Practice-Changing Daratumumab Combinations for the Treatment of Multiple Myeloma

*Threshold: 1 tumor cell per 10⁵ white cells.

Daratumumab received U.S. Food and Drug Administration (FDA) approval in November 2015 based on single-agent efficacy demonstrated in two phase I/II trials (NCT00574288 and NCT01985126) in patients with relapsed or refractory MM after two or more prior lines of therapy. Here, daratumumab as a single-agent was associated with an overall response rate (ORR) of 31 percent.⁵  Only one year later, in November 2016, daratumumab was granted FDA approval in combination with bortezomib and dexamethasone or with lenalidomide and dexamethasone for patients who progressed through one prior line of therapy. These new approvals were based on the results of phase III randomized, controlled trials by Dr. Antonio Palumbo and colleagues in patients with relapsed, or relapsed/refractory MM comparing daratumumab, bortezomib, and dexamethasone with bortezomib and dexamethasone,⁶  and by Dr. Meletios A. Dimopoulos and colleagues comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone (Table 1).⁷ 

The primary end-point of Dr. Palumbo’s study investigating daratumumab in combination with bortezomib and dexamethasone was progression free survival (PFS). Twelve-month PFS strongly favored the daratumumab group at 60.7 percent versus 26.9 percent in the control group. The ORR was 82.9 percent in the daratumumab group versus 63.2 percent in the control (p<0.001). Depth of response was also greater in the daratumumab group, with 59.2 percent versus 29.2 percent, achieving a very good partial response (VGPR) or better (p=0.001), which contributed to the longer PFS in the daratumumab group.

Similarly, the daratumumab, lenalidomide, and dexamethasone combination was superior to the control arm of lenalidomide and dexamethasone in the study by Dr. Dimopoulos and colleagues. The PFS at 12 months for the daratumumab group was 83.2 percent versus 60.1 percent in the control arm. The ORR was also significantly higher in the daratumumab group, at 92.9 percent versus 76.4 percent (p<0.001). As with the data from Dr. Palumbo and colleagues, depth of response was greater for the daratumumab-containing arm, with 75.8 percent versus 44.2 percent achieving a VGPR or better (p<0.001); the rate of complete response or better was also higher (43.1% vs. 19.2%; p<0.001), as was absence of minimal residual disease (22.4% vs. 4.6%, p<0.001).

In terms of safety and tolerability, the daratumumab combination was generally well-tolerated and safe in both trials.^6,7  The most common significant adverse events were neutropenia, thrombocytopenia, and anemia. Infusion-related reactions were reported in 45.3 percent to 47.7 percent of patients receiving daratumumab and were mostly grade 1 or 2. Almost all reactions occurred during the first infusion.

The improvements in PFS and depth of response seen in these two studies, especially in combination with lenalidomide and dexamethasone, are unprecedented in the relapse setting. We are reaching the point where absence of minimal residual disease is increasingly attainable, even at time of relapsed disease, through combinations with daratumumab. Overall, these findings underscore not only the efficacy of the addition of daratumumab to existing backbone regimens, but also the superiority of using daratumumab in combination rather than as a single-agent therapy. These studies add to the growing array of increasingly effective and well-tolerated options for relapsed disease and set the stage for using daratumumab in the upfront setting as well as maintenance therapy. Additionally, looking ahead, subcutaneous delivery of daratumumab may improve the logistics of daratumumab administration, which typically involves a long, eight- to 10-hour infusion initially. A phase I trial presented at the 2016 ASH Annual Meeting (abstract #1149) evaluated daratumumab infused subcutaneously via pump over 20 to 30 minutes in combination with recombinant human hyaluronidase enzyme to enhance absorption.⁸  This was tolerated well, with serum trough concentrations comparable to daratumumab given intravenously. Additional CD38 monoclonal antibodies under investigation include isatuximab (SAR650984) and MOR202. Isatuximab is being investigated in combination with pomalidomide and dexamethasone in a phase Ib study⁹  (abstract #2123) and with carfilzomib and dexamethasone (abstract #2111).¹⁰  A phase I/IIa study of MOR202 alone and in combination with pomalidomide or lenalidomide (abstract #1152) was also presented at ASH,¹¹  and this antibody has the notable feature of a relatively short infusion time of two hours. We look forward to seeing how anti-CD38 monoclonal therapy will improve patient outcomes in the continuum of care of patients with myeloma.