P48 carfilzomib, lenalidomide and dexamethasone in relapsed refractory multiple myeloma: a prospective real-life experience of the regional tuscan myeloma network (rtm)

Background: In recent years, the clinical outcome of multiple myeloma (MM) patients has improved due to the introduction of several new agents, such as the third-generation immunomodulator, the next-generation proteasome inhibitors (PIs) and the introduction of immunotherapy. Carfilzomib, a potent, irreversible, selective proteasome inhibitor, has demonstrated consistent results in relapsed/refractory myeloma (RRMM) combined with lenalidomide and dexamethasone (KRd) [1]. However, no prospective studies are yet available that analysed the efficacy of KRD combination. Aim: We evaluated the response and safety data in patients prospectively treated with the KRd regimen outside of clinical trials. Methods: We reported a multicentre prospective observational study on 85 patients, treated with KRd combination as second or third line of therapy between December 2016 and December 2019. The patients were then followed for the next two years (data cut-off December 2021). Results: Median age was 61 years old; high-risk cytogenetic and renal impairment (eGFR < 60 ml/min) were referred in 26% and 17% of the patients, respectively. Nearly all patients (98%) had received prior bortezomib-based treatment, among them 43% were refractory. Instead, nine patients (10.5%) were exposed to lenalidomide, with a refractory rate of 60%. After a median follow up of 40 months, patients received a median number of 16 cycles of KRd and the median duration of treatment was 18 months (range: 16.1–19.2 months). The overall response rate was 95%, with high-quality response (≥ very good partial remission [VGPR]) in 57% of the patients: stringent complete remission and complete remission were achieved in 10% and 28%, respectively, VGPR in 19%. The median progression free survival (PFS) was 36 months (range: 29.1–43.2 months). PFS was improved by the achievement of at least VGPR (median 38 vs 17 months; HR=1.73, 95% confidence interval [CI]: 0.98-3.13, p=0.002) and by previous ASCT (median 38 vs 28 months, HR=0.59, 95% CI: 0.32-0.83, p=0.02). The median OS was NR (5-year OS rate 73%). Patients with high-risk cytogenetic abnormalities showed a significantly lower OS than those with standard risk (median NR vs 47 months, HR=3.3, 95% CI: 1.06-10.39, p=0.028). Nineteen patients performed KRd treatment as a bridge to autologous transplantation, obtaining a post-transplant MRD negativity in 65% of cases. The most common adverse events were haematological, followed by infection and cardiovascular events. Grade 3 or higher anaemia, thrombocytopenia and neutropenia occurred in 11%, 21% and 28%, respectively. Among the cardiovascular events, the most frequent was arterial hypertension, which occurred in 12%, while congestive heart failure, arrhythmia and ischemic heart disease were less frequent and rarely grade 3-4. Conclusion: Our data confirm that KRd regimen is effective and relatively safe in the early stages of the disease and can be used as a re-induction for a salvage autologous transplant. The prior use of bortezomib did not influence the efficacy of KRd treatment in terms of outcome, unlike high-risk cytogenetic abnormalities. A longer follow-up is needed to also confirm the benefit of the KRd combination after 18 cycles. [1] Stewart AK. et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N. Engl. J. Med.372, 142–152 (2015)