An International Study of 343 Newly Diagnosed MM Patients with Acute Renal Failure Due to Cast Nephropathy: Assessment of Factors Affecting Renal Response

Introduction: Acute kidney injury (AKI) due to cast nephropathy is a medical emergency that leads to a diagnosis of myeloma in less than 3% of cases, but up to 30% of patients develop kidney impairment during the course of their disease. Currently, studies aiming to identify parameters that correlate with kidney function recovery and response to myeloma are limited due to small sample size or single center reports. We have therefore initiated an international collaboration and collected a large number patients (pts) from 16 participating centers.

Objectives: To assess the impact of pts and disease characteristics and treatment-specific factors on renal outcome and overall survival and to validate the IMWG criteria for renal response in pts with cast nephropathy and newly diagnosed MM.

Patients and Methods: Three-hundred forty-three pts (median age: 65.5 range 35-93 yrs) with newly diagnosed MM and an eGFR <40ml/min/1.73m² have been selected from 704 pts that had been enrolled in the database hosted by RedCap. Eligibility criteria were a diagnosis of AKI due to cast nephropathy diagnosed either by kidney biopsy (n=119) or on clinical criteria (AKI in the setting of involved free light chain concentration of ≥500 mg/L), newly diagnosed multiple myeloma, >2 cycles of therapy, time and type of therapy, best eGFR and best myeloma response available.

Results: Median follow up was 36.9 months. Myeloma therapy resulted in renal CR, and PR as defined by the IMWG criteria in 131 (38.2%) and 57 (16.6%) pts, respectively, 54 (15.7%) and 82 (23.9%) pts had minor response or no response, respectively. Nineteen (5.5%) pts were not classifiable by the IMWG response criteria (pts with eGFR 15-<30, with increase to eGFR to ≥30-<40). An eGFR of >60, ≥30-<60, ≥15-<30, and <15ml/min was achieved by 131 (38.2%), 112 (32.7%), 67 (19.5%), and 33 (9.6%) pts respectively. Myeloma response (≥VGPR) correlated significantly with renal response (≥PRrenal) (OR 1.64, CI 1.05-2.56, p=0.03) and with OS compared to no myeloma response (median 89.7 vs. 39.7 months, HR 2.12, CI 1.55-2.89, p<0.0001). A >50% reduction in FLCs from baseline to treatment cycle 2 (OR 5.92, CI 2.15-19.23, p=0.001) and cycle 3 (OR 5.25, CI 2.15-19.25, p=0.006) were strongly associated with renal response

Median OS was 69.6 months (CI 55.4-89.7). Forty-three pts died within the first 12 months of treatment and additional 146 during further FU. Pts with a best GFR of >15ml/min had a significantly longer OS compared to those with GFR <15ml/min (median: 77.9 vs 31.9 months, HR 1.85, CI 1.16-2.94, p=0.01). The comparison of survival of pts with different renal response groups and with the best eGFR showed no statistically significant difference (log rank p=0.1, long rank p=0.057, respectively).

Other factors that correlated with longer OS were bortezomib-based therapy (77.9 vs. 44.0 months, HR 1.59, CI 1.05-2.38, p=0.03), M-protein isotype with κ as compared to l light chain type (84.9 vs. 51.4 months, HR 1.47, CI 1.09-2.00, p=0.013), and higher hemoglobin (HR 1.16, CI 1.06-1.26, p=0.001). In contrast, hypercalcemia which was noted in 101 (29.4%) pts (HR 1.10, CI 1.03-1.18, p=0.005), ISS stage III vs. I-II (57.8 vs. 126.2 months, HR 2.26, CI 1.22-4.17, p=0.009), and ECOG status 3+4 vs. 2 vs. 0+1 (24.4 vs. 44.6 vs. 103 months, HR 2.83, CI 2.15-3.74, p<0.0001) were associated with shorter OS. Hypercalcemia, correlated with renal response (OR 1.27, CI 1.12-1.44, p=0.0002), and best eGFR ≥46.4 ml/min (median dichotomized) (OR 1.28, CI 1.14-1.46, p<0.0001).

119 (34.7%) pts required initial dialysis, OS was significantly longer in those who achieved best eGFR levels of >15ml/min. (77.6 vs 31.9 months, HR 0.54, CI 0.34-0.86, p=0.01); 64 (53%) pts discontinued dialysis.

Conclusion: Myeloma response correlated with renal response as defined by IMWG criteria. A >50% reduction in FLCs from baseline to treatment cycle ≥2 was strongly associated with renal response. OS was longer in pts with renal response, in pts receiving bortezomib-based therapy, and in pts with kappa light chain M-proteins. Hypercalcemia was frequent (29.4%), and associated with higher renal response rate and best eGFR, but shorter OS. Pts on dialysis who achieved eGFR >15ml/min had better survival. Fast diagnostic work up, rapid treatment initiation and achieving significant myeloma response (≥VGPR) is essential to prevent irreversible kidney damage. Including novel immunotherapies may further improve outcome.

Ludwig:Takeda: Other: Honoraria (speakers bureau, advisory boards, DMC); Sanofi: Other: Honoraria (speakers bureau, advisory boards, DMC), Research Funding; Amgen: Research Funding; Bristol Myers Squibb: Other: Honoraria (speakers bureau, advisory boards, DMC); Menarini: Other: Honoraria (speakers bureau, advisory boards, DMC); Oncopeptides: Other: Honoraria (speakers bureau, advisory boards, DMC); GlaxoSmithKline: Other: Honoraria (speakers bureau, advisory boards, DMC); Janssen: Other: Honoraria (speakers bureau, advisory boards, DMC); Pfizer: Other: Honoraria (speakers bureau, advisory boards, DMC). Dimopoulos:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac:GSK: Research Funding; Menarini: Consultancy, Other: advisory; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau. Bridoux:GSK: Speakers Bureau; Lilly: Speakers Bureau; Sanofi: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Consultancy. Cengis-Seval:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Menarini: Consultancy; BMS: Speakers Bureau; Takeda: Consultancy. Arcaini:Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Agis:BMS: Honoraria; AMGEN: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gay:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees. Chaidos:Roche: Consultancy. Havasi:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mangiacavalli:IRCCS Fondazione Policlinico San Matteo, Pavia: Current Employment; BMS: Consultancy, Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini Stem Line: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria. De La Rubia:GlaxoSmithKline: Consultancy, Other: Expert Testimony, Travel, Accommodations, Expenses; Sanofi: Consultancy, Other: Expert Testimony, Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Expert Testimony, Travel, Accommodations, Expenses; Karyopharm Therapeutics: Consultancy, Other: Expert Testimony; Pfizer: Consultancy, Other: Expert Testimony; Menarini: Consultancy; Amgen: Other: Expert Testimony, Travel, Accommodations, Expenses, Speakers Bureau; Bristol Myers Squibb: Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene: Other: Expert Testimony. Jhaveri:PMV pharmaceuticals: Consultancy; Decipher: Consultancy; Otsuka: Consultancy; George Clinicals: Consultancy; Novartis: Consultancy; Citrus Oncology: Consultancy; American Society of Nephrology and Lexicomp: Honoraria; UpToDate.com: Other: paid contributor. Leung:AbbVie: Current holder of stock options in a privately-held company; Checkpoint Therapeutics: Current holder of stock options in a privately-held company. Kastritis:GSK: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria.