Carfilzomib Triplet Improves PFS in Phase III Myeloma Trial

Ajai Chari, MD

Ajai Chari, MD

The combination of carfilzomib (Kyprolis), dexamethasone, and daratumumab (Darzalex; KdD) led to a 37% reduction in the risk of progression or death compared with carfilzomib and dexamethasone (Kd) alone in patients with relapsed or refractory multiple myeloma in the phase III CANDOR trial. According to a press release from Amgen, this met the primary endpoint of progression-free survival (PFS) for the trial.¹

The median PFS had not yet been reached as of the cutoff date for the KdD arm compared with 15.8 months for those treated with Kd, resulting in a hazard ratio of 0.630 (95% CI, 0.464-0.854;P= .0014).  

"While treatment advances have improved outcomes for patients with multiple myeloma, there remains a need for additional therapeutic options for patients who have relapsed," lead investigator Ajai Chari, MD, associate professor of medicine, the director of clinical research in the Multiple Myeloma Program, and the associate director of clinical research, Mount Sinai Cancer Clinical Trials Office, said in a statement. "CANDOR confirms in a large phase III study the benefit for patients demonstrated in the earlier phase I study using the same combination."

A higher rate of adverse events (AEs) were observed with the triplet compared with the doublet. The most common treatment-related AEs (≥20%) observed with the KdD combination were thrombocytopenia, anemia, diarrhea, hypertension, upper respiratory tract infection, fatigue and dyspnea. This was considered to be consistent with the known safety profiles for the individual agents.

Further findings from the phase III trial will be submitted for presentation at a future medical meeting and for discussions in preparation for regulatory submissions.

"The potential to combine Kyprolis with Darzalex, 2 powerful targeted agents, represents an additional therapeutic approach for patients with relapsed or refractory multiple myeloma," David M. Reese, MD, executive vice president of research and development at Amgen, said in the press release. "The results from the CANDOR study confirm the potential for Kyprolis to be used in combination with an anti-CD38 monoclonal antibody."

CANDOR is an ongoing randomized, open-label trial exploring the KdD regimen in comparison with Kd in patients with relapsed and/or refractory multiple myeloma (NCT03158688).

The trial has enrolled 466 patients who have relapsed after 1 to 3 prior treatments, which could include stem cell transplant. In both arms, patients received intravenous (IV) carfilzomib 56 mg/m²twice daily.

Patients enrolling in the trial were allowed to have received prior carfilzomib or an anti-CD38 monoclonal antibody as long as the treatment ended more than 6 months ago, they did not achieve a partial response, and they did not have unacceptable toxicity related to the agent. Those with multiple myeloma of the IgM subtype were excluded from the trial, as well as patients with Waldenström macroglobulinemia, POEMS syndrome, plasma cell leukemia, myelodysplatic syndrome, known moderate or severe asthma within the past 2 years, known chronic obstructive pulmonary disease, or active congestive heart failure or issues.

A phase Ib study previously explored the KdD combination in patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior regimens, including bortezomib (Velcade) and an immunomodulatory drug.²

The triplet demonstrated an objective response rate of 84% in all 85 patients, and patients who were refractory to lenalidomide had an objective response rate of 79%. The median PFS was not reached in the trial, but at 12 months the PFS rate was 74% for all patients and 65% in the lenalidomide-refractory patients.

The most frequently observed grade 3/4 treatment-related AEs included thrombocytopenia in 31% of patients, lymphopenia in 24%, anemia in 21%, and neutropenia in 21%. Infusion-related reactions were observed in 60% of patients who had single first doses of daratumumab and in 43% of patients who had split first doses of daratumumab.

References:

1. Amgen Announces Phase 3 CANDOR Study Combining KYPROLIS (carfilzomib) And DARZALEX (daratumumab) Meets Primary Endpoint Of Progression-Free Survival [press release]. Thousand Oaks, CA: Amgen; September 13, 2019. https://bit.ly/2kn1yIL. Accessed September 16, 2019.
2. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.Blood.2019;134(5):421-431. doi: 10.1182/blood.2019000722.