Treatment Outcomes of Monoclonal Gammopathy of Renal Significance with Novel Agents

Background: Monoclonal gammopathy of renal significance (MGRS) is a rare, heterogeneous disease that is commonly underdiagnosed. There is no consensus on the management of MGRS, particularly the choice of treatment regimen and the role of autologous stem cell transplant (ASCT).

Methods: Adults diagnosed with MGRS from 01/2011 to 12/2023 across five academic centers in the United States were included in this analysis. The study focused on renal disease with monoclonal plasma or B-cell clones that do not meet the definition of another malignancy, had hematopathological confirmation via a renal biopsy; cases of amyloidosis were excluded. Hematological (heme) responses to therapy were evaluated using the International Myeloma Working Group (IMWG) criteria. For light chain predominant MGRS, complete response (CR) was defined as negative serum and urine immunofixation and normal free light chain (FLC) ratio, while very good partial response (VGPR) was difference in FLC (dFLC) <40 mg/L. Renal response was defined as a decline of ≥30% of proteinuria in the absence of renal progression (termed as decline in eGFR ≥25%) (Palladini G, Blood 2014). The Kaplan-Meier method was used to estimate overall survival (OS). Chi-square test, Fisher’s exact test, and Wilcoxon rank sum test was used to compare variables between responders and non-responders.

Results: The 44 adults who met the inclusion criteria had median age at diagnosis of 64 years (38-81), with a male predominance of 57%. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) (30%) was the most common type of MGRS, followed by light chain deposition disease LCDD (20%) and light chain proximal tubulopathy (LCPT) (18%). Most prevalent clonal diagnosis was MGUS (51%) followed by smoldering myeloma (23%), predominantly kappa (64%) and/or IgG type (60%, 21/35). Seven patients (5 PGNMID) had no detectable serum/urine monoclonal protein or clonal light chain elevation at baseline. Renal dysfunction (noted in 76%, mean eGFR 36.3 mL/min/173.m², nine patients requiring dialysis) was more common presenting feature than nephrotic (26%, 9/35) or sub-nephrotic range proteinuria (31%, 11/35). Only one patient recovered independence from dialysis.

Frequently, upfront induction therapy included proteasome-inhibitors (PI) (78%), cyclophosphamide (43%) and/or daratumumab (32%); immunomodulatory (imid) agents were infrequently used (14%). Four patients received ASCT. Heme ORR was 88% (29/33) (24% ≥ complete response (CR), 52% ≥VGPR), and renal ORR was 39% (14/36) (22% CR). Hematological responders had higher rates of daratumumab exposure (92% vs 8%, p=0.05) and lower imid drug exposure (7% vs 93%, p<0.01) compared to the non-responders. Median TTNT for daratumumab use was numerically longer than those who did not receive daratumumab in front line (15 vs 12 months, p=0.4), however this was not statistically significant.

Median TTNT was 4.7 months, majority receiving daratumumab based therapy (61%, 14/23) in the second line, with 65% (13/20) achieving heme response and 43% (9/21) renal response. 5-year OS in the total cohort was 83%. Heme VGPR or better was the only factor significantly affecting time to next treatment (TTNT) (HR 0.07, p<0.001) on univariate and multivariate analysis.

Conclusion: Deeper hematological responses appear to be the most important factor for longer TTNT. Patients receiving novel treatments such as anti-CD38 monoclonal antibodies have better outcomes, however this was not statistically significant in our cohort, likely due to low numbers considering the rarity of MGRS. Renal responses continue to be low.