Predictors of renal recovery in newly diagnosed multiple myeloma with light chain cast nephropathy Free

Background:

Light chain cast nephropathy (LCCN), characterized by monoclonal free light chain (FLC)–mediated tubular obstruction, is a leading cause of severe acute kidney injury (AKI) in multiple myeloma. Historical cohorts reported 6-month mortality of 16–23% and renal response rates of approximately 50%. Daratumumab, an anti-CD38 monoclonal antibody, accelerates plasma cell clearance and may expedite FLC reduction, potentially improving renal outcomes. Pivotal myeloma trials have largely excluded patients with severe renal impairment, creating a therapeutic gap in this high-risk population. Despite this, clinical predictors of renal recovery in patients with LCCN remain poorly defined.

Objective:

To identify clinical and treatment-related predictors of renal response and dialysis-free survival in newly diagnosed multiple myeloma (NDMM) patients with LCCN.

Methods:

We retrospectively analyzed NDMM patients at the University of Kansas Medical Center from January 2020 to July 2025 with a clinical diagnosis of LCCN, defined as creatinine >2 mg/dL, eGFR <40 mL/min/1.73m², and dFLC >50 mg/L. Patients with prior myeloma therapy, AL amyloidosis, or other glomerulopathies were excluded. Baseline demographics, disease features, treatment timing, and response metrics were compared between renal responders—defined as those achieving Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), or Minimal Response (MR) per IMWG 2016 criteria—and non-responders. High-risk cytogenetics were defined according to the new IMS criteria: at least 20% deletion of 17p; biallelic del(1p32); or any two of the following: t(4;14), t(14;16), gain of 1q, or del(1p32).

Results:

Among 129 screened patients with NDMM and AKI, 26 met inclusion criteria; 50% required dialysis at presentation. Median age was 68 years (range 46-80) with 27% Black. RISS stages II and III were present in 58% and 42% of cases, respectively, with similar distribution between responders and non-responders.

High-risk cytogenetics occurred in 23%, and 3 had primary plasma cell leukemia. Median GFR at presentation was 9 mL/min/1.73m² for responders and 6 mL/min/1.73m² for non-responders (p=0.5). Median dFLC was 1004 mg/dL in responders vs. 1523 mg/dL in non-responders (p=0.053). All patients received proteosome inhibitor-based induction; 35% received Daratumumab in cycle 1. Median time to therapy was 3.5 days (IQR 2–19.5); time to Daratumumab was 21 days (IQR 15–38).

Renal response was achieved in 14 patients (54%), consisting of CR in 12%, PR in 12%, and MR in 31%. Responders were significantly younger (67 vs. 73 years, p=0.003) and had higher BMIs (28 vs. 24, p=0.041). The dFLC declined by 73% after one cycle in responders vs. 67% in non-responders. All responders achieved dFLC <100 mg/L; 71% did so within 2 cycles. Among dialysis-dependent patients, 5 (38%) discontinued dialysis by 6 months. Only one patient required dialysis initiation post-induction.

Daratumumab use was numerically higher in responders (43% vs. 25%) and administered earlier (median 18 vs. 38 days) but did not reach statistical significance (p=0.4). Among the 9 patients receiving Daratumumab-based induction, median dFLC reduction was 71% after 1 cycle and 95% after 2 cycles, compared to 67% and 85% in non-Daratumumab patients (p=0.064). Hematologic VGPR or better was achieved in 71% of renal responders vs. 50% of non-responders. Additionally, 57% of responders received ASCT vs. 33% of non-responders.

With median follow-up of 26.3 months, median progression-free survival was not reached in responders and was 47.9 months in non-responders. Median overall survival was not reached in either group.

Conclusion:

In NDMM patients with LCCN, younger age, higher BMI, early FLC reduction, and earlier Daratumumab administration were associated with improved renal response and dialysis independence. While trends favored early Daratumumab use, significance was limited by sample size. These data underscore the importance of rapid initiation of effective therapy in LCCN. Our findings support incorporating early Daratumumab in induction therapy and merit prospective validation.