Daratumumab (Darzalex), when added to the standard two-drug regimen of bortezomib and dexamethasone, reduced the risk of progression or death by 61% compared with the standard regimen alone for patients with recurrent or refractory multiple myeloma.
Antonio Palumbo, MD
Daratumumab (Darzalex), when added to the standard two-drug regimen of bortezomib and dexamethasone, reduced the risk of progression or death by 61%,and doubled response rates compared with the standard regimen alone for patients with recurrent or refractory multiple myeloma,according to initial findings from the phase III CASTOR trial presented at the 2016 ASCO Annual Meeting.
Median progression-free survival (PFS) was 7.2 months in the standard treatment arm and was not yet reached in the daratumumab arm (HR, 0.39; 95% CI, 0.28-0.53;P<.0001). Lead investigator, Antonio Palumbo, MD, hoped these findings would be practice changing.
“The hazard ratio of 0.39 is unprecedented in randomized studies that compare normal treatment of relapsed/refractory multiple myeloma,” Palumbo, chief, myeloma unit, Department of Oncology, University of Torino, Torino, Italy. “We hope that it may be considered today a new standard of care for relapsed and refractory multiple myeloma.”
The study included 498 patients were who were randomized 1:1 to receive 8 cycles of bortezomib/dexamethasone with or without 16 mg/kg of daratumumab. Bortezomib was administered subcutaneously at 1.3 mg/m2on days 1, 4, 8, and 11 of each 21-day cycle for a maximum of 8 cycles. Patients received 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles. Patients in the daratumumab group were administered an IV infusion of the antibody at 16 mg/kg weekly for the first 3 cycles, on day 1 of cycles 4 to 9, and then every 4 weeks. Treatment was administered until disease progression or unacceptable toxicity.
Patients in the trial had received a median of 2 prior lines of therapy (range, 1 10) and 66% had received prior bortezomib, 76% has received prior immunomodulatory drugs (IMiDs), and 48% had received prior proteasome inhibitors and IMiDs. Thirty-three percent were IMiD-refractory and 32% were refractory to last line of prior therapy.
The primary endpoint was progression-free survival (PFS) and secondary endpoints include time-to-progression (TTP), overall response rate (ORR), overall survival (OS), and safety.
The overall response rates were 83% and 63% (P<.0001) in the experimental and control arms, respectively. Nineteen percent of patients in the daratumumab arm had a complete response (CR) or better and 59% of patients had very good partial response (VGPR) or better compared with 9% of patients experiencing a CR and 29% experiencing a VGPR in the control arm (P= .0012, P<.0001, respectively).
“There is a doubling in the rate of CR and VGPR. This is quite relevant because more patients do achieve a profound cytoreduction,” said Palumbo.
The most common treatment-emergent adverse events were thrombocytopenia, which occurred in 59% of patients in the daratumumab arm versus 44% in the bortezomib/dexamethasone arm; sensory peripheral neuropathy, which occurred in 47% and 38% of patients in the experimental and control arms, respectively; diarrhea, which occurred in 32% and 22% of patients in each arm respectively, and anemia, which occurred in 26% and 31% of patients in each arm, respectively.
The higher proportion of thrombocytopenia and peripheral neuropathy in the daratumumab arm was most likely due to the the fact that patients in that arm were exposed to bortezomib longer in comparison with the control arm, which had a higher proportion of early progressions, said Palumbo.
Seven percent of patients in the daratumumab arm discontinued treatment due to adverse events versus 9% of patients receiving bortezomib/dexamethasone alone. Infusion-related reactions (IRRs) were experienced by 45% of patients in the study overall. Nine percent were grade 3, there were no grade 4 IRRs, and 98% occurred during the first infusion.
The safety data from this study was encouraging, said Palumbo.
“Toxicities were consistent with the single agent, but more importantly there were no cumulative toxicities,” he said. “Daratumumab did not significantly increase any toxicities that were already present in the combination of bortezomib and dexamethasone.”
In November 2015, daratumumab was granted an accelerated approval by the FDA as a monotherapy for patients with multiple myeloma who had undergone 3 or more prior therapies based on data from 2 open-label clinical trials. The CASTOR study served as one of the confirmatory trials required for full approval. Daratumumab is the first CD38targeting monoclonal antibody approved for multiple myeloma.
Janssen, which is developing daratumumab in collaboration with Genmab, announced in March that the CASTOR study would be stopped early after meeting its primary endpoint for PFS. Patients in the control arm can now cross over to receive daratumumab. Janssen plans to communicate with the FDA about the potential to file for regulatory approval for a new indication for daratumumab based on the CASTOR trial data.
Longer patient follow-up is planned to determine the impact of the daratumumab combination on patient survival. A clinical trial that combines daratumumab with another standard therapy for recurrent multiple myeloma is underway.
Although the CASTOR study looked solely at patients with relapsed/refractory disease, there is potential for the daratumumab/bortezomib/dexamethasone combination to be used in an earlier setting eventually, said Palumbo. There are additional trials investigating various daratumumab-based regimens for patients with newly diagnosed multiple myeloma.
“This study will open the opportunity to have the combination approach after diagnosis at first relapse,” Palumbo said. “To some extent we do need evidence before entering a new combination into the treatment arena, but on the other hand at diagnosis today in myeloma the remission duration is 5 years. If you double that you go to 10 years. Today, you have around a 1-year remission at first relapse, if you double that, you go to two years. So it is very important to move as fast as we can to get this combination into the early phases of disease where it gives a major advantage.”
Palumbo A, Chanan-Khan A, Weisel K et. al. Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. Presented at: ASCO 2016; June 3-7, 2016; Chicago abstract: LBA4. -