Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma

Daratumumab in combination regimens

The enhanced anti-myeloma activity of daratumumab in combination with other agents in preclinical trials provided rationale for investigation of daratumumab in combination regimens.

Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory myeloma is being studied in an ongoing, phase 1/2, open-label, multicenter trial [29]. In part 1, a 3?+?3 design dose-escalation study, daratumumab was administered at doses of 2 to 16 mg/kg in combination with lenalidomide and dexamethasone until disease progression, unacceptable toxicity, or up to a maximum 24 months. Part 2 was a cohort expansion study, in which daratumumab was administered 16 mg/kg with lenalidomide and dexamethasone. Thirteen patients in total were enrolled in part 1, and MTD was not reached. Preliminary efficacy data from 20 patients presented at the 2014 American Society of Hematology (ASH) annual meeting showed marked decrease in M protein in all patients and a very encouraging ORR of 75 % [30]. The last patient was enrolled in the study in August 2014, and updated efficacy analyses including a total of 32 patients enrolled in the part 2 expansion cohort have been presented [29]. The cohort had a median of two prior lines of therapy. The ORR was 88 %, with 11 PRs, 9 VGPRs, 1 CR, and 7 sCRs [29]. The median time to first response was 1 month and median time to best response was 4.5 months, indicative of deepening responses over time [29]. The median duration of follow-up was 7.8 months, and the median DOR was not reached, with 93 % of responders remaining progression-free at time of analysis [29]. In this study, some of the most frequent reported treatment-emergent AEs were neutropenia, muscle spasms, cough, diarrhea, and fatigue. Grade 3 or 4 neutropenia was reported in 75 % of patients. Fifty six percent of patients had mild to moderate IRR, which were most commonly cough, allergic rhinitis, nausea, vomiting, and dyspnea. Of two patients who had grade 3 IRR, one patient discontinued the study due to laryngeal edema.

Daratumumab is also under investigation in combination with other MM backbone regimens in an ongoing, open-label, four-arm, multicenter, phase 1b study [31, 32]. The four arms of the study include daratumumab (at a dose of 16 mg/kg) in combination with the following regimens: bortezomib/dexamethasone (VD), bortezomib/thalidomide/dexamethasone (VTD), bortezomib/melphalan/prednisone (VMP), and pomalidomide/dexamethasone (POM-D). Inclusion criteria for each of the arms are as follows: VD and VTD arm (newly diagnosed MM, irrespective of transplant eligibility); VMP arm (newly diagnosed MM, transplant ineligible); and POM-D arm (relapsed/refractory to two or more lines of therapy including two or more consecutive cycles of lenalidomide and bortezomib) [32]. Preliminary efficacy results in newly diagnosed MM patients treated with daratumumab (DARA) in combination with VD (n?=?6), VTD (n?=?11), and VMP (n?=?8) were reported by Mateos et al., with an ORR of 100 % in each arm (DARA + VD: 3 PRs, 3 VGPRs; DARA + VTD arm: 7 PRs, 2 VGPRs, and 1 CR; DARA + VMP: 4 PRs, 4 VGPRs) [32]. Median duration of follow-up days was 193, 164, and 267 days for DARA + VD, DARA + VTD, and DARA + VMP, respectively [32]. Chari et al. reported an updated efficacy analysis of the DARA + POM-D arm at the 2015 ASH annual meeting [31]. A total of 77 patients were enrolled (enrollment ongoing) at the time of the report in the POM-D arm, with median number of 3.5 prior therapies. Of the cohort, 65 % were refractory to both a PI and IMiD. Of the 77 patients enrolled, 53 were evaluable for efficacy. The ORR was 58.5 %, with 3 sCRs, 1 CR, 12 VGPRs, and 15 PRs [31]. After a median follow-up of 148 days, 4/31 responders progressed [31]. Notably, the combination of daratumumab with POM-D exhibited remarkable efficacy among 40 evaluable double-refractory patients, with a 57.5 % ORR [31]. In the POM-D arm, 61 % of patients experienced IRR, which were most commonly chills, cough, and dyspnea. Otherwise, no significant additional toxicity was noted when DARA was added to POM-D. Some of the most common AEs of any grade were neutropenia, anemia, fatigue, cough, nausea, dyspnea, and diarrhea. Grade 3 or 4 AEs occurring in 10 % of patients were all hematologic toxicities (neutropenia [50.6 %], anemia [20.8 %], leukopenia [15.6 %], and thrombocytopenia [10.4 %]).

The remarkable efficacy of DARA in combination with both lenalidomide/dexamethasone and POM-D in RRMM and in combination with backbone regimens in newly diagnosed MM has provided rationale for initiation of phase III trials. MMY3003 (POLLUX) and MMY3004 (CASTOR) are currently ongoing randomized, open-label, multicenter, phase III trials for patients with relapsed or refractory MM, in which MMY3003 will compare the efficacy of daratumumab in combination with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone alone, and MMY3004 will compare the efficacy of daratumumab in combination with bortezomib and dexamethasone vs. bortezomib and dexamethasone alone [33]. An interim analysis of the phase III CASTOR (MMY3004) trial presented at the 2016 American Society of Clinical Oncology annual meeting showed that daratumumab significantly improved ORR, PFS, and time to progression (TTP) in combination with bortezomib and dexamethasone [34]. A total of 498 patients with relapsed or refractory myeloma were randomized to receive daratumumab in combination with bortezomib and dexamethasone or bortezomib and dexamethasone alone. The ORR was 83 % in patients who received daratumumab, bortezomib, and dexamethasone compared to 63 % in patients who received bortezomib and dexamethasone alone (p??0.0001) [34]. With a median follow-up of 7.4 months, median PFS and TTP in the daratumumab arm was not reached, whereas the median PFS and TTP in the bortezomib and dexamethasone arm was 7.16 and 7.29 months, respectively [34]. The combination of daratumumab, bortezomib, and dexamethasone significantly improved both PFS (HR 0.39; 95 % CI, 0.28–0.53; p??0.0001) and TTP (HR 0.30; 95 % CI, 0.21–0.43; p??0.001) compared to bortezomib and dexamethasone alone [34]. IRR occurred in 45 % of patients, and the most common grade 3/4 AEs were hematologic toxicities, with higher rates of thrombocytopenia (45 vs. 33 %) and neutropenia (13 vs. 4 %) occurring in the daratumumab arm.

The efficacy of daratumumab in newly diagnosed MM is also to be studied in a randomized, open-label, multicenter, phase III trial (Alcyone) that will compare VMP (bortezomib, melphalan, prednisone) vs. DARA + VMP in patients with newly diagnosed, previously untreated MM who are ineligible for high-dose therapy with stem-cell transplantation [35]. In another randomized, phase III trial (Cassiopeia), newly diagnosed transplant-eligible patients will be treated with VTD with or without daratumumab as induction therapy prior to transplant followed by VTD with or without daratumumab as consolidation therapy and then re-randomized to daratumumab maintenance therapy vs. observation. The ongoing clinical trials of daratumumab are listed in Table 2.