Background Carfilzomib (K), a next-generation proteasome inhibitor, has proven strong efficacy in Multiple Myeloma (MM), and has demonstrated clinical superiority to bortezomib in the ENDEAVOR study in relapsed/refractory (RR) setting. Moreover, its selective action directed against 20S proteasome leads to much lower peripheral neuropathy incidence, although caution must be accorded to cardio-vascular toxicity. However, K is not approved at diagnosis, making its use restricted to subsequent lines of therapy. In this single center retrospective study, we aimed to describe our utilization of K-based combinations in RRMM patients, to report efficacy and tolerability, and to provide guidance in routine practice.

Methods Demographic, safety and efficacy data from RRMM patients having received K-based combinations, apart from clinical trials or bridging therapy to CAR T-cells therapy, in the 2018-2024 period were retrospectively collected. Response evaluation was based on the IMWG criteria. Univariate and multivariate analysis were performed to assess any predictive value of age, cytogenetics, number of previous lines of therapy, bortezomib and/or lenalidomide refractoriness, and cardiovascular medical history for progression-free survival (PFS) and overall survival (OS).

Results Data from 78 patients were collected. Median age was 62 years (46 - 83). Fifty-seven percent were male. Median time between diagnosis of MM and initiation of K was 49.2 months (27.3 – 79.8). Cytogenetics were available in 73% of patients. Eight (13%) and 9 (15%) of all patients harboured t(4;14) and 17p deletion respectively. The median number of previous lines was 2 (range 1 - 9) and 74% had received more than 1 previous therapy. All patients had been exposed to IMiDs (lenalidomide, pomalidomide, thalidomide), 89% to proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and 64% to anti-CD38 monoclonal antibodies (daratumumab, isatuximab). Cardiovascular medical history was documented in 44 (54%) of patients, mostly hypertension (36%). Coronary artery disease was infrequent (n = 6, 7.4%). Before initiation or K, 28 (36%) patients had cardiac evaluation before initiation of K with cardiac echography in 28 patients. K-based combinations were as followed: Kd in 62%, Daratumumab-Kd in 26 %, KRd in 3.7 %. Most patients (67 %) received K in a weekly schedule. In almost half of responding patients, K infusions were spaced to bi-monthly or monthly schedule, after at least 6 cycles of treatment. Overall response rate (ORR) (≥ PR) was 51%, comprising 26% VGPR; and 14% of patients had a stable disease. Median PFS was 6.7 (5.6 - 9.2) months, while median duration of response was 13.8 (0.25 - 48) months. Median overall survival (OS) was 16.6 (13 - 36.8) months. In PFS univariate and multivariate analysis, we did not identify predictive response factors. As for OS, we identified known prognostic factors such as 17p deletion (HR 2.97, p = 0.02), and bortezomib refractoriness (HR 2.94, p = 0.02). In our cohort, toxicity profile was favourable, with only 19 (23.5%) patients having presented cardiovascular adverse event (CTCAE grade 1 to 4), mostly hypertension (n = 14, 17.3%). Heart failure and coronaropathy were both observed in only 2 (2.5%) patients. No thrombotic microangiopathy occurred. Finally, 9% (n=7) of drug discontinuation due to toxicity was reported, due to asthenia or digestive discomfort but not cardiovascular events.

Conclusion This real-life retrospective study showed favourable benefit/toxicity profile of K-based combinations in RRMM patients with a PFS of 16.6 months and an ORR of 51%. Initial weekly dosing of K followed by spacing out infusions in responding patients led to better tolerance. Currently, K-based combinations also represent interesting options as bridging therapy to CAR T-cells therapies.

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2025
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