mo. 0.70 (0.57-0.84) 
TOURMALINE3  Ixazomib/R/D vs. R/D 20.6 vs. 14.7 mo. 0.74 (0.59-0.94) 
More than two lines 
ELOQUENT-315  Elotuzumab/P/D vs. P/D 10.3 vs. 4.7 mo. 0.54 (0.34-0.86) 
ICARIA7  Isatuximab/P/D vs. P/D 11.5 vs. 6.5 mo. 0.59 (0.44-0.81) 
EQUULEUS4  Daratumumab/P/D 8.8 mo. NA 

Abbreviations: D, dexamethasone; mo., months; NA, not applicable; NR, no response; P, pomalidomide; R, lenalidomide.

Late Relapse (> 3 lines)

Ideally, patients in late relapse should be treated on a clinical trial. In the absence of clinical trials, these patients are generally treated with triplets, which contains at least two drugs that the patient is not refractory to. Selinexor has been recently approved by the FDA for patients with RRMM and four prior therapies (including PIs, ImIDs, and CD38 monoclonal antibodies) based on a phase II study that showed an overall response rate of 26 percent in heavily treated patients.9  Belantamab mafadotin is the first BCMA targeted therapy to obtain FDA approval, and is approved as a monotherapy in RRMM patients who have received four prior therapies including an ImID, PI, and a CD38 antibody. This approval is based on a phase II study that showed an overall response rate of 30 percent in heavily treated patients.10  Notable adverse effects for selinexor include nausea and thrombocytopenia, and for belantamab mafadotin, corneal toxicities and cytopenias. Several emerging options are being explored in this setting, but the one worth mentioning is the development of CAR-T therapy with BCMA as the lead target antigen. Table 2 summarizes the results of selected CAR-T trials. As shown, these patients are heavily pretreated, with median prior lines ranging from three to eight, and in early-phase trials, demonstrated high single-agent response. Two major toxicities associated with CAR-T therapy, cytokine release syndrome and neurotoxicity, can reduce its therapeutic potential. Hopefully, we will soon see the approval of this agent in RRMM, but long-term follow-up of the current trials, and randomized studies, are needed to understand the safety, efficacy, and applicability of this approach.

Selected B-cell Maturation Antigen Chimeric Antigen Receptor T-cell Trials

TrialVector/Co-stimulatory DomainNo. of PatientsMedian No. of Prior Lines (Range)ORR/PFS
Bb212111  Lentivirus/4-1BB 33 7 (3-14)
8 (3-23) 
85%/11.8 mo. 
LCAR-B38 M16  Lentivirus/4-1BB 57 3 (1-9) 88%/15 mo. 
JCARH12517  Lentivirus/4-1BB 44 7 (3-23) 82%/NR 
CARTITUDE-118  Lentivirus/4-1BB 25 5 (3-16) 91%/NR 
TrialVector/Co-stimulatory DomainNo. of PatientsMedian No. of Prior Lines (Range)ORR/PFS
Bb212111  Lentivirus/4-1BB 33 7 (3-14)
8 (3-23) 
85%/11.8 mo. 
LCAR-B38 M16  Lentivirus/4-1BB 57 3 (1-9) 88%/15 mo. 
JCARH12517  Lentivirus/4-1BB 44 7 (3-23) 82%/NR 
CARTITUDE-118  Lentivirus/4-1BB 25 5 (3-16) 91%/NR 

Abbreviations: mo., months; NR, no response; ORR, overall response rate; PFS, progression-free survival.

Role of Salvage Transplantation

Second salvage transplantation, one of the treatment options in RRMM, is usually recommended for patients who have never undergone transplantation or have had an excellent remission of at least 18 months from first transplantation. Several studies have demonstrated the safety and efficacy of this approach making it an option in eligible patients as a consolidative strategy after novel reinduction therapy.13 

Patient Follow-up

The patient received two cycles of carfilzomib, pomalidomide, and dexamethasone and achieved an excellent response. Following this, he underwent salvage transplantation with melphalan 200 mg/m2 and has been on complete remission since.

CONCLUSION

Choosing therapy in RRMM is becoming increasingly complex in the crowded space of emerging and existing therapies. The choice of treatment depends on patient-, disease-, and treatment-related factors. Though combination strategy with triplet regimens is preferred, it is important to tailor treatment individually to a patient so as to improve efficacy, limit toxicity, and improve quality of life. When possible, all patients with RRMM at any stage of disease should be treated under clinical trial.

References

References
1.
Rajkumar
SV
,
Dimopoulos
MA
,
Palumbo
A
, et al
.
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
.
Lancet Oncol
.
2014
;
15
:
e538
-
e548
.
2.
Stewart
AK
,
Rajkumar
SV
,
Dimopoulos
MA
, et al
.
Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma
.
N Engl J Med
.
2015
;
372
:
142
-
152
.
3.
Moreau
P
,
Masszi
T
,
Grzasko
N
, et al
.
Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma
.
N Engl J Med
.
2016
;
374
:
1621
-
1634
.
4.
Chari
A
,
Suvannasankha
A
,
Fay
JW
, et al
.
Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
.
Blood
.
2017
;
130
:
974
-
981
.
5.
Lonial
S
,
Dimopoulos
M
,
Palumbo
A
, et al
.
Elotuzumab therapy for relapsed or refractory multiple myeloma
.
N Engl J Med
.
2015
;
373
:
621
-
631
.
6.
Dimopoulos
MA
,
Oriol
A
,
Nahi
H
, et al
.
Daratumumab, lenalidomide, and dexamethasone for multiple myeloma
.
N Engl J Med
.
2016
;
375
:
1319
-
1331
.
7.
Attal
M
,
Richardson
PG
,
Rajkumar
SV
, et al
.
Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study
.
Lancet
.
2019
;
394
:
2096
-
2107
.
8.
San-Miguel
JF
,
Hungria
VTM
,
Yoon
SS
, et al
.
Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial
.
Lancet Oncol
.
2014
;
15
:
1195
-
1206
.
9.
Chari
A
,
Vogl
DT
,
Gavriatopoulou
M
, et al
.
Oral selinexor-dexamethasone for triple-class refractory multiple myeloma
.
N Engl J Med
.
2019
;
381
:
727
-
738
.
10.
Lonial
S
,
Lee
HC
,
Badros
A
, et al
.
Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study
.
Lancet Oncol
.
2020
;
21
:
207
-
221
.
11.
Raje
N
,
Berdeja
J
,
Lin
Y
, et al
.
Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma
.
N Engl J Med
.
2019
;
380
:
1726
-
1737
.
12.
Topp
MS
,
Duell
J
,
Zugmaier
G
, et al
.
Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma
.
J Clin Oncol
.
2020
;
38
:
775
-
783
.
13.
Palumbo
A
,
Chanan-Khan
A
,
Weisel
K
, et al
.
Daratumumab, bortezomib, and dexamethasone for multiple myeloma
.
N Engl J Med
.
2016
;
375
:
754
-
766
.
14.
Dimopoulos
MA
,
Dytfeld
D
,
Grosicki
S
, et al
.
Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma
.
N Engl J Med
.
2018
;
379
:
1811
-
1822
.
15.
Zhao
WH
,
Liu
J
,
Wang
BY
, et al
.
A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma
.
J Hematol Oncol
.
2018
;
11
:
141
.
16.
Mailankody
S
,
Htut
M
,
Lee
KP
, et al
.
JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Initial proof of concept results from a phase 1/2 multicenter study (EVOLVE)
.
Blood
.
2018
;
132
(
Supplement 1
):
957
.
17.
Madduri
D
,
Usmani
SZ
,
Jagannath
S
, et al
.
Results from CARTITUDE-1: A phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM)
.
Blood
.
2019
;
134
(
Supplement_1
):
577
.
18.
Cook
G
,
Ashcroft
AJ
,
Cairns
DA
, et al
.
The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF myeloma X relapse [intensive]): a randomised, open-label, phase 3 trial
.
Lancet Haematol
.
2016
;
3
:
e340
-
e351
.

Competing Interests

Dr. Dhakal indicated no relevant conflicts of interest.

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