Effect of Daratumumab on Renal Outcome in Newly Diagnosed Multiple Myeloma with Light Chain CAST Nephropathy

Introduction:

Renal impairment is common during multiple myeloma (MM) and persistent reduction in kidney function strongly affects long term prognosis. Light chain cast nephropathy (LCCN) is the main mechanism involved in MM renal injury. With typical presentation (acute kidney injury with predominant light chain proteinuria and high serum free light chain), it is possible to forgo kidney biopsy.

Rehydration and correction of precipitating factors are urgent measures. However, it has been shown that fast reduction in free light chains is a key prognostic factor.

Since the MYRE study, bortezomib and dexamethasone-based therapies have become the keystone of first-line treatment. Daratumumab, an anti-CD38 antibody, has been proven efficient in MM and is now a first-line molecule in this setting because of fast and deep responses. However, data is lacking to assess its role in improving renal recovery.

Methods:

Patients with newly diagnosed MM and AKI (creatinine > 2 mg/dL or GFR estimated < 40 mL/min/1.7 m²) with presumed diagnosis of LCCN (iFLC > 400 mg/L and predominant light chain proteinuria) or biopsy proven LCCN treated by anti-CD38 during the first cycle of treatment were included from multiple French centers from 2020-2024. Primary outcome was renal response at 3 months as defined by the 2023 IMWG criteria's.

Results:

We included 85 MM patients, from 5 centers. The median age was 69 years, mostly men (55%) with 88 % who had a prior GFR > 60 mL/min/1.73m². Concerning the other CRAB criterias, 76% had anemia, 45% hypercalcemia and 72% osteolytic bone lesions. Most patients had light chain multiple myeloma (47%) followed by IgG myeloma (28%) and IgA myeloma (22%). Kappa light chain was most frequently involved (55%). Twenty six percent of patients had >= 2 high-risk cytogenetic abnormalities, 50% had 1, and 24% had none. Thirty-five percent of the patients had an R-ISS score of 3 and 57% of the patients had an R-ISS score of 2. Six (7%) had hyperviscosity syndrome.

Regarding renal impairment, the mean creatinine level at diagnosis was 449 µmol/L (5 mg/dL) with a mean estimated GFR of 10 mL/min/1.73m². Mean light chain proteinuria was 312 mg/mmol. The mean iFLC was 3890 mg/L with an average ratio of 279. The mean estimated monoclonal spike was 3 g/L. The most represented precipitating factor was the use of NSAIDs, found in 16% of the patients. Thirty-three (38%) patients had to undergo hemodialysis.

On the first cycle of therapy, the regimen used was either daratumumab bortezomib dexamethasone (DaraVd, 54%), daratumumab bortezomib cyclophosphamide dexamethasone (DaraVCd, 24%), daratumumab bortezomib lenalidomide dexamethasone (DaraVRd, 14%) or daratumumab lenalidomide dexamethasone (DaraRd, 1%). Seventy-two percent of the patients had an initial four-day course of Dexamethasone. Fifty-seven percent of patients had bortezomib twice a week in the first cycle while 43 % had Bortezomib weekly. Only sixty percent had Lenalidomide started on the first cycle, while 45% received it in ulterior cycles. Autologous stem cell transplantation was performed in 32% of pts.

At 3 months, 76% achieved a renal response (37% complete, 10 % partial and 29% minor response). Considering the 33 patients who underwent dialysis, the independence rate at any time was 62%.

Concerning hematologic response, 81% achieved at least a partial response including 40% in partial response and 41% in very good partial response. Ninety percent reduction of iFLC is achieved in 80 % at 1 month and 73 % at 3 months. Overall survival at 1 and 2 years was 80% and 73%, respectively.

One of the predictive factors in univariate analysis associated with renal response at 3 months was IMID's use during the first cycle (p=0.04). The renal response rate did not correlate with hematological response, probably due to a lack of statistical power.

Conclusions:

To our knowledge, it is the largest cohort of newly diagnosed MM patients with renal impairment due to LCCN treated by a daratumumab-based induction therapy. In our study, Daratumumab showed good efficacy in improving renal outcomes with a renal response rate at 3 months of 76%, compared with 45% in the MYRE study patients who were treated with bortezomib and dexamethasone. Furthermore, rapid use of IMID's in combination with daratumumab and bortezomib after the stabilization of the renal function should be considered.

In order to better study the prognostic factors, other centers are being analyzed to expand the cohort.