Adding daratumumab to a combination of carfilzomib and dexamethasone (KdD) led to a 37% improvement in progression-free survival (PFS), compared with carfilzomib and dexamethasone alone (Kd), in patients with relapsed/refractory multiple myeloma (MM), according to results from the phase III CANDOR trial, which were presented as a late-breaking abstract at the 2019 ASH Annual Meeting. However, as lead investigator Saad Z. Usmani, MD, from the Levine Cancer Institute in Charlotte, North Carolina, noted, there was a higher incidence of fatal adverse events (AEs) with the three-drug combination.
Dr. Usmani also highlighted the survival improvement in participants who had previously received lenalidomide. Lenalidomide and bortezomib improve survival outcomes in patients with newly diagnosed myeloma, but many patients discontinue these therapies or progress while on them, so the researchers identified a need for more options for this group of patients. “This subgroup especially benefited from treatment with KdD,” he told ASH Clinical News.
The phase III CANDOR trial patients with relapsed/refractory MM who had received one to three prior lines of therapy, with a partial response (PR) or better to at least one line of therapy. The 466 participants (median age = 64 years; range not provided) were randomized 2:1 to receive either:
- Kd: carfilzomib 20/56 mg/m2 on days 1, 2, 8, 9, 15, and 16 and dexamethasone 40 mg on days 1, 8, 15, and 22 (n=154)
- KdD: Kd regimen plus daratumumab 16 mg/kg on days 1, 8, 15, and 22 of cycle 1-2, then every 2 weeks in cycles 3-6, and every 4 weeks thereafter (n=312)
(Patients older than 75 years received dexamethasone 20 mg each week instead of 40 mg.)
Across the entire population, 90.3% of patients had received a bortezomib-containing regimen and 42.3% had received a lenalidomide-containing regimen. One-third of patients had lenalidomide-refractory disease.
At a median follow-up of 16.9 weeks in the KdD arm and 16.3 weeks in the Kd arm, the median PFS (primary endpoint) was not reached in the KdD group versus 15.8 months for the Kd group (hazard ratio [HR] = 0.63; 95% CI 0.46-0.85; p=0.0014).
The PFS benefit also was observed in prespecified subgroups, including in lenalidomide-exposed patients (i.e., those who had received lenalidomide but were not receiving it as maintenance at the time of relapse) and those with lenalidomide-refractory MM. In the lenalidomide-exposed group, median PFS was not reached in the KdD group versus 12.1 months in the Kd group, translating to a 48% reduction in the risk of disease progression or death (HR=0.52; 95% CI 0.34-0.80). In the lenalidomide-refractory group, median PFS was not reached versus 11.1 months (HR=0.45; 95% CI 0.28-0.74; p values not provided).
Patients who received the three-drug combination also experienced a higher overall response rate (84.3% vs. 74.7% for KdD and Kd, respectively; p=0.004), including a higher complete response rate (28.5% vs. 10.4%). In addition, KdD was associated with deep responses: the rate of minimal residual disease negativity at 12 months was 12.5% versus 1.3% (p<0.0001).
“As expected, we did see a higher incidence of infections and overall adverse events with the three-drug combination, compared with the two-drug combination,” Dr. Usmani said, “but what was interesting is that there were lower incidences of cardiac events in the three-drug [arm].”
The overall safety profile was consistent with the individual agents, the investigators reported. Serious AEs were reported in 56.2% of patients in the KdD group and 45.8% in the Kd group, with a higher incidence of grade ≥3 AEs (82.1% and 73.9%). However, Dr. Usmani noted that the rates of treatment discontinuation due to AEs were similar (22.4% with KdD and 24.8% with Kd). The most common AEs included thrombocythemia, anemia, diarrhea, and hypertension.
He also pointed out the lower rates of grade ≥3 cardiac failure observed in the KdD group (3.9%), compared with the Kd group (8.5%). “This is notable because we do see frequent occurrences of cardiac events with carfilzomib,” he said. “There appears to be some kind of a cardioprotective effect [with daratumumab], so we are looking at [participants’] clinical characteristics from that standpoint.”
During the study, five treatment-related deaths occurred, all in the KdD arm. “Four of the five deaths were infection-related, so we are also looking into that specific data to tease out whether we can create an algorithm to identify patients at risk for infection and give them prophylactic measures if needed,” Dr. Usmani said. Still, these fatal AEs did not translate to a significant difference in overall survival (HR = 0.75; 95% CI 0.49-1.13; p=0.08).
Dr. Usmani concluded that KdD showed a favorable benefit-risk profile overall, but told ASH Clinical News that, given the infection-related deaths, he “would be careful with [using KdD] in older, frail patients, or those who are at risk for recurrent infections.”
Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Abstract #LBA-6. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.