An Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Backbone Regimens in Patients with Multiple Myeloma

Multiple myeloma (MM) remains an incurable disease due to complex molecular abnormalities, lower sensitivity to chemotherapy of MM cells in the bone marrow microenvironment, and the emergence of drug resistance.

Daratumumab (DARA) is a human IgG1κ MAb in clinical development for the treatment of MM. DARA binds to CD38 and elicits signaling cascade and immune effector function engagement leading to multiple direct and indirect mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, and induction of apoptosis. DARA binding to CD38 also modulates vital cellular enzymatic activities associated with calcium mobilization and signaling, independent of its other activities. All of these activities, in concert, lead to elimination of plasma cells from bone marrow in MM patients.

DARA has shown single agent efficacy and a manageable safety profile in patients relapsed or refractory (RR) to 2 prior lines of therapy including immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) (Lokhorst HM, et al. J Clin Oncol 2014;32 Suppl 1: 8513). DARA in combination with lenalidomide (LEN) and dexamethasone (D) has also shown encouraging early efficacy and tolerability in relapsed or RR MM (Plesner T, et al. J Clin Oncol2014;32 Suppl 1: 8533).

The aim of this ongoing open-label, 4-arm, multicenter, phase 1b study was to evaluate the safety, tolerability and dose regimen of DARA in combination with other MM backbone treatments including bortezomib-dexamethasone (VD), bortezomib- thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Newly diagnosed patients were included in the VD, VTD arms irrespective of transplant eligibility. Patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were RR to ≥2 lines of therapy including 2 consecutive cycles of LEN and V.

Initially six patients in each arm were treated with DARA 16 mg/kg and the approved label or standard of care of each backbone treatment as follows. In the VD and VTD arms treatment was for 18 three-week cycles or until transplantation (DARA qw, 2 cycles; q3w, 16 cycles). In the VMP arm treatment was for 9 six-week cycles (DARA qw, 1 cycle; q3w, 8 cycles) and in the POM-D arm four-week cycles until disease progression (DARA qw, 2 cycles; q2w, 4 cycles; q4w remaining cycles).

An independent data safety monitoring board will evaluate dose limiting toxicities (DLT) at the end of Cycles 1, 2 and 3. Combinations are considered safe and well-tolerated if a DLT is observed in ≤1 of the initial 6 patients treated with DARA 16 mg/kg for a given combination regimen and a further 6 patients will be enrolled in the VMP, VTD and POM-D cohorts. If ≥2 DLTs are observed the DARA dose is reduced for the remaining treatment cycles and additional patients may be enrolled at the reduced dose.

Data from 17 subjects treated in the newly diagnosed cohorts (VD [n=5], VTD [n=6], and VMP [n=6]) are described with a median duration of treatment of 44 days (range 1 to 113 days). All subjects were treated with DARA 16 mg/kg. The median duration of treatment was 44 days (range 1 to 113 days). There was no additional toxicity when DARA was added to bortezomib-containing backbone therapy, other than infusion related reactions (IRR) specific to DARA. There were 4/17 subjects with IRRs and all events occurred on Cycle 1 Day 1, were grade 1 in severity, and resolved with supportive treatment allowing the subject to continue DARA treatment. All other AEs were consistent with those associated with the backbone agents. The most common AEs were hematologic toxicity, likely related to the backbone therapy (bortezomib, melphalan and/or thalidomide). There were three episodes of grade ≥3 neutropenia and one episode of grade 3 anemia. There were no grade ≥3 non-hematologic AEs. The most common (3 or more occurrences) grade 1 and 2 AEs included: peripheral sensory neuropathy, headache, asthenia, pyrexia, and constipation. Two episodes of rash were noted. One episode of bronchospasm, noted in a subject with a history of COPD, was classified as an IRR (VMP arm).

In summary, the addition of DARA was well tolerated in all evaluable patients and did not result in significant additional toxicity. Patient enrollment and assessments of safety and efficacy are ongoing.