‘Unprecedented’ efficacy for daratumumab in rel/ref MM
CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.
Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).
Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.
It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.
Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.
Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.
Study design
The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.
Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.
Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).
The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.
The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.
Patient demographics
Overall, patients had advanced stage disease with a long history of prior treatment.
They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.
About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.
Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.
“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”
The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.
Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”
Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”
