Daratumumab-based triplet regimen extends PFS in advanced multiple myeloma
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ORLANDO — A novel triple-agent combination of carfilzomib, dexamethasone and daratumumab outperformed carfilzomib plus dexamethasone in terms of PFS and overall response rate among patients with relapsed or refractory multiple myeloma, according to results of the randomized phase 3 CANDOR trial presented during the late-breaking abstract session of ASH Annual Meeting and Exposition.
The three-drug regimen also conferred a higher rate of minimal residual disease (MRD)-negative complete response than carfilzomib and dexamethasone with a similar overall safety profile; however, the triplet therapy appeared associated with higher rates of serious adverse events and five treatment-related deaths.
“We wanted to see if we could improve PFS by adding daratumumab to the current standard of care, carfilzomib plus dexamethasone,” Saad Z. Usmani, MD, FACP, division chief of plasma cell disorders at Levine Cancer Institute at Atrium Health and a HemOnc Today Editorial Board Member, told Healio. “There is a need for novel therapies for patients with multiple myeloma who have relapsed or are refractory to lenalidomide-based treatments.”
Usmani, one of the study’s co-authors, said the key takeaway from the trial is that this new triplet regimen extended PFS in patients with hard-to-treat relapsed or refractory multiple myeloma who previously had been treated with either lenalidomide (Revlimid, Celgene) or bortezomib (Velcade, Takeda), or a combination of the two.
In the multicenter CANDOR trial, researchers randomly assigned 466 patients with relapsed or refractory multiple myeloma (median age, 64 years) to carfilzomib (Kyprolis, Amgen), dexamethasone and daratumumab (Darzalex; Genmab, Janssen Oncology) triplet therapy (n = 312) or carfilzomib and dexamethasone doublet therapy (n = 154). Patients underwent one to three previous therapies, and 33% were refractory to lenalidomide.
All patients received 28-day cycles of 20 mg/m² IV carfilzomib on days 1 and 2 of the first treatment cycle and 56 mg/m² on days 1, 2, 8, 9, 15 and 16 of subsequent cycles, and 40 mg IV or oral dexamethasone on days 1, 8, 15 and 22. Patients in the triplet therapy group also received 16 mg/kg IV daratumumab on days 1, 8, 15 and 22 of the first and second cycle, then every 2 weeks for four cycles and every 4 weeks thereafter.
Treatment continued until progressive disease or unacceptable toxicity.
PFS served as the study’s primary endpoint. Secondary endpoints included ORR and MRD-negative complete response rate at 12 months.
Results showed median PFS was not reached in the triplet-therapy group compared with 15.8 months for the dual-drug group (HR = 0.63; 95% CI, 0.46-0.85).
The triplet-therapy group had a higher ORR (84.3% vs. 74.7%; P = .004), complete response rate (28.5% vs 10.4%) and MRD-negative complete response rate (12.5% vs 1.3%; P < .0001) than the dual-drug group.
“Compared to standard carfilzomib and dexamethasone, patients who received the three-drug regimen had a 37% lower risk for progression or death,” Usmani told Healio. “They had a nearly 10% higher overall response rate and were nearly 10 times more likely to have a complete response to treatment.”
The PFS benefit of the triplet therapy extended to patients previously exposed to lenalidomide (median, not reached vs. 12.1 months; HR = 0.52; 95% CI, 0.34-0.8), as well as those refractory to lenalidomide (median, not reached vs. 11.1 months; HR = 0.45; 95% CI, 0.28-0.74).
At median follow-up of 17 months, neither treatment group reached median OS (HR = 0.75; 95% CI, 0.49-1.13).
The triplet-therapy group demonstrated a higher rate of grade 3 or greater adverse events (82.1% vs. 73.9%) and serious adverse events (56% vs. 46%) than the dual-drug group.
Five treatment-related deaths occurred in the triplet-therapy group, four of which were related to infection and unlikely a frequent emergent adverse event related to the addition of daratumumab, Usmani said during a press briefing at ASH.
Rates of treatment discontinuation due to adverse events appeared similar between the triplet and doublet therapy groups (22% vs. 25%).
“This research has far-reaching implications,” Usmani told Healio. “Multiple myeloma is the second most common blood cancer in the U.S., and the most common in African Americans. The disease is still considered incurable, but new drug combinations are dramatically improving patient outcomes.” – by Drew Amorosi
Reference:
Usmani SZ, et al. Abstract LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Usmani reports consultant roles with and/or grants, personal fees or research funding from AbbVie, Amgen, Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, MundiPharma, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX and Takeda; honoraria from MundiPharma; and speakers bureau roles with Amgen, Celgene, Janssen Pharmaceuticals, Sanofi and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.