Upfront Use of Anti-CD38 Monoclonal Antibodies Is Associated with Improvement in Renal Failure in Multiple Myeloma: A Flatiron Real World Analysis from 2010 to 2023

INTRO:

Renal failure can occur in newly diagnosed multiple myeloma (NDMM) due to cast nephropathy and other mechanisms. Anti-CD38 monoclonal antibody (CD38 mAb) therapy (namely, daratumumab and isatuximab) is being used more frequently in patients with renal failure and in the broader NDMM setting. However, there is limited information on its clinical efficacy and its impact on improving renal function. We sought to investigate the benefit of the use of these drugs in multiple myeloma in renal failure using real world data.

METHODS:

The nationwide Flatiron Health electronic health record-derived de-identified database was utilized. Patients aged 18 years or older with NDMM beginning treatment between Dec 2010 - Nov 2023 were included in this retrospective analysis. Patients with unavailable lab data or frontline treatment data were excluded. Patients were separated by renal failure status by creatinine clearance (CrCl), calculated by the Cockgroft-Gault equation. Creatinine clearance was chosen as patients were expected to have evolution in the serum creatinine levels and fluctuations in body mass during the course of treatment. Patients with CrCl < 45 mL/min were deemed to be in renal failure and those with CrCl ≥ 45 ml/min were not. Patients were considered to have been treated with anCD38 mAb if they had daratumumab, daratumumab/hyaluronidase, or isatuximab exposure as part of frontline treatment. We utilized descriptive statistics and constructed a generalized linear mixed model (GLMM) to assess the impact of CD38 mAb over time on CrCl as the dependent variable. Included variables were CD38 mAb status (binary variable), time, an interaction term, and adjustments for age, sex, and race/ethnicity. We further conducted a Cox proportional hazards model to assess the association of CD38 mAb status on overall survival (OS) adjusting for age, sex, and race/ethnicity. All analysis was done in SAS version 9.4 (SAS Institute, Cary, NC).

RESULTS:

A total of 14,125 patients were included in the total cohort. 3680 (26%) patients had renal failure (CrCl < 45 mL/min) and 10,445 (74%) did not (CrCl ≥ 45 mL/min). 8120 (57.5%) patients had CrCl > 60. Overall, twelve percent of patients were treated with a CD38 mAb. Among patients with renal failure (CrCl < 45), 11.4% received CD38 mAb compared to 12.1% without renal failure (p = 0.2365). Among those treated with a CD38 mAb, intravenous daratumumab was given in 39%, subcutaneous daratumumab/hyaluronidase was given in 60%, and isatuximab was given in 1%. Males represented 54.2% of the cohort while females were 45.8%. Non-Hispanic Whites were 55.0%, non-Hispanic Blacks 17.4%, Asians 2.0%, and Other/unknown 25.6% of the cohort. Patients with renal failure were older (81.7% were ≥ 65 years old vs 59.5% were ≥ 65 years old; p < 0.0001). Among those with renal failure, 47.8% were male compared to 56.5% without renal failure (p < 0.0001). Over the study period of 13 years, 55.8% of patients with renal failure died with median OS 1.7 years while 37.1% of patients without renal failure died with median OS 2.7 years. These findings highlight significant differences in demographics and outcomes between patients with and without renal failure. In the Cox proportional hazards model adjusting for age, sex, and race/ethnicity, CD38 mAb status did not change overall survival (HR = 0.93, p = 0.444, 95% CI 0.759 to 1.128. In the GLMM for patients with renal failure and adjusting for age, sex, and race/ethnicity, the effect of CD38 mAb exposure over time was statistically significant and favorable for CrCl compared to those with no exposure to CD38 mAb, β = 0.020, p < 0.0001, 95% CI 0.013 to 0.025. Time alone was significant with β = 0.019, p < 0.0001, 95% CI 0.017 to 0.021.

CONCLUSION:

In this large real-world study, frontline use of CD38 mAb (daratumumab, daratumumab/hyaluronidase, and isatuximab) in NDMM patients with renal failure showed a statistically significant improvement in renal function. The upfront use of these drugs was overall low in about 11% of patients with renal failure (CrCl < 45 mL/min). The OS of patients with renal failure remains expectedly lower compared to patients without renal failure. This study was limited by the retrospective nature of the data and thus the results are correlational rather than causal. Future research should delve further into finer subgroup analyses with more specific drug regimens and their impact on renal function over time.