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Better response rates and increased MRD negativity with KRd compared to KCd in newly diagnosed multiple myeloma patients, including high-risk patients

Proteasome inhibitor-based induction is the standard of care in newly diagnosed multiple myeloma (NDMM) patients eligible for melphalan 200 mg/m2 followed by autologous stem cell transplant (MEL200-ASCT). However, the treatment of patients with high-risk disease still represents an unmet medical need. The results of this study demonstrate that the second-generation proteasome inhibitor carfilzomib in combination with lenalidomide-dexamethasone (KRd) is more effective than the combination with cyclophosphamide-dexamethasone (KCd), also in high-risk patients.

NDMM patients ≤65 years were randomized (1:1:1; stratification by International Staging System (ISS) and age) to arm A: four 28-day induction cycles with KCd (carfilzomib 20/36 mg/m2 intravenously days 1, 2, 8, 9, 15, 16; cyclophosphamide 300 mg/m2 days 1, 8, 15; dexamethasone 20 mg days 1, 2, 8, 9, 15, 16) followed by MEL200-ASCT and consolidation with 4 KCd cycles; Arm B: four 28-day cycles with KRd (carfilzomib 20/36 mg/m2 intravenously days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1, 2, 8, 9, 15, 16) followed by MEL200-ASCT and 4 KRd cycles; arm C: 12 KRd cycles. Primary endpoint of this analysis was to evaluate the response rate of KRd versus KCd induction. Secondary endpoints included rate of minimal residual disease (MRD) negativity with KRd versus KCd and efficacy of KRd versus KCd in different subgroups of patients according to baseline prognostic features: ISS, chromosomal abnormalities, and Revised-ISS (R-ISS). For this analysis, the 2 KRd groups were pooled (2:1), since the treatment was the same until that point.

In total 474 patients were randomized (KRd: n=315; KCd: n=159) and data analyzed. Patients characteristics were well balanced with 49% of KRd versus 49% of KCd patients presenting at baseline with ISS Stage II/III, 31% versus 35% with high-risk chromosomal abnormalities (del17 and/or t(4;14) and/or t(14;16) detected by FISH), and 68% versus 74% with R-ISS Stage II/III disease. Rates of stringent complete response (sCR)/complete response (CR) (14% versus 4%; P=0.018), ≥ near CR (nCR) (32% versus 21%; P=0.003) and ≥VGPR (73% versus 57%; P<0.001) were significantly higher with KRd versus KCd. Partial response rate was 94% with KRd and 86% with KCd and only 1% of patients in the KRd group was primary refractory compared to 3% in the KCd group. The advantage of KRd versus KCd was consistent in all the analyzed subgroups (high-risk FISH, ISS II-III and R-ISS II-III). MRD evaluation was available in a subset of patients (144 KRd patients and 56 KCd patients). Rate of MRD negativity on evaluable patients was 53% with KRd versus 29% with KCd (P=0.002). MRD negativity in high-risk patients was comparable to the overall population.

The safety profile showed more dermatologic and hepatic grade 3/4 adverse events in the patients treated with KRd versus KCd (dermatologic: 8% versus 1%, and hepatic: 7% versus 1%). In addition, 29% of the patients in the KRd group had at least 1 extra-hematologic adverse event versus 16% in the KCd group.

In conclusion, carfilzomib-based induction in transplant-eligible patients is well tolerated and induces deep responses. KRd induction significantly improved sCR/CR, ≥nCR and ≥VGPR in comparison with KCd. Moreover, the rate of MRD negativity on evaluable patients was also higher with KRd. Importantly, the regimen was similarly effective in high-risk patients, currently representing an unmet medical need.


Gay F, Scalabrini DR, Belotti A, et al. Updated efficacy and mrd data according to risk-status in newly diagnosed myeloma patients treated with carfilzomib plus lenalidomide or cyclophosphamide: results from the forte trial. Presented during EHA 2018; Abstract S109.

Spreker Francesca Gay


Francesca Gay, MD, PhD, University of Torino, Torino, Italy


Zie: Keyslides


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