January-February 2017, Volume 14, Issue 1
Practice-Changing Daratumumab Combinations for the Treatment of Multiple Myeloma
Published on: January 01, 2017
Daratumumab, a human IgG1κ monoclonal antibody that targets CD38, has emerged as an effective therapy in multiple myeloma (MM) that is changing the landscape of how we treat the disease. CD38 is a type II transmembrane glycoprotein that is highly expressed on MM cells and expressed in low levels on lymphoid and myeloid cells. In preclinical models, daratumumab was shown to elicit cell death through multiple mechanisms including: 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 increase in T-helper cells, cytotoxic T-cells, T-cell functional response, and T-cell receptor clonality.1-4
Table 1. Phase III Trials of Daratumumab
|Reference||Name of Trial||Arm||N||Progression-Free|
|Hazard Ratio||Overall Response Rate||≥ Very Good|
|≥ Complete Response||Minimal Residual|
|Palumbo et al6||CASTOR||Vd-dara||251||NE||0.39||82.9%||59.2%||19.2%|
|Dimopoulos et al7||POLLUX||Rd-dara||286||NE||0.37||93%||76%||43%||22.4%|
Abbreviations: dara, daratumumab; Rd, lenalidomide and dexamethasone; Vd, bortezomib and dexamethasone.
*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.
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 hematological tumors. J Immunol. 2011;186:1840-1848.
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.
Lammerts van Bueren J, 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.
Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phogosytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-321.
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.
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
Usmani SZ, Nahi H, Mateos M-V, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). Blood. 2016;128:1149.
Richardson PG, Mikhael J, Usmani SZ, et al. Preliminary results from a phase 1b study of isatuximab in combination with pomalidomide and dexamethasone in relapsed and refractory multiple myeloma. Blood. 2016;128:2123.
Martin III TG, Mannis GN, Chari A, et al. Phase Ib study of isatuximab and carfilzomib in relapse and refractory multiple myeloma. Blood. 2016;128:2111.
Raab MS, Chatterjee M, Goldschmidt H, et al. A phase I/IIa study of the CD38 antibody MOR202 alone and in combination with pomalidomide or lenalidomide in patients with relapsed or refractory multiple myeloma. Blood. 2016;128:1152.
Conflict of Interests
Dr. O'Donnell, Dr. Yee, and Dr. Raje indicated no relevant conflicts of interest.
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