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

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.

Figure 1

Oligoclonal reconstitution (OCR) illustrated by the change of monoclonal IgA_L at diagnosis (Dx) to OCR of IgGk+IgG_L+IgMk during complete remission.

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 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.