News & Perspective

New ‘KdD’ triple drug combination enhances clinical efficacy in the treatment of relapsed/refractory myeloma

Hematology
4 months ago, OP Editor

There has been a shift in the treatment paradigm for relapsed/refractory (R/R) multiple myeloma (MM) over the last decade due to the emergence of novel drugs and combination regimens. At the recent American Society of Hematology (ASH) Annual Meeting 2019, Dr. Saad Z. Usmani presented primary analysis results from a phase 3 study that compared the efficacy of triple drug combination of carfilzomib, dexamethasone and daratumumab (KdD) to carfilzomib and daratumuab (Kd) in R/R MM patients.1 This new KdD regimen reduced risk for disease progression or death by 37% compared with Kd, and almost doubled the complete response (CR) rate.2 Overall, KdD was not associated with increased risk of adverse events (AEs) or treatment discontinuation compared with Kd and represents an efficacious immunomodulator-free regimen for R/R MM patients.2

MM is a common hematologic malignancy which affects 2.1 per 100,000 population and causes over 98,000 deaths per year.3 Although there have been substantial advancements in the treatment landscape, a majority of patients would relapse or discontinue medication due to toxicity. Therefore, additional therapeutic options are needed for this patient population.4 Both the proteasome inhibitor carfilzomib and anti-CD38 monoclonal antibody daratumumab have been approved as single agents or as components of combination regimens for the treatment of R/R MM.4 The addition of dexamethasone to carfilzomib and daratumumab treatment has recently been shown to enhance clinical efficacy in R/R MM, in a multicenter and randomized phase 3 trial.2

Results of the CANDOR study were presented at the 2019 Annual ASH Meeting by Dr. Saad Z. Usmani of the Levine Cancer Institute at Atrium Health in Charlotte, North Carolina.2 A total of 466 R/R MM patients with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to more than 1 line of therapy, were randomized 2:1 to receive KdD or Kd. Treatment was continued until disease progression or development of unacceptable toxicity. 42.3% and 90.3% of the patients were previous recipients of lenalidomide and bortezomib-containing regimens respectively.2

After a median follow-up of 16.9 months and 16.3 months for the KdD and Kd arms respectively, data showed that patients in the KdD arm had a statistically significant 37% reduction in the risk of progression or death (HR=0.63, 95% CI: 0.46-0.85, p=0.0014).2 This benefit in progression-free survival (PFS) was also maintained across clinical subgroups, as the median PFS was not reached vs. 12.1 months in the lenalidomide-exposed group (HR=0.52; 95% CI: 0.34-0.80), and was not reached vs. 11.1 months in the lenalidomide-refractory group (HR=0.45; 95% CI: 0.28-0.74).2

Secondary endpoints included overall response rate (ORR), minimal residual disease (MRD)-negative CR at 12 months and overall survival (OS), all of which favored the KdD regimen. Patients in the KdD group achieved an ORR of 84.3% vs. 74.7% in the Kd group (p=0.0040), and MRD-negative CR at 12 months for the KdD group was almost 10-fold than the Kd group (12.5% vs. 1.3%, respectively (p<0.0001)). Median OS was not reached in either arm, although analysis showed a trend in favour of KdD (HR=0.75; 95% CI: 0.49-1.13; p=0.08). Additionally, the rate of CR or better in the KdD arm was almost twice that of the Kd arm (28.5% vs. 10.4%). The incidence of AEs above grade 3 (82.1% vs. 73.9%), serious AEs (56.2% vs. 45.8%) and treatment discontinuation rates (22.4% vs. 24.8%) were similar in the KdD and Kd groups respectively.2

Overall, the KdD combination demonstrated significant PFS benefits compared to Kd which was extended across clinically important subgroups, with a manageable safety profile. The CANDOR study includes important findings to support the clinical use of KdD in R/R MM and thus extends existing treatment options for this challenging patient group.

1. Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03158688. Accessed January 16, 2020.

2. Usmani S. 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). In: ASH; 2019. https://ash.confex.com/ash/2019/webprogram/Paper132629.html. Accessed January 16, 2020.

3. Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227.

4. Rajkumar SV, Kumar S. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc. 2016;91(1):101-119.

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