Just as this latest round of innovation has transformed the therapeutic paradigm, it is anticipated that this next new wave of change will follow and further expand the therapeutic horizon for our patients.— Paul G. Richardson, MD
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The advent of successful monoclonal antibody therapy in the treatment of relapsed/refractory myeloma has dramatically improved the prognosis of patients for whom currently approved novel therapies have failed. In 2015, the approval of the combination of elotuzumab (Empliciti) with lenalidomide (Revlimid) and dexamethasone reflected the significant improvement of progression-free survival seen in patients with relapsed disease in the pivotal phase III Eloquent 2 study.1
The accelerated approval of daratumumab (Darzalex) in the same year for the treatment of relapsed/refractory myeloma in patients whose disease had progressed despite treatment with both proteasome inhibitors and immunomodulatory drugs was based upon clinical studies that demonstrated a favorable safety profile and encouraging efficacy in these heavily pretreated patients, with overall response rates of 29% and 36%.2,3
The premise for the use of daratumumab in this setting was built around the construct that multiple myeloma cells uniformly overexpress CD38, and that as a CD38-targeting human immunoglobulin G (IgG1) kappa monoclonal antibody, this agent would be active in refractory patients. Through binding to a unique CD38 epitope, daratumumab induces targeted cell killing by means of multiple mechanisms (including complement-mediated and antibody-dependent cell-mediated cytotoxic effects, antibody-dependent cellular phagocytosis, apoptosis, and to a lesser extent, inhibition of the enzymatic activity of CD38).
Given that daratumumab may have a role in immune modulation by means of depletion of CD38-positive regulator immune suppressor cells, which leads to a greater clonal expansion of T cells in patients who respond, a phase I/II study of daratumumab, lenalidomide, and dexamethasone in patients with relapsed and refractory multiple myeloma was performed. The study showed that this combination provided therapeutic benefit, no dose-limiting toxic effects, and an 81% rate of overall response, including a 25% rate of stringent complete response.4 In this trial, the rate of progression-free survival at 18 months was 72%, and the rate of overall survival was 90%.4
Clinical Trials Behind FDA Approval
In 2016, two phase III trials showed striking efficacy of daratumumab-based combinations in previously treated patients.5,6 The landmark results of the phase III POLLUX trial—reviewed in this issue of The ASCO Post—are remarkable; in this trial, the combination of daratumumab with the immunomodulatory agent lenalidomide and dexamethasone reduced the risk of disease progression or death by 63% compared with lenalidomide and dexamethasone alone in patients who had received a median of 1 prior therapy (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.27–0.52, P < .001).6 These results were comparable to those seen in the phase III CASTOR trial, where patients who had received a median of 2 prior lines of therapy had a 61% reduction in the risk of disease progression or death (HR = 0.39, 95% CI = 0.28–0.53, P < .001).5
Taken together, these outstanding results led to U.S. Food and Drug Administration (FDA) approval for daratumumab in combination with both lenalidomide and dexamethasone and with bortezomib (Velcade) and dexamethasone for the treatment of patients who have received at least one prior therapy. The approval came 3 months after a supplemental license application was submitted to the FDA in August 2016, with daratumumab receiving breakthrough designation for this indication just a month before.
This reflects real progress toward both combining monoclonal antibody therapies successfully with other backbone novel agents as well as moving the treatment earlier in the management of disease. Especially compelling in both the CASTOR and POLLUX studies were the high rates of minimal residual disease negativity seen in those patients with very good partial responses or better. Moreover, after continued treatment, responses deepened, with a rate of complete response that was twice as high with daratumumab-based therapy compared with lenalidomide and dexamethasone alone in the POLLUX trial and similarly favorable results in the CASTOR trial.5,6
In terms of future directions, current studies are exploring daratumumab in combination with lenalidomide and dexamethasone and in other combinations with bortezomib and lenalidomide in newly diagnosed patients. Results from these trials are eagerly awaited, with the benefit of treatment earlier in the disease likely to be substantial. Further, the role of daratumumab as part of maintenance strategy is an area of active investigation. Other agents targeting CD38 (such as isatuximab) are also under evaluation and show considerable promise, particularly in combination.7,8
Expanding Therapeutic Horizons
The advent of successful monoclonal antibody therapy in the treatment of multiple myeloma has revolutionized the outlook for improving outcome in this otherwise incurable disease. The successful integration of monoclonal antibody therapy for newly diagnosed patients in particular holds great promise and will likely change the treatment paradigm not only among younger patients who may be transplant eligible but also for the older population in whom the intensive strategies are less appropriate. Other immuno-oncologic strategies are also being added, including promising platforms evaluating checkpoint inhibition and vaccines, as well as other modes of cellular therapy, such as chimeric antigen receptor (CAR) T-cell approaches. Just as this latest round of innovation has transformed the therapeutic paradigm, it is anticipated that this next new wave of change will follow and further expand the therapeutic horizon for our patients. ■
Disclosure: Dr. Richardson has served as an advisor to Bristol-Myers Squibb, Genmab, Janssen, and Celgene.
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