Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

Abstract

BACKGROUNDMultiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODSIn part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTSNo maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.

Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

“…The anti-CD38 monoclonal antibody daratumumab has shown a favorable safety profile and encouraging efficacy in patients with refractory multiple myeloma (25)(26)(27), and the anti-CD38 SAR650984 is being examined as a treatment for CD38 ϩ hematological malignancies, including AML (clinicaltrials.gov registration NCT01084252). Here, we have found that treatment of AML cell lines and primary AML apheresis samples with IFN␥ leads to the up-regulation of M1-related markers and of the daratumumab target CD38.…”

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

“…9 Other new promising immune therapies include anti-PD1 agents, vaccines and CAR T-cell approaches in MM and monoclonal Abs against CD38. 8,[53][54][55][56] Abbreviations: Auto-HCT = autogeneic hematopoietic cell transplantation; CIBMTR = Center for International Blood and Marrow Transplant Research; m = months; NRM = non-relapse mortality; NS = not stated; OS = overall survival; RIC = reduced-intensity conditioning; RR = relapse rate; yrs = years.…”

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

“…A phase I trial of elotuzumab in combination with bortezomib induced responses in 48% of patients with relapsed/refractory myeloma . The anti-CD38 daratumumab looks promising in phase I/II trials (Plesner et al, 2014;Moreau et al, 2014;Lokhorst et al, 2015), and three phase III trials of daratumumab plus various chemotherapy regimens are currently recruiting in newly diagnosed and relapsed populations. The antibody-drug conjugates lorvotuzumab mertansine (with lenalidomide/dexamethasone, ORR 59%) (Berdeja et al, 2012) and indatuximab ravanstine (with lenalidomide/dexamethasone, ORR 78%) (Kelly et al, 2014); and the AKT inhibitor afuresertib (with bortezomib/dexamethasone, ORR 49%) (Voorhees et al, 2013) demonstrate activity in phase I trials in relapsed/refractory patients.…”

“…Monoclonal antibodies are not particularly myelosuppressive: elotuzumab has lower neutropenia rates than the control group (Lonial et al, 2015), and although a minority of patients receiving daratumumab developed low cell counts this was not dose-dependent (Lokhorst et al, 2015). Given this low toxicity they are attractive targeted therapies for use in consolidation and maintenance phases, to inhibit residual myeloma clones.…”