Daratumumab, bortezomib, thalidomide and dexamethasone improves renal outcomes in multiple myeloma transplant eligible patients presenting with renal failure: A real life experience from northeastern Italy

Abstract

Abstract Introduction: Renal impairment (RI) in multiple myeloma (MM) is defined by IMWG as creatinine >2 mg/dL (170 umol/L) or creatinine clearance (CrCl) <40ml/min due to myeloma. Criteria for renal response have been recently defined by IMWG with the strong recommendation to use it in clinical practice. It has been demonstrated that RI in MM is related to a poorer outcome, indeed in the International staging system (ISS) the value of serum β2-microglobulin reflects in part the grade of RI. It is well established that bortezomib-based treatment improves renal overall remission, but data in the era of quadruplets in transplant eligible newly diagnosed MM (TENDMM) patients are not available, primarily due to the exclusion of these patients from clinical trials. From December 2021 the combination of Daratumumab, bortezomib, thalidomide, dexamethasone (D-VTd) has been approved by AIFA in Italy representing the standard of care in TENDMM patients. Interestingly, in the registrative phase 3 Cassiopeia study, that compared D-VTd vs VTd, although none of the drugs is considered nephrotoxic, patients with creatinine clearance <40 ml/min were excluded. Aim. The aim of our study was to assess the renal response in patients with TENDMM, who underwent D-VTd treatment, in the real-life setting. Patients and Methods. From January 2022 to February 2025 a total of 440 patients were diagnosed with symptomatic MM and considered transplant eligible. The patients were admitted to several haematology unit of northeastern macroregional area, including Friuli-Venezia-Giulia and Veneto. Among these patients, 28 presented with acute kidney injury (CrCl< 40 ml/min ) and were included in the study. Evaluation of renal failure and renal response was done according to IMWG criteria. Patients with concomitant AL amyloidosis were excluded. Results. Median follow-up was 20.5 months. The median age of patients was 62 years. At diagnosis 7 patients (25%) presented with ECOG score >1, 11 (39%) had hypertension and none of them had type II diabetes. In 8 patients LDH value was above the upper normal limit and in almost all of them the value of β2-microglobulin was increased, with 75% of patients with a value above 5.4 mg/L. Eighteen patients (64%) had an haemoglobin value <10g/dL, 21 (75%) had a serum free light chain ratio >100, 20 (71%) a plasma cells bone marrow infiltrate >60%. 24h urine protein was > 2g in 12 patients (43%), with a Bence Jones positivity in almost all cases. Median creatinine clearance was 25.5 ml/min (range 4-39). All patients received D-VTd regimen as first line of therapy. Seven cases received a lower dose of thalidomide and 2 did not receive the drug at all. No other dose drug adjustment was observed in the induction phase. Up to now, 17 patients (61%) underwent at least one autologous stem cell transplantation, with a reduced dose of Melphalan (Mel140) in 3 patients. ORR was 96%, with sCR/CR in 68% of patients, VGPR in 18% and PR in 11%. Median time to best response was 3 months. 71% achieved a complete renal response, while a PR was observed in 11% and MR in 8%. Median time to renal response was 80 days (range 8-635). Almost all patients underwent high dose steroids with dexamethasone from 20 to 40 /day for 1-2 cycles. Finally, we observed that even if 23 patients achieved a good quality response (≥ VGPR o), not in all of them renal recovery was observed (5 patients achieved MR, 3 PR). Conclusions: defining renal response is a crucial endpoint of treatment, especially in TENDMM. If relapse occurs, it is relevant to have recovered from RI in order to be considered for clinical trials or new approved therapies, such as CART, which in Italy is feasible only in patient with CrCl ≥ 45ml/min. Finally, in the near future D-VRd will become the standard of care for TENDMM eligible patients but, due to the renal toxicity of lenalidomide, D-VTd might still remain a valid option.