Background
Pathophysiology
Classifications
Prognostic factors
Established treatments
Novel agents
Immunomodulators
Pomalidomide
Proteasome inhibitors
Carfilzomib
Ixazomib
Marizomib
Oprozomib
Monoclonal antibodies
Daratumumab
Elotuzumab
Indatuximab
SAR (SAR650984)
Histone deacetylase inhibitors
Panobinostat
Ricolinostat
Vorinostat
Alkylating agents
Bendamustine
AKT inhibitors
Afuresertib (PKB115125)
Bcl-2 inhibitors
ABT 199
BTK inhibitors
Ibrutinib
CDK inhibitors
Dinaciclib
IL-6 inhibitors
Siltuximab
Kinesin spindle protein inhibitors
Filanesib (ARRY-520)
PI3K inhibitors
The role of novel agents in emerging treatment paradigms
Conclusions
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] | *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] |