Carfilzomib: A new proteasome inhibitor for relapsed or refractory multiple myeloma.

PURPOSE: The pharmacology, pharmacokinetics, clinical trials, adverse effects, dosage recommendations, and economic considerations of carfilzomib are reviewed. SUMMARY: Multiple myeloma accounts for approximately 10-15% of all hematologic malignancies and 20% of blood-related cancer deaths. Despite recent advances in the treatment of multiple myeloma, most patients will eventually relapse, requiring further treatment. Carfilzomib is a new proteasome inhibitor that primarily targets the chymotrypsin-like activity of the 20S proteasome. The safety and efficacy of carfilzomib was demonstrated in the PX-171-003-A1 trial, a prospective phase II trial in patients with relapsed or refractory multiple myeloma who had received at least 2 prior therapies including a proteasome inhibitor and an immunomodulatory agent. Common adverse effects included fatigue (55.5%), anemia (46.8%), nausea (44.9%), and thrombocytopenia (36.3%). The recommended dose of carfilzomib for the first cycle is 20 mg/m(2) on 2 consecutive days each week for 3 weeks in a 4-week cycle escalating to 27 mg/m(2) for subsequent cycles. It is recommended that patients receive premedication with dexamethasone during cycle 1 and cycle 2 to minimize risk of infusion reactions. CONCLUSION: Carfilzomib provides a clinical benefit to patients with relapsed or refractory multiple myeloma who have been previously treated with a proteasome inhibitor and an immunomodulatory agent.

Once-weekly vs. twice-weekly carfilzomib dosing in a subgroup of Japanese relapsed and refractory multiple myeloma patients from a randomized phase 3 trial (A.R.R.O.W.) and comparison with ENDEAVOR.

A.R.R.O.W. evaluated the superiority of once-weekly carfilzomib plus dexamethasone (Kd) 20/70 mg/m2 vs. twice-weekly Kd 20/27 mg/m2 based on progression-free survival (PFS) in relapsed and/or refractory multiple myeloma patients. Forty Japanese patients (once-weekly arm, n = 26; twice-weekly arm, n = 14) were randomized in A.R.R.O.W. In the Japanese subgroup of A.R.R.O.W., median PFS was 14.8 months (95% confidence interval [CI], 7.5-not evaluable [NE]) and 9.7 months (95% CI, 3.8-NE) in the once- and twice-weekly arms, respectively. The overall response rate (ORR) was 73.1% (19/26; 95% CI, 52.2-88.4) and 57.1% (8/14; 95% CI, 28.9-82.3) in each arm. The adverse events (AEs) incidence was 100% in both arms. Grade ≥ 3 AE incidence was 80.8% (21/26) and 78.6% (11/14) in each arm. Two fatal treatment-related AEs (acute lung injury and acute respiratory distress syndrome) occurred in the once-weekly arm. In exploratory unadjusted analyses of A.R.R.O.W. (once-weekly Kd 20/70 mg/m2) vs. ENDEAVOR (twice-weekly Kd 20/56 mg/m2), median PFS was 14.8 months vs. NE due to not yet being reached, and ORR was 73.1% (19/26) vs. 42.9% (3/7). In the Japanese subgroup, once-weekly Kd tended to improve ORR vs. twice-weekly Kd. Results from A.R.R.O.W. tended to be consistent with results from ENDEAVOR.

Incidence and Management of Carfilzomib-induced Cardiovascular Toxicity; A Systematic Review and Meta-analysis.

BACKGROUND: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta- analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%. RESULTS: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6%, respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7%, respectively. There was no difference in the event rate of all and highgrade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86, respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73, respectively). CONCLUSION: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.

Cardiotoxicity associated with carfilzomib: systematic review and meta-analysis.

Carfilzomib is a second-generation proteasome inhibitor (PI) that is approved for patients with relapsed or refractory multiple myeloma (RRMM) who failed ≥1 prior lines of therapy. We performed a systematic review of carfilzomib literature with meta-analysis to determine cumulative incidence of cardiotoxicity. After the literature search, we included a total of 29 eligible phase I/II, phase II and phase III clinical trials which used carfilzomib. The cumulative incidence and overall odds ratios (OR) were calculated with random effect model, using 'R' software with metaphor package. A total of 4164 patients with various malignancies were included. The overall estimated cumulative incidence of cardiotoxicity was 8.68% and 4.92%, respectively, for all-grade and high-grade (≥ grade 3) toxicity, which seems higher than other PIs. Compared to control group, the odds of developing cardiotoxicity due to carfilzomib was significantly higher with OR of 2.03 (95% CI: 1.19-3.46, p = .010) and 2.04 (95% CI: 1.31-3.17, p = .002) for all-grades and high grades, respectively. Concomitant immunomodulatory agents seem to increase the risk of cardiotoxicity (high-grade cardiotoxicity 6.45% and 4.34% with and without concomitant immunomodulatory agents, respectively (p = .033)). There was no variation in the incidence of cardiotoxicity among newly diagnosed versus RRMM (p = .38), and high versus standard dose carfilzomib (p = .86).

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

OBJECTIVE: Carfilzomib (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. METHODS: Based 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. RESULTS: 2906 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). CONCLUSIONS: Carf 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.