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Cited by 305Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchBone health and treatments

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Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond

Open access
Chim, C S, Kumar, S K, Orlowski, R Z, Cook, G, Richardson, P G, Gertz, M A, Giralt, S, Mateos, M V, Leleu, X, Anderson, K C·2018·Leukemia
DOI 10.1038/leu.2017.329PMC PMC5808071
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Abstract

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

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Figures

Figure 1 Oligoclonal reconstitution (OCR) illustrated by the change of monoclonal IgAL at diagnosis (Dx) to OCR of IgGk+IgGL+IgMk during complete remission.
Figure 1 Oligoclonal reconstitution (OCR) illustrated by the change of monoclonal IgAL at diagnosis (Dx) to OCR of IgGk+IgGL+IgMk during complete remission.CC BY-NC-ND · PubMed Central
Figure 2 An array of salvage regimens for RRMM comprising proteasome inhibitor (PI), immunomodulatory agents (IMiD), anti-CD38 (daratumumab [Dara]) or anti-SLAMF7 (elotuzumab [Elo]) monoclonal antibodies, BCL2 inhibitor (BCL2i), exportin-1 inhibitor (XPO1-i), anti-PD1 check-point inhibitors or CAR-T cells. PI (bortezomib [V], carfilzomib [K] and ixazomib [Ixa]) and dexamethasone [Dex] induces intrinsic/mitochondrial apoptosis (via activation of caspase 9 through formation of the apoptosome) while IMiD (lenalidomide [R] and pomalidomide [P]) extrinsic apoptosis via activation of caspase 8. Low-dose dexamethasone (d) can be combined with either IMiD (Rd or Pd), or PI (Vd or Kd) to yield effective doublets, or both IMiD and PI to generate even more potent triplets including VRd, VPd, KRd, KPd and Ixa-Rd. Monoclonal antibody combinations targeting CD38 (Dara-Vd, Dara-Rd or Dara-Pd) or SLAMF7 (Elo-Rd) are effective salvage regimens. Venetoclax (VEN), or in combination with Vd, induces mitochondrial apoptosis. Selinexor (SEL)is an exportin-1 inhibitor, resulting in nuclear retention of tumor suppressor proteins (TSP). Check-point inhibitors (anti-PD1) such as pembrolizumab (Pem) or its combinations (Pem-Rd, Pem-Pd) unleash endogenous myeloma-specific cytotoxic T-cells (MM CTL) to induce cell-mediated myeloma cytotoxicity. Adoptive cell therapy with engineered autologous BCMA-specific CAR-T cells leads cell-mediated cytotoxicity.
Figure 2 An array of salvage regimens for RRMM comprising proteasome inhibitor (PI), immunomodulatory agents (IMiD), anti-CD38 (daratumumab [Dara]) or anti-SLAMF7 (elotuzumab [Elo]) monoclonal antibodies, BCL2 inhibitor (BCL2i), exportin-1 inhibitor (XPO1-i), anti-PD1 check-point inhibitors or CAR-T cells. PI (bortezomib [V], carfilzomib [K] and ixazomib [Ixa]) and dexamethasone [Dex] induces intrinsic/mitochondrial apoptosis (via activation of caspase 9 through formation of the apoptosome) while IMiD (lenalidomide [R] and pomalidomide [P]) extrinsic apoptosis via activation of caspase 8. Low-dose dexamethasone (d) can be combined with either IMiD (Rd or Pd), or PI (Vd or Kd) to yield effective doublets, or both IMiD and PI to generate even more potent triplets including VRd, VPd, KRd, KPd and Ixa-Rd. Monoclonal antibody combinations targeting CD38 (Dara-Vd, Dara-Rd or Dara-Pd) or SLAMF7 (Elo-Rd) are effective salvage regimens. Venetoclax (VEN), or in combination with Vd, induces mitochondrial apoptosis. Selinexor (SEL)is an exportin-1 inhibitor, resulting in nuclear retention of tumor suppressor proteins (TSP). Check-point inhibitors (anti-PD1) such as pembrolizumab (Pem) or its combinations (Pem-Rd, Pem-Pd) unleash endogenous myeloma-specific cytotoxic T-cells (MM CTL) to induce cell-mediated myeloma cytotoxicity. Adoptive cell therapy with engineered autologous BCMA-specific CAR-T cells leads cell-mediated cytotoxicity.CC BY-NC-ND · PubMed Central
Figure 3 Proposed algorithm for the treatment of ‘initial’, ‘intermediate’ or ‘advanced’ myeloma relapses. Those with ‘initial’ relapse may have been treated with bortezomib (V)-based, lenalidomide (R)-based, or VR-based induction regimens. In ‘initial’ relapse, in which patients had prior bortezomib-based induction regimens including VTd, VCd, VMP or VTP, if they are bortezomib-refractory, the first choice of salvage is Dara-Rd (red font), followed by KRd. In resource-restricted countries, doublets such as Rd is feasible (blue font). On the other hand, if patients are only bortezomib-exposed but not resistant, Dara-Rd and Dara-Vd (red font) are the most potent options, followed by other PI-based triplets (KRd, Ixa-Rd or VRd), or less expensive doublet (Kd, Rd) (blue font). Moreover, one may repeat the original regimen if the duration of response is ⩾2 years. In those who relapse from Rd induction, if they are R-refractory, pomalidomide combinations (PCd, VPd, Pd), second-generation PI-combinations (KPd, Kd) or V-based regimens (Dara-Vd, VCd, Vd) are viable options. By contrast, in those R-sensitive relapse, Dara-Rd and Dara-Vd are the most potent options, followed by KRd, Ixa-Rd, VRd, Elo-Rd, pomalidomide combinations (PCd, KPd, VPd), or less expensive regimens such as VCd, Vd or Kd (blue font). For patients who relapse on VRd induction, they are double V- and R-refractory, hence managed as ‘intermediate’ relapse. However, if they relapse 2 years after VRd induction, they remain V- and R-sensitive; hence, both V- and R-containing regimens will remain viable. Therefore, Dara-Rd and Dara-Vd are first choices, followed by KRd, Ixa-Rd, Elo-Rd, in addition to pomalidomide-containing regimens such as KPd, VPd, or to repeat VRd. In the ‘intermediate’ relapse category, who may be double V/R-refractory, pomalidomide, daratumumab and carfilzomib-combinations are the main options in addition to single agent daratumumab. In ‘advanced’ relapse, clinical trials of agents with novel mechanism including exportin-1 inhibitor (selinexor combinations), or BCL2 inhibitor (venetoclax combinations) in addition to immunotherapy (anti-BCMA CAR-T cells, allo-HSCT or anti-PD1 antibodies) have to be considered.
Figure 3 Proposed algorithm for the treatment of ‘initial’, ‘intermediate’ or ‘advanced’ myeloma relapses. Those with ‘initial’ relapse may have been treated with bortezomib (V)-based, lenalidomide (R)-based, or VR-based induction regimens. In ‘initial’ relapse, in which patients had prior bortezomib-based induction regimens including VTd, VCd, VMP or VTP, if they are bortezomib-refractory, the first choice of salvage is Dara-Rd (red font), followed by KRd. In resource-restricted countries, doublets such as Rd is feasible (blue font). On the other hand, if patients are only bortezomib-exposed but not resistant, Dara-Rd and Dara-Vd (red font) are the most potent options, followed by other PI-based triplets (KRd, Ixa-Rd or VRd), or less expensive doublet (Kd, Rd) (blue font). Moreover, one may repeat the original regimen if the duration of response is ⩾2 years. In those who relapse from Rd induction, if they are R-refractory, pomalidomide combinations (PCd, VPd, Pd), second-generation PI-combinations (KPd, Kd) or V-based regimens (Dara-Vd, VCd, Vd) are viable options. By contrast, in those R-sensitive relapse, Dara-Rd and Dara-Vd are the most potent options, followed by KRd, Ixa-Rd, VRd, Elo-Rd, pomalidomide combinations (PCd, KPd, VPd), or less expensive regimens such as VCd, Vd or Kd (blue font). For patients who relapse on VRd induction, they are double V- and R-refractory, hence managed as ‘intermediate’ relapse. However, if they relapse 2 years after VRd induction, they remain V- and R-sensitive; hence, both V- and R-containing regimens will remain viable. Therefore, Dara-Rd and Dara-Vd are first choices, followed by KRd, Ixa-Rd, Elo-Rd, in addition to pomalidomide-containing regimens such as KPd, VPd, or to repeat VRd. In the ‘intermediate’ relapse category, who may be double V/R-refractory, pomalidomide, daratumumab and carfilzomib-combinations are the main options in addition to single agent daratumumab. In ‘advanced’ relapse, clinical trials of agents with novel mechanism including exportin-1 inhibitor (selinexor combinations), or BCL2 inhibitor (venetoclax combinations) in addition to immunotherapy (anti-BCMA CAR-T cells, allo-HSCT or anti-PD1 antibodies) have to be considered.CC BY-NC-ND · PubMed Central

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Cites

Research works printed but not linked: 2

  1. San-Miguel J, Weisel K, Cook G, Leiba M, Suzuki K, Kumar S et alEfficacy by cytogenetic risk status for daratumumab in combination with lenalidomide and dexamethason or bortezomib and dexamethason in replapsed or refractory multiple myeloma EHA 2017. EHA Learning Center: Madrid, 2017 Haematologica 2017; 102 (S2): 1.
  2. Dimopoulos MA, Lonial S, White D, Moreau P, Mateos M-V, Miguel JS et alPhase 3 eloquent-2 study: extended 4-year follow-up of elotuzumab plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone in replapsed/refractory multiple myeloma EHA 2017. EHA Learning Center: Madrid, 2017 Haematologica 2017; 102 (S2): 167.

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Metadata

Authors
Chim, C. S., Kumar, S. K., Orlowski, R. Z., Cook, G., Richardson, P. G., Gertz, M. A., Giralt, S., Mateos, M. V., Leleu, X., & Anderson, K. C.
Affiliations
  • Queen Mary Hospital (CN)
  • Mayo Clinic (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Leeds (GB)
  • Harvard University (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Universidad de Salamanca (ES)
  • Centre Hospitalier Universitaire de Poitiers (FR)
Corresponding author
Chim, C S
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2017-11-16
Volume
32
Issue
2
Pages
252-262
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/leu.2017.329
PMC
PMC5808071
OpenAlex
W2781388087
Cited by
305
References
76
Citations by year
2026: 7 · 2025: 18 · 2024: 19 · 2023: 26 · 2022: 36 · 2021: 68 · 2020: 64 · 2019: 39 · 2018: 27
FWCI
5.61
Type
journal article
Language
en
Update notices
correction (2019-03-06)
Open access
Licence
Locations
  • Leukemia (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • Queen Mary University of London
  • Université de Nantes
  • National Cancer Institute (P30CA008748, P50CA186781)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Oncology › Bone health and treatments
Keywords
relapsed/refractory multiple myeloma, novel agents, monoclonal antibodies, daratumumab, elotuzumab, anti-CD38 monoclonal antibody, isatuximab, SLAMF7, lenalidomide, pomalidomide, carfilzomib, ixazomib, venetoclax, selinexor, pembrolizumab, CAR T-cell therapy, BCMA, salvage autologous stem cell transplantation, progression-free survival, treatment algorithm
MeSH terms
Progression-Free Survival, Antibodies, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Multiple Myeloma, Neoplasm Recurrence, Local, Randomized Controlled Trials as Topic

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