The addition of daratumumab to bortezomib and dexamethasone (DVD) improved outcomes in patients with relapsed or refractory multiple myeloma (RRMM), including a 61% reduction of risk of disease progression or death. The treatment doubled the rates of very good partial response (VGPR) and complete response (CR) compared with bortezomib and dexamethasone (VD) only, and it was not associated with any cumulative toxicities (LBA4).
Dr. Antonio Palumbo
Daratumumab is a fully human anti-CD38 IgGk monoclonal antibody. “This is relevant,” Dr. Palumbo said, “because CD38 is the most important tumor antigen on myeloma plasma cells.” This immunomodulatory drug (IMiD) has both direct and indirect antimyeloma activity, he said. It depletes CD38+ immunosuppressive regulatory cells and promotes T-cell expansion and activation, as well as causing a major reduction in tumor load by directly killing myeloma cells.
Dr. Palumbo presented a prespecified interim analysis of the multicenter, randomized, open-label, active-controlled phase III CASTOR study, which randomly assigned patients with RRMM with at least one prior line of therapy to one of two regimens: patients who received VD were administered eight cycles of 1.3 mg/m2 bortezomib subcutaneously and eight cycles of 20 mg of oral dexamethasone; patients who received DVD were, in addition to VD, administered 16 mg/kg of daratumumab intravenously every week during cycles one to three, every 3 weeks during cycles four to eight, and then every 4 weeks until disease progression.
The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), VGPR or better, CR, minimal residual disease, and other measures.
Baseline characteristics were well-balanced between the treatment arms. Patients had received a median of two previous lines of treatment (range, 1 to 10), which included bortezomib (DVD, 62%; VD, 60%) and IMiDs (DVD, 71%; VD, 80%). Thirty percent of patients who received DVD and 34% who received VD were refractory to their last line of previous therapy.
Accrual in the study was rapid, Dr. Palumbo said, with 498 patients enrolled in 1 year, ending in September 2015. Approximately 4 months later, a difference in efficacy was noted, and the trial was halted. “So the median follow-up is short for this reason,” he said.
With a median follow-up of 7.4 months, the 1-year PFS was 60.7% in the DVD arm compared with 26.9% in the VD arm, which translated into a 61% reduction in the risk of disease progression or death (HR 0.39, 95% [CI 0.28, 0.53]; p < 0.0001). Median PFS was not reached in the DVD arm and was 7.2 months in the VD arm. There was a 70% reduction in the risk of disease progression for DVD compared with VD; 1-year TTP was 65.4% in the DVD arm compared with the 28.8% in the VD arm (HR 0.30, 95% CI [0.21, 0.43]; p < 0.0001).
Dr. Paul G. Richardson
The most common treatment-emergent adverse events (TEAEs) were thrombocytopenia (DVD, 59%; VD 44%), sensory peripheral neuropathy (DVD, 47%; VD, 38%), diarrhea (DVD, 32%; VD, 22%), anemia (DVD, 26%; VD, 31%), upper respiratory tract infection (DVD, 25%; VD, 18%), and cough (DVD 24%; VD, 13%). Seven percent of patients who received DVD and 9% of patients who received VD discontinued therapy because of a TEAE. Infusion-related reactions occurred in 45% of patients who received daratumumab, most of which (98%) occurred during the first infusion. No grade 4 or 5 infusion reactions were observed.
Discussant Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, called this an “outstanding” and potentially practice-changing study. He pointed to other recent studies in RRMM that have also reported promising results, and he said another “raft of next generation molecules” are in development, “which we believe will further transform outcomes for our patients.”
Deborah Schrag, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, discussed value considerations of the study using the Value Framework developed by ASCO. The ASCO Value Framework uses a scoring algorithm based on clinical benefit, durable benefit, and other parameters.
“The individual value of this novel product, which has achieved a major benefit in terms of PFS that is almost certainly likely to translate into an OS benefit, will also be very high,” she said. However, the added cost of more than $10,000 per month for the drug could result in financial strain for individuals. Health systems would feel the burden of the price along with the relatively high incidence of the disease (approximately 125,000 cases globally per year), she said. High-income countries will seek to adopt the treatment or negotiate a discount for the drug cost, and middle-income countries will find the cost prohibitive, she said.
–Tim Donald, ELS