Efficacy and Safety of Carfilzomib-Lenalidomide-Dexamethasone (KRd) in Newly Diagnosed Multiple Myeloma: Pooled Analysis of 4 Single-Arm Studies
Authors: Landgren Ola , Attal Michel , Kazandjian Dickran , Roussel Murielle , Jasielec Jagoda K. , Dytfeld Dominik , Anderson Aparna , Kervin Tara , Iskander Karim , Mezzi Khalid , Welliver Tim , Yusuf Akeem , Jakubowiak Andrzej 
Published: November 2019

Introduction: Carfilzomib (K) is a second-generation proteasome inhibitor that is approved as a single agent and in combination with lenalidomide and dexamethasone (KRd) or dexamethasone alone for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM) (Siegel et al., Blood, 2012; Siegel et al., JCO, 2018; Dimopoulos et al., Lancet Oncol, 2017). While KRd is not approved for patients with newly diagnosed multiple myeloma (NDMM), the efficacy and safety of this regimen have been examined in several independent investigator-driven studies (Kazandjian et al., ASH 2018, Abstract 1957; Jakubowiak et al., ASCO 2013, Abstract 8543; Roussel et al., ASH 2016, Abstract 1142; Zimmerman et al., ASH 2016, Abstract 675). The four phase 1 and phase 2 studies (NCT01029054 [N=55], NCT01402284 [N=45], NCT01816971 [N=76], NCT02405364 [N=46]) have shown that KRd is safe and effective in NDMM. However, the studies were single-arm with relatively small numbers of enrolled patients. A pooled analysis of individual patient data would provide an overall assessment of clinical outcomes for KRd, allowing further assessment of the efficacy and safety of KRd in NDMM.
Methods: Patient-level data from four single-arm phase 1 and phase 2 studies of KRd in NDMM were combined (3 in the U.S. and one in France); three of the four studies were multicenter studies. Patients were treated in 28-day cycles of KRd: carfilzomib (most received 20/36 mg/m2, days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg/day, days 1‒21), and dexamethasone (20‒40 mg/week).
The primary endpoint was to estimate the rate of very good partial response or better (≥VGPR). The secondary endpoints included assessments of overall response rate (ORR), the rate of complete response or better (≥CR), median progression-free survival (mPFS), landmark PFS, and safety. Response rate analyses were based on best overall response for stringent CR, CR, VGPR, or partial response (PR) that were reported in each study.
The patients were separated into two cohorts: those who received stem cell transplant (SCT) (NCT01816971 and NCT02405364) and those who did not (NCT01029054 and NCT01402284).
Results: The first cohort of patients from the SCT studies included 122 patients (table). The average age for this cohort was 57.1 years, and 63% were male. The percentages of patients with ISS stages I, II, and III were 46%, 37%, and 11%, respectively. High-risk cytogenetics were observed in 25% of patients (table). The pooled proportion of patients who had ≥VGPR was 93% (95% CI: 89%, 98%), while the pooled ≥CR rate was 79% (95% CI: 72%, 86%). All patients had at least a partial response or better. The 1- and 2-year PFS rates were 95% (95% CI: 89%, 98%) and 88% (95% CI: 80%, 93%), respectively. The limited patient follow-up beyond 2 years did not allow estimation of mPFS. 109 patients (89%) reported at least one grade 3 or 4 treatment-emergent adverse event (TEAE). Selected grade 3 or 4 TEAEs of interest were acute renal failure (2%), cardiac failure (2%), and hypertension (2%) (table).
The second cohort of patients from the non-SCT studies included 99 patients (table). The average age for this cohort was 60.9 years, and 67% were male. The percentages of patients with ISS stages I, II, and III were 44%, 39%, and 16%, respectively. High-risk cytogenetics were observed in 35% of patients (table). The pooled proportion of patients who had ≥VGPR was 90% (95% CI: 84%, 96%). The pooled ORR was of 98% (95% CI: 95%, >99%), while the pooled ≥CR rate of 71% (95% CI: 62%, 80%). The 1- and 2-year PFS rates were 96% (95% CI: 90%, 98%) and 85% (95% CI: 76%, 90%), respectively. The limited patient follow-up beyond 2 years did not allow estimation of mPFS. 91 patients (92%) reported at least one grade 3 or 4 TEAE. Selected grade 3 or 4 TEAEs of interest were peripheral neuropathy (1%), acute renal failure (4%), cardiac failure (3%), and hypertension (5%) (table). Additionally, the results of the individual studies are consistent in efficacy and safety.
Conclusion: The results of this study demonstrate deep and sustained responses, highlighting KRd as an effective and tolerable treatment option for patients with NDMM in both the transplant and non-transplant settings. The promising results presented here should be evaluated against standard of care regimens.

Disclosures
Landgren: Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Roussel:Celgene Corporation: Consultancy, Other: travel fees, lecture fees, Research Funding; Janssen: Honoraria, Other: travel fees, lecture fees, Research Funding; Amgen: Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees, Research Funding. Anderson:Statistics Collaborative, Inc.: Employment. Kervin:Statistics Collaborative, Inc.: Employment. Iskander:Amgen Inc.: Employment, Other: stockholder of Amgen. Mezzi:Amgen Inc.: Employment, Other: stockholder of Amgen. Welliver:Amgen Inc.: Employment, Other: stockholder of Amgen. Yusuf:Amgen Inc.: Employment, Other: stockholder of Amgen. Jakubowiak:Adaptive Biotechnologies: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.