Proteinuria with Preserved Renal Function: A Retrospective Cohort Study of Myeloma Patients with Significant Proteinuria without Acute Kidney Injury
Authors: Hughes Michael Sang , Balev Metodi , Radhakrishnan Jai , Bhutani Divaya , Mapara Markus , Eisenberger Andrew , Lentzsch Suzanne , Chakraborty Rajshekhar 
Published: December 2024

INTRODUCTION
Myeloma cast nephropathy (MCN), in which patients present with renal dysfunction and Bence-Jones proteinuria, is a well-described negative prognostic marker in newly diagnosed multiple myeloma (NDMM). Some patients with NDMM present with significant Bence-Jones proteinuria without renal dysfunction. There are no data on their natural history. We describe the clinical course of patients who exhibit proteinuria with preserved renal function (PPRF).
METHODS
274 NDMM patients were treated 6/01/17-12/15/23, of which 21 were excluded for lack of data. We divided the cohort into three subgroups: (a) PPRF, defined by ≥1g/d proteinuria and involved FLC ≥50mg/dL with serum creatinine &lt;2mg/dL or eGFR of &gt;40mL/min/1.73m2; (b) MCN, defined by evidence of light chain casts on biopsy; or, involved FLC ≥50 mg/dL and serum creatinine of &gt;2mg/dL, or eGFR of &lt;40mL/min/1.73m2 and ≥1g/d proteinuria; and (c) controls, who did not meet PPRF or MCN criteria. We obtained retrospective data regarding clinical features and outcomes.
RESULTS
In our cohort, 31/253 patients (12.3%) had PPRF and 48/253 (18.9%) had MCN. The remaining 174 patients were contemporary controls. Median age for PPRF, MCN, and control patients was 65.0 years (IQR 57.0-75.0), 68.5 years (IQR 60.8-74.0), and 68.0 years (IQR 60.0-74.0) respectively (p=0.753). Sex, race, and ethnicity did not differ across cohorts and will be presented. The fraction of light chain myeloma in PPRF, MCN, and control patients was 41.9% (13/31), 58.3% (28/48), and 10.9% (19/174), respectively (p&lt;0.001). Baseline eGFR for PPRF, MCN, and control patients was 67.2 (IQR 52.4-91.8), 15.4 (IQR 9.9-25.7), and 75.7 mL/min/1.73m2 (IQR 55.7-98.2), respectively (p&lt;0.001). Median involved/uninvolved FLC ratio for PPRF, MCN, and control patients was 302.3 (IQR 94.0-438.9), 300.9 (IQR 161.4-694.8), and 16.3 (IQR 4.6-50.1), respectively (p&lt;0.001). Median 24 hour urine protein in PPRF, MCN, and control patients was 2.350g (IQR 1.435-4.061), 3.218g (IQR 1.520-6.465), and 0.209g (IQR 0.120-0.453) respectively (p&lt;0.001). Median urinary albumin fraction for PPRF, MCN, and control patients was 27.4% (IQR 21.3-32.9), 21.1% (IQR 18.4-31.3), and 82.2% (IQR 51.2-93.5%) respectively (p&lt;0.001).
Median time to treatment for PPRF, MCN, and control patients was 8.0 days (IQR 1.5-20.5), 6.0 days (IQR 1.0-11.5), and 19.0 days (IQR 7.0-37.0), respectively (p&lt;0.001). The fraction of those who received upfront anti-CD38+ monoclonal antibody for PPRF, MCN, and control patients was 58.1% (18/31), 62.5% (30/48), and 52.9% (92/174) respectively (p=0.006). The rate of autologous stem cell transplant (ASCT) for PPRF, MCN, and control patients was 41.9% (13/31), 41.7% (20/48), and 37.4% (65/174, p=0.800).
No PPRF patient needed renal replacement therapy (RRT) within 6 months of treatment initiation; 7 MCN patients initially required RRT, and 4 required RRT after 6 months. Overall response rate by International Myeloma Working Group criteria in PPRF, MCN, and control cohorts was 86.7% (26/30), 93.6% (44/47), and 91.3% (137/150); and the rate of VGPR or better was 66.7% (20/30), 65.2% (30/46), and 69.8% (104/149), respectively (p=0.569, p=0.141). Median follow-up for PPRF, MCN, and control patients was 18.4 months (IQR 9.3-55.1), 24.4 months (IQR 14.9-37.9), and 33.6 months (IQR 17.9-49.8), respectively. Cox survival analysis showed no overall survival (OS) difference among the cohorts (p=0.361). Mortality estimates at 6 months for PPRF, MCN, and control patients were 6.6 +/- 4.5%, 0.0 +/- 0.0%, and 1.2 +/- 0.8% (p=0.257); OS estimates at 18 months for PPRF, MCN, and control patients were 82.1 +/- 7.3%, 90.7 +/- 4.5%, and 93.6 +/- 2.0% (p=0.193). Mean OS for PPRF and control patients were within 9 months by equivalence testing (p=0.042). Factors for increased mortality in stepwise multivariate analysis were age (β 1.035, p=0.033); and ISS stages 2 (β 4.943, p=0.031) and 3 (β 10.624, p=0.003).
CONCLUSIONS
We present the first description of clinical outcomes in NDMM patients with significant proteinuria without renal dysfunction, in the context of modern therapy. They exhibit proteinuria comparable to MCN patients but do not develop new need for RRT over 6 months. They do not have a higher risk of early 6 month or later 18 month mortality compared to controls. Updated data on trajectory of proteinuria and renal function in the PPRF cohort compared to MCN patients will be presented at the meeting.