November-December 2016, Volume 13, Issue 6
Combining Daratumumab With Backbone Antimyeloma Agents
Published on: October 28, 2016
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
Monoclonal antibodies designed to target cell surface proteins have emerged across all cancers as a potential strategy for targeted cancer therapy. Daratumumab is a human IgG1κ monoclonal antibody that targets CD38. CD38 is a type II transmembrane glycoprotein that is expressed in low levels on lymphoid and myeloid cells and is highly expressed on multiple myeloma (MM) cells, making it an attractive therapeutic target in this disease. In preclinical models, daratumumab was shown to elicit cell death through multiple mechanisms: antibody-dependent cell-mediated cytotoxicity; complement-dependent cytotoxicity; antibody-dependent cellular phagocytosis; inhibition of the enzymatic activity of CD38; and depletion of CD38+ immunosuppressive regulatory T and B cells and myeloid-derived suppressor cells, which is associated with an increase in T-helper cells, cytoxic T-cells, T-cell functional response, and T-cell receptor clonality.1-4 Daratumumab received 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 relapsed and refractory MM (RRMM) resistant to two or more prior lines of therapy. The approval was for use as a single agent, but current research is focused on identifying effective combinations of daratumumab with other potent MM drugs both in the relapsed or refractory (RR) setting and in the upfront setting.
In their article, Dr. Antonio Palumbo and colleagues report the interim results of the phase III randomized, controlled trial comparing daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone alone in patients with RRMM. Eligible patients had to have documented progressive disease after having received at least one prior line of therapy for MM. Patients were randomized in a 1:1 ratio to either bortezomib (1.3 mg/m2) and dexamethasone (20 mg) alone, or in combination with daratumumab (16 mg/kg). A total of 498 patients were enrolled. The median number of prior lines of therapy was two (range, 1-10), and median time from diagnosis was 3.8 years. Across the two groups, 61.2 percent of patients had undergone autologous stem cell transplantation, and 65.5 percent had received prior bortezomib.
The primary endpoint of this study 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. Prior investigation of daratumumab as a single agent was associated with an overall response rate (ORR) of 31 percent.5 This improvement in PFS underscores not only the efficacy of the addition of daratumumab to bortezomib and dexamethasone but also the superiority of daratumumab in combination with other therapies versus monotherapy. The ORR was 82.9 percent in the daratumumab group versus 63.2 percent in the control group (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 or better (p=0.001), which contributed to the longer PFS in the daratumumab group.
In terms of safety and tolerability, the daratumumab combination was generally well tolerated and safe. The most common significant adverse events in the daratumumab versus control groups were neutropenia (45.3% vs. 32.9%, respectively) and thrombocytopenia (12.8% vs. 4.2%, respectively). The rates of grade 3 or 4 infections were similar in the two groups (4.5% vs. 6.8%, respectively). Infusion-related reactions were reported in 45.3 percent of patients receiving daratumumab and were mostly grade 1 or 2 (grade 3 in 8.6%). Almost all reactions (98.2%) occurred during the first infusion.
This study, along with the recently presented POLLUX study (NCT02076009) comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone alone, has led the U.S. Food and Drug Administration to grant daratumumab Breakthrough Therapy Designation in combination with bortezomib or lenalidomide and dexamethasone for the treatment of patients with MM who have received one prior line of therapy. The efficacy and tolerability of daratumumab were demonstrated in the trial and provide a strong foundation for further work to incorporate monoclonal antibodies in the upfront and RR setting to improve outcomes in MM and ultimately move toward a cure for this disease.
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other haematological tumors. J Immunol. 2011;186:1840-1848.
Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-321.
van Bueren JL, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124:3474.
Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-394.
Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128:37-44.
Conflict of Interests
Dr. O'Donnell and Dr. Raje indicated no relevant conflicts of interest.
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