Real-World KRd Results Comparable to Phase 3 Trial Results in Myeloma

Carfilzomib, lenalidomide, and dexamethasone results from the real world continued to show effective responses and a tolerable safety profile.

A real-world analysis of the carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone scheme (KRd) found that the regimen led to positive efficacy and a safety profile comparable to what was seen in clinical trials in patients with relapsed or refractory multiple myeloma, according to findings from the retrospective, observational GEMMAC-KRd study published in Annals of Hematology.¹

The overall response rate (ORR), per International Myeloma Working Group (IMWG) criteria, was 73% (95% CI, 66%-79%); a complete response (CR) or better was achieved by 72 patients (37%), and a very good partial response (VGPR) was achieved by 101 patients (52%). Those with International Staging System (ISS) stage 1 disease experienced an ORR of 86% (95% CI, 73%-93%). Prior progression on lenalidomide and receiving 2 or more prior lines of therapy led to ORRs of 57% (95% CI, 34%-77%) and 56% (95% CI, 40%-71%), respectively.

Additionally, at a median follow-up of 32 months (range, 1-75), the median progression-free survival (PFS) was 26 months (95% CI, 21-34), and the 12-month PFS rate was 64% (95% CI, 57%-71%). The median overall survival (OS) was 65 months (95% CI, 43-87); the 12-month OS rate was 77% (95% CI, 71%-83%), and the 24-month rate was 70% (95% CI, 63%-76%).

“In conclusion, the KRd scheme led to an effectiveness comparable to the phase 3 clinical trials in patients with [relapsed or refractory multiple myeloma], despite the inclusion of patients with higher risk (renal impairment or high cytogenetic risk) and might be a good treatment option for second or third treatment lines regardless of age or renal functioning, and especially for patients progressing to T-based schemes,” senior study author Carlos Fernandez De Larrea, in the Hematology Department of Hospital Clinic and IDIBAPS at the Universitat de Barcelona in Barcelona, Spain, and fellow authors wrote.¹

The study included 194 patients diagnosed with multiple myeloma between January 2007 and June 2022 at hospitals in the Catalan region of Spain. Eligible patients were 18 years or older who received at least 1 prior treatment with documented progression. Those who received the KRd scheme in the context of a clinical trial or who were treatment-naïve before KRd were excluded from participation.

The median age of patients was 64 years (range, 40-88), and the majority of patients had R-ISS stage II disease (49%), standard cytogenetic risk (39%), 1 prior line of treatment (79%), and no previous autologous stem cell transplantation (59%).

The study’s primary end point was ORR per IMWG criteria including all stringent CRs, CRs, VGPRs, and PRs. Secondary end points included describing the demographic parameters of patients treated with KRd, analyzing the PFS to KRd and OS, analyzing the effectiveness of the treatment in specific patient groups, and analyzing the safety profile associated with the KRd scheme.

In patients who received KRd before stem cell transplantation (n = 44), the ORR was 89% (95% CI, 76%-95%), with 13 patients (30%) achieving a CR or better; the median PFS was 52 months (95% CI, 49-not reached), and the 24-month OS rate was 93% (95% CI, 86%-100%).

Although the study authors noted that they found “outstanding effectiveness”, the phase 3 ASPIRE trial (NCT01080391) that evaluated KRd in the same patient population elicited a higher ORR of 87.1%.² The higher rate of patients with high cytogenetic risk—20% in this study vs 12.1% in the ASPIRE study—may have been a partial factor of this.

Regarding safety, treatment-emergent adverse events (TEAEs) of any grade and grade 3 or higher occurred in 71% and 38% of patients. The most common AEs were anemia (35%), leukopenia (33%), and thrombocytopenia (29%), with most being grade 3 or higher: 29%, 22%, and 22%, respectively. Two patients died as a result of hematologic toxicities, including 1 due to thrombopenia and leukopenia each.

At the time of data cutoff, KRd treatment was discontinued by 81% of patients; 37% discontinued due to progression, 22% due to subsequent stem cell transplantation, 16% due to toxicities, 4% due to death, and 3% due to secondary malignancies.

References

1. Garcia-Guiñon A, Charry PA, Jimenez M, et al. Real-world evidence of Carfilzomib, Lenalidomide and Dexamethasone (KRD) Scheme in patients with relapsed / refractory multiple myeloma. Ann Hematol. Published online February 15, 2025. doi:10.1007/s00277-025-06240-1
2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 372:142–152. doi:10.1056/ NEJMoa1411321.