From fit to frail: Effectiveness and safety of fixed-dose carfilzomib in the treatment of multiple myeloma – a single-center, real world evidence in China Free

Background

Carfilzomib, a second-generation proteasome inhibitor, has been dosed twice weekly (27/56 mg/m²) ^[1][2]or once weekly (70 mg/m²)^[2] in pivotal trials, with dose intensity (27–70 mg/m²)^[3] correlating with deeper responses. Given typical body surface area in Chinese patients, a fixed 60 mg (~35 mg/m²) twice-weekly regimen is pharmacoeconomically favorable, with >96% utilization. Robust real-world data on the effectiveness and safety of fixed-dose carfilzomib in multiple myeloma remain limited. Further studies should clarify remission rates across risk subgroups, including frail patients, and assess safety, treatment cycles, tolerance, improvement in frailty, and factors influencing adherence.

Method

This retrospective study included MM treated with ≥2 cycles of a carfilzomib-based regimen at Zhengzhou University People's Hospital (Jan 2023 – Jan 2025). Two cohorts: (1) first-line conversion—switched within ≤4 bortezomib cycles owing to intolerance or poor response; (2) relapse/refractory—progressed after ≥2 prior lines. Fit patients: 20 mg/m² on days 1-2 of cycle 1, then 60 mg on days 1, 2, 8, 9, 15, 16 each cycle; frail patients: 60 mg once weekly. Primary outcome was overall response rate (IMWG-2016); progression-free and overall survival were tracked to Apr 2025. Safety was graded by CTCAE v5.0.

Results

The study included 93 MM patients, with 67 in the first-line conversion group and 26 in the RRMM group, median age 61.1 years. Males were 46.2%, and 54.8% had high-risk cytogenetics. 32.3% of the patients were frail.The first-line conversion group showed better ORR (94.0% vs. 68.2%, p=0.005) and CR rate (53.7% vs. 9.1%, p<0.001) than the RRMM group, maintaining CR for a median of 9.7 months. Transplanted patients in this group had a higher CR rate than non-transplanted (76.2% vs. 39.1%, p=0.005), while those with ≥2 risk factors tended to have a lower CR rate (31.3% vs. 65.0%). Among the 29 patients achieving CR, the median onset was 3 cycles, with 75.8% reaching CR within ≤3 cycles. Thirty frail patients treated with carfilzomib had an ORR of 86.7% and a CR rate of 46.7%, with 86.7% achieving fit/intermediate status.

At a median follow-up of 10.6 months, the median OS and PFS were not reached in the whole group, with 2-year OS at 80.4% (95% CI 71.2-90.7%) and PFS at 65.8% (95% CI 48.5-89.3%). By the final follow-up, 43% of patients remained on treatment, with a median of 5 cycles (range 2-11). Treatment interruptions were primarily due to patient choice (30.1%), bridging to ASCT (15.1%), disease progression (5.4%), cardiovascular events (3.2%), and other reasons (2.2%). 50.7% experienced grade ≥3 hematologic adverse events, mainly including neutropenia (29.8%), thrombocytopenia (19.4%), and anemia (16.4%), while infections were the most frequent non-hematologic events (34.3%). The incidence rate of cardiac events was only 3.2%. The incidence of these events in frail patients (50.0%) was similar to non-frail patients.

Conclusion

This real-world study demonstrates that a fixed-dose regimen of carfilzomib in first-line converted patients achieves profound remissions and significantly prolongs survival, exhibiting superior efficacy compared to the relapse-refractory cohort. However, the efficacy of this treatment remains constrained within the high-risk genetic subgroup, indicating a necessity for more intensive combination strategies. The regimen is characterized by a manageable safety profile, with a low incidence of cardiac events. Notably, the 60 mg weekly regimen resulted in functional reversal in 86.7% of frail patients and was well tolerated. Further expansion of the sample size is warranted for validation of these findings.

References