Table 1 Novel agents in the treatment of multiple myeloma
From: Novel agents in the treatment of multiple myeloma: a review about the future
Category | Agent | Stage of development | Major trials (All trials in relapsed/refractory pts unless otherwise stated) Major trials (All trials in relapsed/refractory pts unless otherwise stated) | Adverse events (Grade 3/4 only unless otherwise stated) Adverse events (Grade 3/4 only unless otherwise stated) |
|---|---|---|---|---|
AKT inhibitors | Afuresertib | Phase 1 clinical trials | *Afuresertib monotherapy in 34 pts, PR 9 %, MR 9 % [95] | *Nausea (35.6 %), diarrhea (32.9 %), dyspepsia (24.7 %) [95] |
Alkylating agents | Bendamustine | Phase 2 clinical trials | *Bendamustine-lenalidomide-dexamethasone in 29 pts, 1-year OS 93 %, 1-year PFS 20 % [90] *Bendamustine-bortezomib-dexamethasone in 79 pts, OR 60.8 %. PFS 9.7 months, OS 25.6 months [91] *Bendamustine-lenalidomide-dexamethasone in 29 pts, 1-year OS 93 %, 1-year PFS 20 % [90] *Bendamustine-bortezomib-dexamethasone in 79 pts, OR 60.8 %. PFS 9.7 months, OS 25.6 months [91] | *Neutropenia (62 %), thrombocytopenia (38 %), leukopenia (38 %) [90] *Thrombocytopenia (38 %), infections (23 %), polyneuropathy (grade 4) (7 %), polyneuropathy (52 %) [91] *Neutropenia (62 %), thrombocytopenia (38 %), leukopenia (38 %) [90] *Thrombocytopenia (38 %), infections (23 %), polyneuropathy (grade 4) (7 %), polyneuropathy (52 %) [91] |
Bcl-2 inhibitors | ABT 199 | Preclinical studies | N/A | N/A |
BTK inhibitors | Ibrutinib | Phase 1/2 clinical trials | *Ibrutinib single agent or in combination with dexamethasone, trial ongoing [104] | *Trial ongoing [104] |
CDK inhibitors | Dinaciclib | Phase 1/2 clinical trials | *Dinaciclib monotherapy in 27 pts, PR 11 %, CBR 19 % [105] | *Diarrhea (87 %), fatigue (67 %), neutropenia (27 %) [105] |
Histone deacetylase inhibitors | Panobinostat | Phase 3 clinical trials Postmarketing surveillance Phase 3 clinical trials Postmarketing surveillance | *PANORAMA 2: panobinostat-bortezomib-dexamethasone in 55 pts, OR 34.5 %, CBR 52.7 %, PFS 5.4 months [76] *PANORAMA 1: 768 pts randomized to bortezomib-dexamethasone with either panobinostat or placebo. PFS panobinostat group 12 months, PFS placebo group 8.1 months (HR 0.63) [77] *PANORAMA 2: panobinostat-bortezomib-dexamethasone in 55 pts, OR 34.5 %, CBR 52.7 %, PFS 5.4 months [76] *PANORAMA 1: 768 pts randomized to bortezomib-dexamethasone with either panobinostat or placebo. PFS panobinostat group 12 months, PFS placebo group 8.1 months (HR 0.63) [77] | *Thrombocytopenia (64 %), fatigue (20 %), diarrhea (20 %) [76] *Thrombocytopenia (67 vs 31 %), neutropenia (35 vs 11 %), diarrhea (26 vs 8 %) [77] *Thrombocytopenia (64 %), fatigue (20 %), diarrhea (20 %) [76] *Thrombocytopenia (67 vs 31 %), neutropenia (35 vs 11 %), diarrhea (26 vs 8 %) [77] |
Ricolinostat | Preclinical studies | N/A | N/A | |
Vorinostat | Phase 3 clinical trials | *VANTAGE 095: vorinostat-bortezomib in 143 pts (all bortezomib refractory), OR 17 %, CBR 31 % [85] *VANTAGE 088: 637 pts randomized to bortezomib-vorinostat or bortezomib-placebo. PFS vorinostat group 7.63 months, PFS placebo group 6.83 months, p = 0.01 [81] *VANTAGE 095: vorinostat-bortezomib in 143 pts (all bortezomib refractory), OR 17 %, CBR 31 % [85] *VANTAGE 088: 637 pts randomized to bortezomib-vorinostat or bortezomib-placebo. PFS vorinostat group 7.63 months, PFS placebo group 6.83 months, p = 0.01 [81] | *Thrombocytopenia (67 %), anemia (38 %), neutropenia (32 %) [85] *Thrombocytopenia (45 vs 24 %), neutropenia (28 vs 25 %), anemia (17 vs 13 %) [81] *Thrombocytopenia (67 %), anemia (38 %), neutropenia (32 %) [85] *Thrombocytopenia (45 vs 24 %), neutropenia (28 vs 25 %), anemia (17 vs 13 %) [81] | |
IL-6 inhibitors | Siltuximab | Phase 2 clinical trials | *106 pts randomized to bortezomib-melphalan-prednisone with vs without siltuximab. OR 88 vs 80 %, VGPR 71 vs 51 %, (p = 0.0382). Median PFS (17 months) and 1-year OS (88 %) identical across both arms [108] *281 pts randomized to bortezomib with siltuximab vs placebo. PFS 8.0 vs 7.6 months (HR 0.869, p = 0.345). OR 55 VS 47 % (p = 0.213) [107] *106 pts randomized to bortezomib-melphalan-prednisone with vs without siltuximab. OR 88 vs 80 %, VGPR 71 vs 51 %, (p = 0.0382). Median PFS (17 months) and 1-year OS (88 %) identical across both arms [108] *281 pts randomized to bortezomib with siltuximab vs placebo. PFS 8.0 vs 7.6 months (HR 0.869, p = 0.345). OR 55 VS 47 % (p = 0.213) [107] | *Neutropenia (62 vs 43 %), thrombocytopenia (44 vs 25 %), pneumonia (17 vs 17 %) [108] *Neutropenia (49 vs 29 %), thrombocytopenia (48 vs 34 %), all-grade infections (62 vs 49 %) [107] *Neutropenia (62 vs 43 %), thrombocytopenia (44 vs 25 %), pneumonia (17 vs 17 %) [108] *Neutropenia (49 vs 29 %), thrombocytopenia (48 vs 34 %), all-grade infections (62 vs 49 %) [107] |
Immunomodulators | Pomalidomide | Phase 2 clinical trials Postmarketing surveillance Phase 2 clinical trials Postmarketing surveillance | *Pomalidomide and dexamethasone in 60 pts. OR 63 %, PFS 11.6 months [37] *Pomalidomide and dexamethasone in 84 pts. OR 35 %, OS 14.9 months, 18-month OS 44 % [39] *Pomalidomide and dexamethasone in 60 pts. OR 63 %, PFS 11.6 months [37] *Pomalidomide and dexamethasone in 84 pts. OR 35 %, OS 14.9 months, 18-month OS 44 % [39] | *Neutropenia (32 %), anemia (5 %), thromboembolism (2 %) [37] *Neutropenia (62 %), anemia (36 %), infections (23 %) [39] *Neutropenia (32 %), anemia (5 %), thromboembolism (2 %) [37] *Neutropenia (62 %), anemia (36 %), infections (23 %) [39] |
KSP inhibitors | Filanesib | Phase 2 clinical trials | *Filanesib with and without low-dose dexamethasone in 82 pts. OR 16 % in both cohorts. Among pts with high and low serum AAG, OR was 0 % and 24 % respectively across both cohorts [111] | *Thrombocytopenia (44 vs 42 %), anemia (38 vs 50 %), neutropenia (38 vs 38 %) [111] |
Monoclonal antibodies | Daratumumab | Phase 2 clinical trials Postmarketing surveillance | *Daratumumab monotherapy in 106 pts. OR 29.2 %, 1-year OS 65 % [65] | *Anemia (33.0 %), thrombocytopenia (26 %), neutropenia (22.6 %) [65] |
Elotuzumab | Phase 3 clinical trials Postmarketing Surveillance | *ELOQUENT 2: 646 pts randomized to lenalidomide-dexamethasone with and without elotuzumab. OR 79 vs 66 %(p < 0.001). PFS 19.4 vs 14.8 months, HR 0.70 (CI 0.57 to 0.85, p < 0.001) [70] | *Lymphocytopenia (77 vs 49 %), anemia (19 vs 21 %), thrombocytopenia (19 vs 20 %) [70] | |
Indatuximab | Phase 1/2 clinical trials | *Indatuximab-lenalidomide-dexamethasone in 15 pts. OR 78 % [72] | *Hypokalemia, fatigue, diarrhea reported as “most common adverse events” [72] | |
SAR650984 | Phase 1 clinical trials | *SAR650984 monotherapy in 35 pts. ORR 33 %, CR 11 % [73] *SAR650984 and lenalidomide in 31 pts. ORR 64.5 %, CBR 71 % [74] | *Pneumonia 9 % [73] *Fatigue (41.9 %), nausea (38.7 %), upper respiratory tract infection (38.7 %), and diarrhea (35.5 %) [74] | |
PI3K inhibitors | Numerous agents | Preclinical studies | N/A | N/A |
Proteasome inhibitors | Carfilzomib | Phase 3 clinical trials Postmarketing surveillance | *ASPIRE: 792 pts randomized to lenalidomide-dexamethasone with and without carfilzomib. PFS 26.3 vs 17.6 months, HR 0.69, p = 0.0001. OR 87.1 vs 66.7 %, CR 31.8 vs 9.3 % [45] *ENDEAVOR: 929 pts randomized to carfilzomib/dexamethasone vs bortezomib/dexamethasone. PFS 18.7 vs 9.4 months, HR 0.53, CI 0.44 - 0.65, p = 0.0001. Complete results pending [46], [47] | *Hypokalemia (9.4 vs 4.9 %), fatigue (7.7 vs 6.4 %), hypertension (4.3 vs 1.8 %) [45] |
Ixazomib | Phase 3 clinical trials Postmarketing surveillance | *TOURMALINE-MM1:722 pts randomized to lenalidomide and dexamethasone with and without ixazomib. PFS 20.6 vs 14.7 months (p = 0.012), OR 78 % (median duration 21 months) vs 72 % (median duration 15 months) [54] | *“Most common events” included neutropenia, anemia, thrombocytopenia, and pneumonia [54] | |
Marizomib | Phase 1 clinical trials | *Marizomib monotherapy in 15 pts. PR 20 %, CBR 57 % [56] | *Fatigue, gastrointestinal AEs, dizziness, and headache reported as “most common adverse events” [56] | |
Oprozomib | Phase 1 clinical trials | *Oprozomib-dexamethasone in 29 pts. OR 33.3 %, CBR 46.7 % [59] | *Diarrhea (38 %), vomiting (19 %), thrombocytopenia (10 %) [59] |