The combination of carfilzomib, daratumumab, and dexamethasone (KdD) showed better overall survival (OS) and confirmed progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (R/R MM) when compared with carfilzomib and dexamethasone (Kd) alone, according to the final analysis of the CANDOR trial published in Blood Advances.
Saad Usmani, MD, MBA, of Memorial Sloan Kettering Cancer Center in New York, and colleagues conducted the CANDOR trial, which compared the efficacy and safety of KdD with Kd. In the primary analysis, the study achieved its primary endpoint of PFS. The final analysis includes updated efficacy and safety results in clinically relevant patient subgroups and reports on the secondary endpoint, median OS.
The trial included 466 adult patients with R/R MM from 102 international sites who received between one and three prior lines of therapy with a partial response or better to at least one previous therapy. Patients were randomized 2:1 to receive 28-day cycles of either KdD (n=312) or Kd (n=154). The final analysis data cutoff was April 15, 2022.
“Patients treated with KdD had deep responses,” the researchers noted. Measurable residual disease-negative complete response rates at any time during the trial were higher in the KdD group (22%) than the Kd group (8%); this has been associated with extended periods of PFS. Likewise, median PFS was higher in patients treated with KdD (28.4 months; 95% CI 22.7-36.2) than in patients treated with Kd (15.2 months; 95% CI 11.1-19.9).
OS was also higher in the KdD arm than in the Kd arm (50.8 vs. 43.6 months, respectively). Despite not achieving the prespecified level of statistical significance for OS (one-sided p=0.021), there was a significant 7.2-month disparity in median OS between the two arms in favor of KdD, with a hazard ratio (HR) of 0.78 (95% CI 0.60-1.03), thus “reassuring that there was no detriment to patients receiving this therapy,” Dr. Usmani said.
The final analysis showed lower OS HRs, suggesting that KdD provides a greater benefit than Kd in prespecified subgroups, including patients who are refractory to lenalidomide (HR=0.69 [0.43-1.11]), patients who are refractory to bortezomib (HR=0.70 [0.45-1.09]), and patients with high-risk cytogenetics (t[4;14], t[14;16] and/or del17p; HR=0.52 [0.29-0.94]). “Many of the patients in our practice are on lenalidomide maintenance,” Dr. Usmani said, and the CANDOR trial “may address treatment needs in these patient populations.”
“The median PFS and even OS were quite remarkable compared with the standard of care,” Dr. Usmani noted.
Fewer patients in the KdD arm received subsequent anti-myeloma therapy compared with the Kd arm (49% vs. 68%, respectively), and the median time to next treatment was longer in the KdD arm (37.4 months vs. 17.8 months, respectively). Still, researchers acknowledge that “availability of other MM therapies with subsequent lines influences secondary endpoints like OS.”
The safety outcomes in the treatment arms were largely similar and consistent with the results observed in previous analyses. Although fatal treatment-emergent adverse events (AEs) occurred in 11% and 6% of patients in the KdD and Kd arms, respectively, no new treatment-related fatal AEs occurred after the primary analysis.
Researchers note the small number of study patients age 75 years and older as a limitation, making it challenging to fully assess the treatment’s benefit-risk in this age group.
The final analysis of the CANDOR trial confirms the KdD regimen’s safety and strong efficacy in patients with R/R MM who are refractory to lenalidomide, showing enhanced PFS and OS compared with Kd. “This combination is safe to give to patients who have high-risk features or refractoriness to their previous treatment, especially in a first relapse setting,” Dr. Usmani concluded.
Any conflict of interest declared by the authors can be found in the original article.
Reference
Usmani SZ, Quach H, Mateos MV, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR study [published online ahead of print, 2023 May 10]. Blood Adv. doi: 10.1182/bloodadvances.2023010026.
Perspectives
The final analysis of the CANDOR study confirmed the study’s initial findings of the KdD triplet arm having better PFS of more than one year versus the Kd doublet arm.1-4 About half of the patients in the study had only received one prior line of therapy. The study’s final analysis also showed a numerically higher OS with the triplet arm of seven months more than the doublet arm, although it did not meet the prespecified endpoint.
The findings were not surprising and confirmed prior results that have been published from this study and those from the IKEMA study that had a similar design and used isatuximab instead of daratumumab as the anti-CD38 antibody.5 In a study like this, the lack of significant OS benefit in general can be due to two reasons: subsequent therapy or toxicity. Even though crossover was not allowed in this study, 28% of patients received an anti-CD38 antibody after relapse in the doublet arm. Fatal treatment-emergent AEs, excluding disease progression, were more common in the triplet arm at 11% compared with 6% in the doublet arm, with infection being the leading cause of death, followed by cardiac causes.
What is interesting and reassuring is that patients in the high-risk disease subgroup seemed to derive significant benefit, including OS benefit.1-3 In prior studies of other daratumumab-based combinations, the subgroup analyses for high-risk disease have not been associated with the same benefit seen in standard-risk disease, although a meta-analysis showed that daratumumab-based combinations resulted in favorable outcomes in patients with high-risk disease.6 These findings, taken together with data from the IKEMA study, suggest that a triplet combination with an anti-CD38 antibody, carfilzomib, and dexamethasone may be preferred in patients with high-risk disease at the time of relapse.5
There are several considerations for use of this regimen in clinical practice. First, the dose of carfilzomib used in this study was 56 mg/m2 twice weekly, which is higher than typically used in clinical practice. Second, myeloma is a disease of older adults, and AEs were more common in patients older than 65 years. Cardiac toxicity and infections are both significant concerns in older adults. Third, there are other approved daratumumab-based triplet combinations, including combination with pomalidomide and dexamethasone, which is commonly used in clinical practice.7 Combinations with bortezomib and dexamethasone or lenalidomide and dexamethasone are also approved and, in fact, were the regimens that led to initial approval of daratumumab in earlier relapse of myeloma.8,9 These latter regimens are less commonly used in the U.S., as most patients are either refractory or have been exposed to these agents. There are no head-to-head studies comparing KdD to daratumumab, pomalidomide, and dexamethasone; however, PFS of 28 months in CANDOR and 36 months with isatuximab, carfilzomib, and dexamethasone in the IKEMA study compare favorably to around 10 to 12 months seen with daratumumab, pomalidomide, and dexamethasone in other randomized trials (APOLLO trial and CARTITUDE-4 trial).7,10
As therapies for MM continue to advance, high rates of severe infections and infection-related mortality in the CANDOR study and other recent studies of CAR T-cell therapy and bispecific T-cell recruiting antibodies underscore the importance of continuing to address this very important issue in treatment of MM.
Surbhi Sidana, MD
Stanford University School of Medicine
Stanford, CA
References
- Usmani SZ, Quach H, Mateos MV, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR study [published online ahead of print, 2023 May 10]. Blood Adv. doi: 10.1182/bloodadvances.2023010026.
- Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76.
- Landgren O, Weisel K, Rosinol L, et al. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol. 2022;198(6):988-993.
- Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.
- Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023;13(1):72.
- Giri S, Grimshaw A, Bal S, et al. Evaluation of daratumumab for the treatment of multiple myeloma in patients with high-risk cytogenetic factors: a systematic review and meta-analysis. JAMA Oncol. 2020;6(11):1759-1765.
- Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812.
- Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
- Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
- San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma [published online ahead of print, 2023 June 5]. N Engl J Med. doi: 10.1056/NEJMoa2303379.
