Efficacy and safety of carfilzomib in relapsed and/or refractory multiple myeloma: systematic review and meta-analysis of 14 trials

Abstract

ObjectiveCarfilzomib (Carf) is a second-generation proteasome inhibitor approved for patients with relapsed and/or refractory multiple myeloma (RRMM) who failed ≥ 1 prior lines of therapy. We performed a systematic review of Carf literature with meta-analysis to determine the efficacy and safety in RRMM patients.MethodsBased on literature search, we included a total of 14 eligible phase I/II, phase II and phase III Carf based clinical trials. The cumulative incidence and odds ratios (OR) were calculated with random effect model, using ‘’R’’ software with metaphor package.Results2906 evaluable RRMM patients from published clinical trials included. The pooled overall response rate (ORR) was 45% (95% CI: 29–62). The pooled clinical benefit rate (CBR) was 56% (95% CI: 41–71). OR from 3 randomized clinical trials showed that Carf significantly improved ORR and CBR compared to control groups (OR 2.4, P < 0.0001; 2.02, P = 0.0007, respectively). Subgroup analysis showed significantly better ORR (P < 0.0001) and CBR (P < 0.001) with combination regimens compared to monotherapy. Response was significantly higher with high dose of Carf (>20/27 mg/m2) compared to standard dose (ORR 65% vs. 35%, P = 0.03). Compared to control group, the OR of developing cardiotoxicity (P = 0.002) and hypertension (P < 0.0001) were significantly higher with Carf, while no difference in peripheral neuropathy (P = 0.28).ConclusionsCarf produces significantly better responses with acceptable safety profile in RRMM patients. Combination regimens and higher dose Carf offers better response with no significant extra toxicity. Its efficacy is regardless of cytogenetics or disease stage. Incidences of cardiotoxicity and hypertension seem higher with Carf.

Feasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network

“…(NCT02412878) trial, that compared RRMM patients treated with carfilzomib once a week (70 mg/m 2 ) or twice a week (27 mg/m 2 ), showed that weekly carfilzomib at 70 mg/m 2 significantly prolonged PFS, while in the control arm PFS and ORR were inferior to the phase III ASPIRE trial [20]. In a meta-analysis of 14 trials, combination regimens and higher carfilzomib dose offered better response with no significant extra toxicity [21]. Our data therefore confirm that in order to ensure the largest and deepest clinical benefit, carfilzomib should be administered without reduction and adverse events should be prevented and faced with a proactive management.…”

A phase I study of carfilzomib in combination with ibrutinib for relapsed refractory mantle cell lymphoma

“…Although fungal infection has recently been associated with ibrutinib, the cause has mostly been aspergillosis in the central nervous system or, much less frequently, disseminated Cryptococcus , mucormycosis, or Pneumocystis pneumonia (Ghez et al , ). Carfilzomib has not been associated with an increased incidence of fungal infections (Shah et al , ), and we are unaware of any literature reporting an increased incidence of infections with the carfilzomib/ibrutinib combination.…”

Cardiotoxicity due to targeted anticancer agents: a growing challenge

“…7–10 For instance, within the proteasome inhibitors, carfilzomib was shown to cause significantly more CVCs compared with bortezomib which is less cardiotoxic but causes neuropathy more frequently. 11 Similarly, among different tyrosine kinase inhibitors (TKIs), imatinib showed minimal CVCs, 7 while dasatinib 12 was associated with more cardiopulmonary issues, while ponatinib was associated with more vascular than cardiac events. 13 Of note, although many of these new drugs are supposedly targeted towards one gene, apart from a few drugs, most of the time other targets or the same target in other normal organs are also affected.…”