Promising investigational agents in advanced clinical development in MM
| Drug class . | Drug name . | Relevant pharmacokinetic/ pharmacodynamic properties . | Mechanisms of effectiveness . | Most advanced phase of development . | Study design . |
|---|---|---|---|---|---|
| PI | Ixazomib (MLN9708) | Orally bioavailable, reversible, boronate-based inhibitor of CT-L proteasome activity | PolyUb protein accumulation | Phase 3 | Ixazomib/Len/Dex vs placebo/Len/Dex in RRMM |
| Caspase-8– and caspase-9–mediated apoptosis | Ixazomib/Len/Dex vs placebo/Len/Dex in transplant-ineligible NDMM | ||||
| p53 and p21 upregulation | |||||
| Terminal UPR induction | |||||
| miR33b upregulation | |||||
| PIM1 downregulation | |||||
| Marizomib (NPI-0052) | Orally bioavailable, irreversible, β-lactone-γ-lactam inhibitor of CT-L, T-L, and C-L proteasome activities | PolyUb protein accumulation | Phase 1 | Marizomib/Pom/Dex in RRMM | |
| Caspase-8– and caspase-9–mediated apoptosis | |||||
| Oprozomib (ONX 0912, PR-047) | Orally biovailable, irreversible epoxyketone inhibitor of CT-L proteasome activity | PolyUb protein accumulation | Phase 1b/2 | Oprozomib/Dex in RRMM | |
| Caspase-8– and caspase-9–mediated apoptosis | Oprozomib in RRMM | ||||
| HDACI | Vorinostat (SAHA) | Small molecule class I/II HDACI | p21 and p53 upregulation | Phase 3 | Vorinostat/Bort vs Bort alone in RRMM |
| Rb dephosphorylation | |||||
| BID cleavage | |||||
| Calpain activation | |||||
| Ricolinostat | Orally bioavailable, small-molecule HDAC6 inhibitor | Caspase-8– and caspase-9–mediated apoptosis | Phase 1/2 | Ricolinostat/Len/Dex in RR MM | |
| Terminal UPR induction | Ricolinostat/Bort/Dex in RRMM | ||||
| PolyUb protein accumulation | Ricolinostat/Pom/Dex in RRMM | ||||
| Aggresome disruption | |||||
| mAbs | Elo | Anti-SLAMF7 humanized mAb | ADCC | Phase 3 | Elo/Len/Dex vs placebo/Len/Dex in NDMM |
| Enhanced NK function | |||||
| Dara | Anti-CD38 human mAb | Cross-linking–mediated cytotoxicity | Phase 3 | Dara/Len/Dex vs placebo/Len/Dex in RRMM | |
| ADCC | Dara/Bort/Dex vs placebo/Bort/Dex in RRMM | ||||
| CDC | |||||
| ADCP | |||||
| Sar | Anti-CD38 humanized IgG1 mAb | Homotypic aggregation–mediated cytotoxicity | Phase 1 | Sar/Len/Dex in RRMM | |
| ADCC | Sar/Pom/Dex in RRMM | ||||
| CDC | |||||
| Indatuximab ravtansine (BT062) | Chimeric, anti-CD138–conjugated maytansinoid DM4 | Maytansinoid DM4 released intracellularly upon CD138-mAb internalization | Phase 1/2 | Indatuximab ravtansine/Len/Dex in RRMM | |
| Tubulin polymerization inhibition leading to cell cycle arrest and apoptosis | |||||
| J6M0-mcMMAF (GSK2857916) | Humanized and afucosylated anti-BCMA–conjugated monomethyl auristatin F | Monomethyl auristatin F released intracellularly upon BCMA-mAb internalization | Phase 1 | Dose escalation of J6M0-mcMMAF in RRMM | |
| Tubulin polymerization inhibition leading to cell cycle arrest and apoptosis | |||||
| Blockade of BAFF- and APRIL-induced NF-κB activation | |||||
| Immune therapies | Pembrolizumab (MK-3475) | Humanized, anti-PD-1 mAb | Increased anti-MM T, NK, and NK-T cell–mediated cytotoxicity | Phase 1/2 | Pembrolizumab + Len post-ASCT |
| Pembrolizumab + Pom/Dex in RRMM | |||||
| Pidilizumab (CT-011) | Humanized, anti-PD-1 mAb | Increased anti-MM T, NK and NK-T-mediated cytotoxicity | Phase 1/2 | Pidilizumab + Len in RRMM | |
| Nivolumab (BMS936558) | Human IgG4 anti-PD-1 mAb | Increased T, NK, and NK-T antitumor cytotoxicity | Phase 1 | Nivolumab ± ipilimumab or lirilumab in R/RMM | |
| PVX-410 | XBP-1–, CD138-, and SLAMF7-derived peptide vaccine targeting HLA2-restricted antigen-presenting cells | Expansion and activation of MM-specific T cells | Phase 1 | PVX-410 alone or in combination with Len in SMM | |
| MM-DC vaccine | Chemically fused autologous MMCs and DCs targeting CD4+ and CD8+ T cells | Anti-MM humoral and cytotoxic response | Phase 2 | MM-DC vaccine alone or in combination with pidilizumab post-ASCT | |
| Anti-BCMA CAR-T cells | Anti-BCMA CAR-T cells | Specific, anti-MM T-cell response | Phase 1 | Anti-BCMA CAR-T cells in RRMM | |
| BM-targeting therapies | TH-302 | Hypoxia-activated DNA alkylator prodrug | Genotoxic damage | Phase 1/2 | TH-302/Bort/Dex in RRMM |
| NOX-A12 | CXCL12 pegylated mirror-image l-oligonucleotide | CXCL12/CXCR4 signaling inhibition | Phase 2a | NOX-A12/Bort/Dex in RRMM | |
| Molecularly targeted therapies | Filanesib (ARRY-520) | KSP inhibitor | Mitotic arrest | Phase 2 | Filanesib alone or in combination with Carf/Dex in RRMM |
| Apoptosis | |||||
| Selinexor (KPT-330) | CRM-1 inhibitor | Cell cycle arrest | Phase 1/2 | Selinexor/Dex | |
| Apoptosis | Selinexor/liposomal Dox/Dex | ||||
| MYC inhibition | Selinexor/Pom/Dex | ||||
| Mcl-1 inhibition | Selinexor/Bort/Dex | ||||
| NF-κB inhibition | Selinexor/Carf/Dex in RRMM | ||||
| GSK2141795 Afuresertib (GSK2110183) | Akt inhibitors | IL-6 pro-MM effect inhibition | Phase 2 | GSK2141795 + trametinib in RRMM | |
| Cell cycle arrest | GSK2110183 in PI-refractory MM | ||||
| UPR induction | |||||
| Apoptosis | |||||
| Dinaciclib (SCH 727965) | Inhibitor of CDK 1, 2, 5 and 9 | Apoptosis | Phase 2 | Dinaciclib in RRMM | |
| Inhibition of nuclear localization of spliced XBP-1 | |||||
| p53 accumulation | |||||
| MCL-1 downregulation | |||||
| GSK525762 CPI-0610 | BET bromodomain small molecule inhibitor | Myc downregulation | Phase 1 | GSK525762 in relapsed and refractory hematologic malignancies | |
| Cell cycle arrest | CPI-0610 in RRMM | ||||
| Cell senescence |
| Drug class . | Drug name . | Relevant pharmacokinetic/ pharmacodynamic properties . | Mechanisms of effectiveness . | Most advanced phase of development . | Study design . |
|---|---|---|---|---|---|
| PI | Ixazomib (MLN9708) | Orally bioavailable, reversible, boronate-based inhibitor of CT-L proteasome activity | PolyUb protein accumulation | Phase 3 | Ixazomib/Len/Dex vs placebo/Len/Dex in RRMM |
| Caspase-8– and caspase-9–mediated apoptosis | Ixazomib/Len/Dex vs placebo/Len/Dex in transplant-ineligible NDMM | ||||
| p53 and p21 upregulation | |||||
| Terminal UPR induction | |||||
| miR33b upregulation | |||||
| PIM1 downregulation | |||||
| Marizomib (NPI-0052) | Orally bioavailable, irreversible, β-lactone-γ-lactam inhibitor of CT-L, T-L, and C-L proteasome activities | PolyUb protein accumulation | Phase 1 | Marizomib/Pom/Dex in RRMM | |
| Caspase-8– and caspase-9–mediated apoptosis | |||||
| Oprozomib (ONX 0912, PR-047) | Orally biovailable, irreversible epoxyketone inhibitor of CT-L proteasome activity | PolyUb protein accumulation | Phase 1b/2 | Oprozomib/Dex in RRMM | |
| Caspase-8– and caspase-9–mediated apoptosis | Oprozomib in RRMM | ||||
| HDACI | Vorinostat (SAHA) | Small molecule class I/II HDACI | p21 and p53 upregulation | Phase 3 | Vorinostat/Bort vs Bort alone in RRMM |
| Rb dephosphorylation | |||||
| BID cleavage | |||||
| Calpain activation | |||||
| Ricolinostat | Orally bioavailable, small-molecule HDAC6 inhibitor | Caspase-8– and caspase-9–mediated apoptosis | Phase 1/2 | Ricolinostat/Len/Dex in RR MM | |
| Terminal UPR induction | Ricolinostat/Bort/Dex in RRMM | ||||
| PolyUb protein accumulation | Ricolinostat/Pom/Dex in RRMM | ||||
| Aggresome disruption | |||||
| mAbs | Elo | Anti-SLAMF7 humanized mAb | ADCC | Phase 3 | Elo/Len/Dex vs placebo/Len/Dex in NDMM |
| Enhanced NK function | |||||
| Dara | Anti-CD38 human mAb | Cross-linking–mediated cytotoxicity | Phase 3 | Dara/Len/Dex vs placebo/Len/Dex in RRMM | |
| ADCC | Dara/Bort/Dex vs placebo/Bort/Dex in RRMM | ||||
| CDC | |||||
| ADCP | |||||
| Sar | Anti-CD38 humanized IgG1 mAb | Homotypic aggregation–mediated cytotoxicity | Phase 1 | Sar/Len/Dex in RRMM | |
| ADCC | Sar/Pom/Dex in RRMM | ||||
| CDC | |||||
| Indatuximab ravtansine (BT062) | Chimeric, anti-CD138–conjugated maytansinoid DM4 | Maytansinoid DM4 released intracellularly upon CD138-mAb internalization | Phase 1/2 | Indatuximab ravtansine/Len/Dex in RRMM | |
| Tubulin polymerization inhibition leading to cell cycle arrest and apoptosis | |||||
| J6M0-mcMMAF (GSK2857916) | Humanized and afucosylated anti-BCMA–conjugated monomethyl auristatin F | Monomethyl auristatin F released intracellularly upon BCMA-mAb internalization | Phase 1 | Dose escalation of J6M0-mcMMAF in RRMM | |
| Tubulin polymerization inhibition leading to cell cycle arrest and apoptosis | |||||
| Blockade of BAFF- and APRIL-induced NF-κB activation | |||||
| Immune therapies | Pembrolizumab (MK-3475) | Humanized, anti-PD-1 mAb | Increased anti-MM T, NK, and NK-T cell–mediated cytotoxicity | Phase 1/2 | Pembrolizumab + Len post-ASCT |
| Pembrolizumab + Pom/Dex in RRMM | |||||
| Pidilizumab (CT-011) | Humanized, anti-PD-1 mAb | Increased anti-MM T, NK and NK-T-mediated cytotoxicity | Phase 1/2 | Pidilizumab + Len in RRMM | |
| Nivolumab (BMS936558) | Human IgG4 anti-PD-1 mAb | Increased T, NK, and NK-T antitumor cytotoxicity | Phase 1 | Nivolumab ± ipilimumab or lirilumab in R/RMM | |
| PVX-410 | XBP-1–, CD138-, and SLAMF7-derived peptide vaccine targeting HLA2-restricted antigen-presenting cells | Expansion and activation of MM-specific T cells | Phase 1 | PVX-410 alone or in combination with Len in SMM | |
| MM-DC vaccine | Chemically fused autologous MMCs and DCs targeting CD4+ and CD8+ T cells | Anti-MM humoral and cytotoxic response | Phase 2 | MM-DC vaccine alone or in combination with pidilizumab post-ASCT | |
| Anti-BCMA CAR-T cells | Anti-BCMA CAR-T cells | Specific, anti-MM T-cell response | Phase 1 | Anti-BCMA CAR-T cells in RRMM | |
| BM-targeting therapies | TH-302 | Hypoxia-activated DNA alkylator prodrug | Genotoxic damage | Phase 1/2 | TH-302/Bort/Dex in RRMM |
| NOX-A12 | CXCL12 pegylated mirror-image l-oligonucleotide | CXCL12/CXCR4 signaling inhibition | Phase 2a | NOX-A12/Bort/Dex in RRMM | |
| Molecularly targeted therapies | Filanesib (ARRY-520) | KSP inhibitor | Mitotic arrest | Phase 2 | Filanesib alone or in combination with Carf/Dex in RRMM |
| Apoptosis | |||||
| Selinexor (KPT-330) | CRM-1 inhibitor | Cell cycle arrest | Phase 1/2 | Selinexor/Dex | |
| Apoptosis | Selinexor/liposomal Dox/Dex | ||||
| MYC inhibition | Selinexor/Pom/Dex | ||||
| Mcl-1 inhibition | Selinexor/Bort/Dex | ||||
| NF-κB inhibition | Selinexor/Carf/Dex in RRMM | ||||
| GSK2141795 Afuresertib (GSK2110183) | Akt inhibitors | IL-6 pro-MM effect inhibition | Phase 2 | GSK2141795 + trametinib in RRMM | |
| Cell cycle arrest | GSK2110183 in PI-refractory MM | ||||
| UPR induction | |||||
| Apoptosis | |||||
| Dinaciclib (SCH 727965) | Inhibitor of CDK 1, 2, 5 and 9 | Apoptosis | Phase 2 | Dinaciclib in RRMM | |
| Inhibition of nuclear localization of spliced XBP-1 | |||||
| p53 accumulation | |||||
| MCL-1 downregulation | |||||
| GSK525762 CPI-0610 | BET bromodomain small molecule inhibitor | Myc downregulation | Phase 1 | GSK525762 in relapsed and refractory hematologic malignancies | |
| Cell cycle arrest | CPI-0610 in RRMM | ||||
| Cell senescence |
The table summarizes the most salient properties of novel agents in advanced clinical development.
ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; Bort, bortezomib; Carf, carfilzomib; CDC, complement-dependent cytotoxicity; C-L, caspaselike; CRM-1, chromosome region maintenance 1; CT-L, chymotrypsin-like; CXCL, chemokine (CXC motif) ligand; Dara, daratumumab; DC, dendritic cell; Dex, dexamethasone; Dox, doxorubicin; Elo, elotuzumab; Ig, immunoglobulin; IL, interleukin; Len, lenalidomide; MCL-1, myeloid leukemia cell 1; miR, microRNA; MMC, MM cell; NDMM, newly diagnosed MM; NF, nuclear factor; NK, natural killer; PD-1, programmed cell death 1; PolyUb, polyubiquitinated; Pom, pomalidomide; RR, relapsed and refractory; R/R, relapsed or refractory; RRMM, relapsed and refractory MM; SAHA, suberoylanilide hydroxamic acid; Sar, SAR650984; SMM, smoldering MM; T-L, trypsinlike; UPR, unfolded protein response; XBP-1, X-box binding protein 1.