Daratumumab Plus Carfilzomib and Dexamethasone Extends PFS in Relapsed/Refractory Myeloma

Saad Z. Usmani, MD

Adding daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone (KdD) reduced the risk of disease progression or death by 37% compared with carfilzomib and dexamethasone alone (Kd) in patients with relapsed/refractory multiple myeloma, according to findings from the phase III CANDOR trial presented at the 2019 ASH Annual Meeting.

The median progression-free survival (PFS) was not yet reached with the addition of the anti-CD38 antibody daratumumab compared with 15.8 months with Kd alone (HR, 0.63; 95% CI, 0.46-0.85; P = .0014). At a median follow-up of 17 months, the median overall survival (OS) had not yet been reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08).

“Patients treated with KdD achieved deeper responses than patients treated with Kd, with a nearly 10-times higher MRD negative—complete response rate at 12 months versus Kd-treated patients,” said lead study author Saad Z. Usmani, MD, Levine Cancer Institute. “KdD should be considered as a novel, efficacious, and tolerable IMiD-free treatment option for relapsed/refractory multiple myeloma,” Usmani added.

The open-label phase III CANDOR trial (NCT03158688) randomized (2:1 ratio) 466 patients with relapsed/refractory multiple myeloma previously treated with 1 to 3 prior therapies to either KdD (n = 312) or Kd (n = 154). Prior treatment with anti-CD38 antibodies and carfilzomib was allowed, as long as the patient reached at least a partial response, did not relapse ≤60 days from treatment discontinuation, and had a ≥6-month treatment-free interval at the time of initiating study therapy. Overall, 90% of patents had prior bortezomib (Velcade) and 42% of patients had prior lenalidomide (Revlimid). One-third (33%) of patients were lenalidomide-refractory.

All treatments were administered over 28-day cycles. Daratumumab (16 mg/kg) was administered on days 1, 8, 15, and 22, of cycles 1 and 2, every 2 weeks during cycles 3 to 6, and every 4 weeks during cycle 7 and beyond. Usmani noted that for patient convenience, the initial dose of daratumumab was split into two 8-mg/kg doses and administered on cycle 1, day 1 and cycle 2, day 2.

Carfilzomib and dexamethasone were administered at the same dose and schedule in both arms. Patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 of each cycle. For cycle 1 only, patients received a 20-mg/m² loading dose of carfilzomib on days 1 and 2; the proteasome inhibitor was given at a dose of 56 mg/m² for all subsequent treatments thereafter. Dexamethasone was administered at 40 mg on days 1, 8, 15, and 22 of each cycle. During weeks when patients received carfilzomib and/or daratumumab infusions, a split dose of 20 mg each of dexamethasone was administered.

The primary endpoint was PFS, with key secondary endpoints including overall response rate (ORR), minimal residual disease (MRD)-negative status, complete response (CR) rate at 12 months, OS, duration of response, and safety.

Among patients exposed to lenalidomide, the median PFS had not been reached in the KdD arm compared with 12.1 months in the Kd arm (HR, 0.52; 95%, 0.34-.80). In patients refractory to lenalidomide, the median PFS was not reached versus 11.1 months, respectively (HR, 0.45; 95% CI, 0.28-0.74).

“The PFS benefit of KdD is maintained in both lenalidomide-exposed and -refractory patients,” said Usmani.

The ORR was 84.3% with KdD compared to 74.7% with Kd (P = .0040). The rates of CR or better were 28.5% versus 10.4%, respectively. The median time to first response was 1 month in both treatment arms. Among patients receiving KdD, the MRD-negative rate at 12 months was 12.5% compared to 1.3% with Kd.

“Patients treated with KdD showed improved and deeper responses than with Kd alone,” said Usmani.

The safety analysis included 308 patients in the KdD arm and 153 patients in the Kd arm.

The overall safety profile with the treatment regimens was similar to what has been previously reported with single-agent use of these agents. The median treatment duration was 70.1 weeks in the KdD arm and 40.3 weeks in the Kd arm.

The rates of grade ≥3 adverse events (AEs) were 56.2 % versus 45.8% and the rates of serious AEs were 56.2% versus 45.8% in the KdD and Kd arms, respectively. The discontinuation rates due to AEs were 22.4% versus 24.8%, respectively. In the KdD arm, 3.9% of patients had grade ≥3 cardiac failure compared with 8.5% in the Kd arm. Cardiac failure led to carfilzomib discontinuation in 3.9% versus 4.6% of the 2 arms, respectively.

“Although KdD patients had higher rates of grade ≥3 AEs, treatment discontinuations due

to AEs were similar in both arms and the safety profile was tolerable,” said Usmani.

There were 5 treatment-related deaths, all occurring in the KdD arm, 1 each from pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest.

“Four of the [5 deaths] were related to infections and we know from other randomized phase III relapsed/refractory as well as frontline studies that the incidence of infection tends to be higher in both daratumumab- as well as carfilzomib-based regimens. But we haven’t [previously] seen a fatal AE signal. I think you have to keep in context the patient population and also the fact that there were no differences in overall survival,” said Usmani.

“The attribution [of the deaths] was definitely associated with treatment as per the definition—it is [considered] a treatment-emergent AE even if the therapy has been discontinued and the event happens within 30 days after that. But it’s certainly pointing more toward infections rather than any other worrisome signal,” added Usmani.

Usmani SZ, Quach H, Mateos M-V, 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). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract LBA6. bit.ly/2LEwAGf.

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