Carfilzomib–lenalidomide–dexamethasone vs lenalidomide–dexamethasone in relapsed multiple myeloma by previous treatment

Abstract

Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide–dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib–lenalidomide–dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after ⩾2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomide-exposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit–risk profile and should be considered an appropriate treatment option for patients with 1 or ⩾2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.

Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies

“…24 While cardiovascular events occurred more frequently in the elderly population compared with patients aged <70 years, KRd demonstrated a favorable benefit-risk profile in elderly patients. 25 The ENDEAVOR study of carfilzomib and dexamethasone (Kd) versus Vd demonstrated prolonged PFS with Kd in patients with RRMM who received one to three prior lines of therapy and were aged 65 to 74 years (median: 15.6 vs 9.5 months; HR, 0.528, 95% CI, 0.382-0.728) or ≥ 75 years (median: 18.7 vs 8.9 months; HR, 0.383, 95% CI, 0.227-0.647). 26 While hypertension was the most common grade Due to the nature of drug development, clinical trials and regulatory approvals usually proceed with patients with more advanced disease.…”

Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials

“…Among patients who received Kd or Vd at first relapse, median PFS (Kd vs Vd) was not evaluable vs 12.1 months for patients who were bortezomib‐naïve and 18.7 months vs 8.7 months for patients who received prior bortezomib, suggesting that patients who respond to prior proteasome inhibitor therapy benefit from carfilzomib . Similarly, in the ASPIRE trial, the median PFS was 29.6 months for patients who received KRd at first relapse and 25.8 months for patients who received KRd at second or third relapse (risk of progression or death compared with Rd arm was reduced by 29% and 28%, respectively) . Also, in ASPIRE, patients benefitted from carfilzomib at first relapse regardless of prior exposure to bortezomib (median PFS [KRd vs Rd], 29.6 months vs 20.6 months for bortezomib‐naïve; 29.3 months vs 15.9 months for prior bortezomib) …”

“…Previous studies have investigated the efficacy of carfilzomib in subgroups of patients categorized by number of previous lines of therapy, and among subgroups of patients with or without prior exposure to a proteasome inhibitor. In both ASPIRE and ENDEAVOR, patients who received carfilzomib‐containing regimens had improved median PFS compared with control groups regardless of whether patients were previously exposed to proteasome inhibitors . Additionally, patients who received carfilzomib at first relapse had a significant and clinically relevant improvement in PFS compared with patients who received standard of care at first relapse in both ASPIRE and ENDEAVOR .…”

“…Among patients who received Kd or Vd at first relapse, median PFS (Kd vs Vd) was not evaluable vs 12.1 months for patients who were bortezomib-naïve and 18.7 months vs 8.7 months for patients who received prior bortezomib, suggesting that patients who respond to prior proteasome inhibitor therapy benefit from carfilzomib 23. Similarly, in the ASPIRE trial, the median PFS was 29.6 months for patients who received KRd at first relapse and 25.8 months for patients who received KRd at second or third relapse (risk of progression or death compared with Rd arm was reduced by 29% and 28%, respectively) 19. Also, in ASPIRE, patients benefitted The results of this study demonstrate that patients who received KRd or Kd had improved PFS and ORR compared with those who received Rd or Vd, respectively, regardless of whether they had an early or late relapse following the most recent prior therapy.Safety results among early and late relapsers were comparable to those previously reported for ASPIRE and ENDEAVOR for the overall population.…”

Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis

“…Efficacy and safety of twice-weekly carfilzomib-based therapies were previously demonstrated in the phase 3 ASPIRE and ENDEAVOR trials [16][17][18][19] . Importantly, the treatment effect of carfilzomib was confirmed across several patient subgroups [20][21][22][23][24][25][26] . The favorable benefit-risk profile of twiceweekly carfilzomib-based therapies versus standards of care (SOCs) provided an opportunity to consider the value of more convenient once-weekly carfilzomib therapy for patients with RRMM.…”