Renal Response in Patients (Pts) with Relapsed Refractory Multiple Myeloma (RRMM): Interim Data of a Large Observational, Prospective Study
Authors: de la Rubia Javier , Morales Enrique , Escalante Fernando , Durán Mª Soledad , Perez Encinas Manuel , Gironella Merche , Gonzalez-Lopez Tomas J , Español Ignacio , Sarrà Josep , Cabezudo Elena , Gonzalez Esther , Calle Carmen , Martinez Rafael , Arnao Mario , González Yolanda , Márquez José Antonio , Cabañas Valentin , Blade Joan , Ruiz Boza Antonio , Garcia Antonio 
Published: October 2019

Abstract
Introduction:Renal impairment (RI) is a common complication in multiple myeloma (MM) with an incidence of 20-40%, due to the older age of the affected patients (pts) and the nature of the disease. Prognosis of pts with RI has improved in recent years (yrs), but remains closely associated with the recovery of renal function. There is little information on the renal response of relapsed refractory MM (RRMM) to new antimyeloma drugs within clinical practice, using standardized criteria such as glomerular filtration rate (GFR) estimated by the Cockroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) formulas.The primary objective of the study is to describe the renal response in RRMM pts with moderate (CrCl 30–50 mL/min) or severe renal impairment (RI) (CrCl < 30 mL/min) after initiating treatment (Tx). Secondary objectives include response rate, overall survival (OS), safety, and health resource utilization. We present results from a pre-planned, interim analysis with a data cut-off of June 15, 2014.
Methods:This is a large ongoing observational, prospective, multicenter study in RRMM pts with moderate or severe RI (based on the CG formula) receiving antimyeloma Tx. The overall planned sample size is 300 pts to be followed for up to 36 months (mos) after the end of Tx. Renal and MM responses are evaluated according to the International Myeloma Working Group criteria. Renal complete response (renalCR) is defined as a sustained (for at least 2 mos) increase of baseline estimated glomerular filtration rate (eGFR) to ≥ 60 mL/min; a partial renal response (renalPR) is defined as an increase from < 15 to 30–59 mL/min, and a minor renal response (renalMR) from < 15 to 15–29 mL/min or, from 15–29 to 30–59 mL/min.
Results:A total of 150 pts were included in the interim analysis, mean ± SD age was 74 ± 9 yrs, 53% were male, and 53% had moderate and 47% had severe RI. At baseline, 57% of pts were in first relapse. At diagnosis, 45% of pts had ISS stage III, 29% had ISS stage II, 9% had ISS stage I, and 17% had no ISS stage available. Main antimyeloma therapies were: lenalidomide (LEN)-based (37%), bortezomib (BORT)-based (30%), BORT + LEN based (5%), chemotherapy-based (25%) and, thalidomide-based (3%). The median follow-up was 4 mos. To date 38% of pts have discontinued Tx, 13% due to adverse events (AEs), and 29% have died. The main causes of death were: disease progression (8.7%), infection (6.7%), respiratory failure (3.3%), kidney insufficiency (2%), fractures (2%). The mean baseline CG/MDRD was 39.7/42.2 (± 6.3/10.2) mL/min in the moderate RI subgroup and 20.2/19.8 (± 7.6/9.8) mL/min in pts with severe RI (correlation coefficient CG vs. MDRD: 0.93). Overall, 15.3% (n = 23; 95% confidence interval [CI] 9.5–21.1,) had a renal response according to the CG formula, i.e. renal function iimproved by at least 1 KDIGO stage; 4.7% had renalCR, 0.7% renalPR and 10% renalMR. According to the MDRD formula, the renal response was 21.3% (8.6% renalCR, 12.7% renalMR). Median time to best renal response was 1.5 (range 0.6–4.6) mos. The renal response based on CG/MDRD according to antimyeloma therapies was 10.9%/20% for LEN-based, 26.7%/31.1% for BORT-based, 0%/12.5%, for LEN + BORT-based, and 10.2%/15.4%, for chemotherapy-based therapies. 24 hour (hr) proteinuria measurement was available at baseline in 70 pts (median of 1.3 g/24 hr), 77.1% of whom had > 0.3g/24 hr. Of these, 4 (7.4%) achieved complete proteinuria response (< 0.3g/24 hr) and 4 (7.4%) achieved partial response (< 1g/24 hr) by the 4th follow-up visit. The overall myeloma response (≥ partial response) was 38.0% achieved after a median of 2.9 (1.3–5.2) mos. LEN-based myeloma response was 45.5%, BORT-based 48.9% and LEN + BORT-based 50.0%. These responses seemed to be higher than those obtained with chemotherapy-based therapies (17.6%). The median time to progression (TTP) was 4.5 mos (95% CI 4.2–7.3). TTP was 16.2 mos with LEN-based, 11.8 mos with BORT-based, not reached with LEN + BORT-based, and 8.3 mos with chemotherapy-based therapies. Overall, 52% of pts had an AE and 12% a serious related AE.
Conclusions: The most commonly used Tx in clinical practice in RRMM pts with RI are LEN or BORT-based. The results of this interim analysis suggest that these Tx can improve RI in approximately 15% of cases, and are associated with a higher antimyeloma response than chemotherapy-based Tx.

Disclosures
Morales: Celgene: Consultancy. Ruiz Boza:Celgene : Employment, Other. Garcia:Celgene: Honoraria.