Three drug combo slows progression of multiple myeloma
An interim analysis from the multinational phase III CASTOR trial, presented recently at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that adding daratumumab to the standard two-drug regimen of bortezomib and dexamethasone (Vd) markedly improved outcomes of patients with recurrent or refractory multiple myeloma (RRMM). [ASCO 2016, abstract LBA4]
“Daratumumab is a human CD38 selective monoclonal antibody with direct and indirect anti-myeloma activity that has been approved in the US and Europe for RRMM. It depletes CD38+ immunosuppressive regulatory cells and promotes expansion of cytotoxic and helper T cells,” said lead author Dr. Antonio Palumbo from the University of Torino, in Torino, Italy. “We’ve suspected for a long time that CD38 is the major treatment target for multiple myeloma, but these results are unprecedented in this cancer.”
CASTOR was a multicentre open-label trial that randomized RRMM patients who had received one or more prior lines of therapy to receive daratumumab plus bortezomib and dexamethasone (DVd; n=251) or Vd (n=247) for 8 cycles, followed by daratumumab maintenance in the DVd arm. Baseline demographics and disease characteristics were well balanced between study arms. The primary endpoint was progression-free survival (PFS), with secondary endpoints for response rates, overall survival (OS), time to response and duration of response.
“At a median follow-up of 7.4 months, daratumumab significantly improved PFS, with an unprecedented 61 percent reduction in the risk of progression [p<0.0001]. Median PFS was 7.2 months in the standard treatment arm and not yet reached in the experimental arm,” reported Palumbo. “The estimated 1-year PFS was doubled from 26.9 percent with the standard regimen to 60.7 percent with the addition of daratumumab.”
The PFS benefits of daratumumab were consistent in all patient subgroups regardless of age, disease stage, prior stem cell transplantation or type of prior therapy. "According to the subgroup analysis, patients who had had only one prior line of therapy benefited the most, suggesting that early intervention can maximize the benefit of DVd," Palumbo emphasized.
Response rates were also significantly improved with daratumumab, including overall response (83 vs 63 percent with Vd, p<0.0001), very good partial response (59 vs 29 percent, p<0.0001) and complete response (19 vs 9 percent, p=0.0012). Time to response was relatively shorter in the DVd arm than in the Vd arm, with about 80 percent of the patients on daratumumab achieving partial response at 1 month.
”Importantly, adding daratumumab does not substantially increase toxicity. The rates of common adverse events such as thrombocytopenia, anaemia, and neutropenia, were only slightly higher in the daratumumab arm,” remarked Palumbo. “Given the encouraging results, this three drug regimen with daratumumab can potentially be considered a new standard of care for RRMM patients.”
A longer follow-up of CASTOR will help to determine the impact of adding daratumumab on patient OS. Ongoing trials are also evaluating daratumumab in combination with another standard therapy for RRMM and testing various daratumumab-based regimens in newly diagnosed multiple myeloma.