Early daratumumab therapy improves renal outcomes in newly diagnosed patients with myeloma admitted with kidney injury Open Access

Renal impairment is a frequent complication in multiple myeloma (MM), significantly affecting both disease prognosis and treatment efficacy. Cast nephropathy is a major cause of renal injury in patients with MM experiencing severe acute kidney injury (AKI), in which the accumulation of monoclonal light chains in the distal nephron leads to the formation of aggregates and subsequent obstruction of the distal and collecting tubules. The risk of cast nephropathy increases when serum free light chain (sFLC) levels exceed 500 mg/L.¹ Up to half of newly diagnosed patients with MM exhibit renal impairment, with 2% to 4% requiring dialysis.² In addition, patients presenting with severe AKI (estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m²) historically have increased risk of earlier mortality.^3,4 The likelihood of renal recovery depends on several factors, such as the initial treatment regimen, severity of renal impairment, and calcium levels.⁵ Importantly, restoration of renal function depends on early reduction of sFLCs, and this was an independent predictor of survival.⁶ 

Daratumumab, a monoclonal antibody targeting CD38, is highly effective for relapsed or refractory MM, beginning with its approval in the United States in 2015 for relapsed disease. Subsequently, its application extended to first-line therapy in combination with standard-of-care regimens in 2018.⁷ The mechanism of action of daratumumab involves multiple processes, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and immunomodulatory effects.⁸ Through these mechanisms, daratumumab directly reduces tumor burden and reduces the production of immunoglobulins and monoclonal light chains.⁸ Although daratumumab demonstrates remarkable efficacy in clinical trials, its impact on renal responses in the first-line setting is not as well described. We investigated the effects of early initiation of daratumumab-based therapy on sFLC reduction and renal recovery in patients hospitalized with a new diagnosis of MM and AKI.

This was a retrospective, single-center study. The institutional review board approved a protocol for retrospective review of patient data. We conducted a database search to identify patients who received daratumumab during or shortly after inpatient admission at Massachusetts General Hospital between December 2018 and December 2023. Included in the analysis were adult patients hospitalized with newly diagnosed MM who met all the following criteria: presenting with AKI (serum creatinine [sCr] ≥2 mg/dL and/or eGFR <30 mL/min per 1.73 m² by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]); involved sFLC ≥500 mg/L; and initiation of daratumumab-based therapy within 14 days of disease presentation. Outcome measures included the following: (1) light chain kinetics after 1 cycle of daratumumab-based therapy, including time to sFLC reduction by at least 50% from initial presentation and time to sFLC reduction <500 mg/L; (2) renal response outcomes at 3 months and the rate of achieving dialysis independence at 3 and 12 months; and (3) MM disease outcomes. The timing of measuring sFLCs was per the treating physician. We assessed renal and MM disease response according to the International Myeloma Working Group (IMWG) criteria.^9,10 Follow-up was determined by reverse Kaplan-Meier (KM) method.¹¹ Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the first dose of daratumumab.

We identified 20 patients who met the inclusion criteria. Key baseline characteristics are summarized in Table 1. The median age at diagnosis was 65 years (range, 44-87). At the time of admission, the median peak serum creatinine was 6.5 mg/dL (range, 3.1-17.8), with a median eGFR of 8 mL/min per 1.73 m² (range, 2-16). Nine patients required the initiation of dialysis during their hospitalization. The median peak involved sFLC at diagnosis was 6603 mg/L (range, 1839-26 023). sFLCs were measured at a median interval of 4 days for the first 30 days after starting daratumumab treatment (range, 1-17). Five patients (25%) had high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. All patients received daratumumab as part of combination therapy. The initial daratumumab-based regimens were with bortezomib, cyclophosphamide, and dexamethasone (VCd; dara-VCd) in 11 patients (55%) and with bortezomib and dexamethasone (Vd; dara-Vd) in 9 patients (45%). Three patients (15%) were treated with the IV formulation of daratumumab before the approval of subcutaneous daratumumab in 2020, and 17 patients (85%) received subcutaneous daratumumab. The median time between the day of admission and daratumumab initiation was 3 days (range, 0-10), and no patients underwent plasmapheresis. The median number of inpatient administrations was 1 dose (range, 1-3); 2 patients started daratumumab as outpatients shortly after discharge. The median length of stay was 11.5 days (range, 2-46). Lenalidomide was added in subsequent cycles in 14 patients (70%), with the majority of patients starting it in their second cycle (range, 2-5) at a median of 36 days (range, 21-118). The median starting dose was 10 mg (range, 5-25). Only 1 patient increased the dose from 5 to 15 mg, 59 days after starting lenalidomide. Stem cells were collected in 8 patients (40%), and 3 patients (15%) underwent high-dose melphalan and autologous stem cell transplant. Treatment details are summarized in Table 2.

Within the first cycle of daratumumab-based therapy, all patients achieved ≥50% reduction from their baseline sFLC, with a median of 3 days (95% confidence interval [CI], 3-7; Figure 1A). The median time to reach reduction of sFLC to ≤500 mg/L was 14.5 days (95% CI, 9-49), and this was achieved in 15 of 17 patients (88%) assessable for response at 28 days (Figure 1B). Three patients were not assessable after completing 1 cycle: 1 patient did not have a sFLC measurement by 28 days; 1 patient died; and 1 patient was lost to follow-up.

Using the IMWG criteria for renal response to antimyeloma treatment,² the overall renal response (minor response or better) at 3 months after daratumumab-based therapy was 85% (n = 17), with complete, partial, and minor responses in 50% (n = 10), 10% (n = 2), and 25% (n = 5), respectively (Figure 2). There was a trend toward a faster time to sFLC ≤500 mg/L in patients who achieved a complete renal response (median, 10 days) compared with patients with less than a complete response (median, 22.5 days; P = .2, by log-rank test). By subgroup, the time to sFLC ≤500 mg/L was as follows: partial (20.5 days), minor (18 days), and no response (49 days; supplemental Figure 1). At 3 months, 12 patients (60%) recovered their renal function to creatinine clearance of 40 mL/min or better, exceeding the cutoff definition of renal impairment as a result of symptomatic myeloma per IMWG critera.^2,12 

Nine patients required dialysis during admission. Baseline sFLC was not significantly different between the 2 groups (required dialysis [mean sFLC, 6933 mg/L] vs no dialysis [mean sFLC, 9348 mg/L]; P = .37). Of the 9 patients who required dialysis at presentation, 4 of 7 (57.1%) and 6 of 7 (85.7%) achieved dialysis independence at 3 months and 12 months, respectively (Figure 2). Two patients on dialysis died within 3 months (age 86 years, from aspiration pneumonia; age 87 years, from disease progression); and 1 patient continued dialysis at 12 months. All 3 patients who had CKD before diagnosis of MM required dialysis, and 2 of these 3 were able to discontinue dialysis; 1 patient died from disease progression, as noted earlier. Moreover, the time to sFLC ≤500 mg/L was longer in patients who discontinued dialysis (n = 3) than those who continued dialysis (n = 6), at a median of 24 vs 11 days (P = .4 by log-rank test), while noting caution in making these comparisons given the very small number of patients.

All patients responded, with VGPR in 90% and partial response (PR) in 10%. With a median follow-up of 25 months, the median PFS was 47 months (95% CI, 12 to not reached; supplemental Figure 2A), and the 2-year OS was 84% (95% CI, 68-100; supplemental Figure 2B).

The introduction of novel agents and new treatment combinations has significantly improved both hematologic response and OS of patients with MM. Despite these advances, patients with renal impairment continue to have poor prognosis, especially those who require dialysis. Historically, patients with cast nephropathy who required dialysis and had no recovery in renal function had 50% survival of less than a year, with improvement to 50% survival at 3 years in those who eventually became dialysis independent.¹³ Early initiation of therapy to rapidly reduce sFLCs is essential to recover renal function in cast nephropathy, and this recovery is associated with significantly improved survival, with a median survival of ∼43 months in those with renal recovery compared with 8 months in those without.^6,13,14 

For patients with MM presenting with de novo AKI, bortezomib-based therapies have emerged as a key treatment due to their ability to rapidly reduce sFLC concentrations, provide favorable effects on the kidney and tubular cells, and undergo nonrenal metabolism, leading to safe administration at full doses.^2,13 In recent years, the incorporation of the CD38-directed monoclonal antibody daratumumab into frontline therapy for MM has emerged as a new treatment paradigm due to its ability to induce deep and durable response without significantly adding toxicities.¹⁵ However, data are limited in patients with severe renal impairment or dialysis, because these patients are often excluded in major trials.¹⁶ In addition, concerns about reimbursement are often a barrier to inpatient initiation of daratumumab.

In our study, we present a cohort of newly diagnosed patients with MM who were hospitalized with severe AKI and a significant disease burden, based on a median peak SCr of 6.5 mg/dL and peak sFLC of 6603 mg/L. Almost half of the patients (45%) required dialysis during their hospitalization. We started daratumumab-based therapy at a median of 3 days, either in combination with VCd or with Vd, and we observed rapid and substantial reduction of sFLC within the first cycle of treatment. All 20 patients (100%) rapidly achieved a sFLC reduction of ≥50% from their initial value, and after 1 cycle, 15 of 17 patients (88%) assessable for response achieved sFLC reduction to ≤500 mg/L in a median of 14.5 days. Achieving sFLC ≤500 mg/L is an important goal, because it was a predictor of dialysis independence at 12 months in the MYRE study.¹⁷ Similarly, timely responses are essential, because analysis of patients with severe renal failure showed that 60% reduction of sFLC by day 21 was associated with renal recovery in 80% of the patients in the model.⁶ Results from our cohort with daratumumab-based therapy reflected these findings. Although the numbers are small in our analysis, patients with a complete renal response trended toward an earlier reduction of sFLC to ≤500 mg/L compared with those without a complete response (10 vs 22.5 days, respectively). However, we did not observe this association with the early reduction of sFLC and achieving dialysis independence. This may be due to the even smaller number of patients in the comparison, as well as other factors playing a role in dialysis; for example, 2 of the 3 patients who continued dialysis were aged ≥85 years.

Acknowledging the limitations of crosstrial comparisons, our results incorporating daratumumab compare favorably with a previous study of bortezomib-based therapies in patients with MM with AKI.¹⁸ That study evaluated VCd vs Vd and showed sFLC ≤500 mg/L occurring after 1 cycle in 72.8% and 75% of patients, respectively, compared with 88% of patients in our cohort.

Notably, the outcomes in our patients were achieved without plasmapheresis. Mechanical removal of free light chains with plasmapheresis has been recommended in combination with antimyeloma therapy for acute light chain cast nephropathy.¹⁶ More recently, a retrospective study assessed the outcomes of plasmapheresis in 80 patients with cast nephropathy after the introduction of novel agents; these patients presented with a median creatinine of 6.03 mg/dL, and 56.25% required dialysis.¹⁹ Most patients (64%) received proteasome inhibitor–based therapy, whereas only 25% of the patients received daratumumab-based therapy concurrently with plasmapheresis. In their study, 72.5% achieved an sFLC reduction of ≥50% from their initial level, which is less favorable than our cohort of patients treated with daratumumab combinations who all met this goal.

An alternative to plasma exchange for mechanically removing circulating light chains is dialysis using high-cutoff membranes. However, 2 randomized studies, MYRE¹⁷ and EuLITE,²⁰ did not show improvement in dialysis independence when dialysis with high-cutoff membranes was combined with bortezomib-based treatment. Moreover, OS was worse in the EuLITE study. An approach without plasmapheresis has the advantage of avoiding access-related complications, as well as the burden of transfer to a site for performing plasmapheresis and the resource demands of coordinating this procedure. Moreover, plasmapheresis may potentially lower the efficacy of daratumumab by removing daratumumab from circulation.

The goal of early and rapid reduction in sFLCs is to improve the rates of renal recovery. In our study, the overall renal response (minor response or better) at 3 months after daratumumab-based therapy initiation was 85% (n = 17). This compares positively with the findings from the randomized study of VCd vs Vd, in which the renal response rate at 3 months was 47% vs 41%.¹⁸ Similarly, in the plasmapheresis retrospective study, the renal response rates at 3 and 6 months were 47.5% and 43.75%, respectively.¹⁹ Moreover, 6 of 7 patients in our study were free of dialysis at 12 months (although 2 patients who were frail and aged 85 years and 86 years died before the 3-month mark), compared with 40.4% of the patients in the retrospective study.¹⁹ 

Early use of daratumumab-based combinations showed high hematologic responses, in which all 20 patients responded, with 90% achieving VGPR, and the median PFS was 46.5 months (95% CI, 11.9 to not reached), and the 2-year OS was 83.7% (95% CI, 68.4-100). This performs well relative to the above plasmapheresis retrospective study, in which the overall response rate was 67.5%, and the median OS was 11 months, with a median follow-up of 36.4 months.¹⁹ Similarly, compared with the trial evaluating bortezomib-based therapy as initial management, VGPR or better was achieved in only 51% in the VCd arm.¹⁸ 

Recent studies are beginning to highlight the use of daratumumab combinations in this patient population, with similar findings. This includes a phase 2 trial evaluating daratumumab in combination with Vd (and later thalidomide or lenalidomide) in 13 newly diagnosed patients with a median creatinine clearance of 13.8 mL/min.²¹ The study showed a 100% overall response rate and general improvement in renal function, although details of the renal response or sFLC kinetics have not been reported. A French group has recently presented data on 89 patients treated across 6 centers in France, with a mean creatinine of 5 mg/dL with daratumumab-based combinations, including dara-Vd (54%) and dara-VCd (24%).²² Their study showed a 90% reduction of sFLC in 80% at 1 month and renal response rate of 76% at 3 months, similar to our cohort.

Our study had several limitations including the retrospective study design and small sample size. Cast nephropathy was not pathologically confirmed by kidney biopsy, but increasingly, the role of kidney biopsy has been minimized²; moreover, all our patients had sFLCs well above 500 mg/L. We did not have a comparator arm who did not receive daratumumab as initial treatment, because our practice has evolved to include early initiation of daratumumab. Finally, we note that these findings are likely generalizable to anti-CD38 monoclonal antibodies as a class; isatuximab, another approved anti-CD38 monoclonal antibody, may be an option as well.

To our knowledge, this is the largest reported cohort in the United States of newly diagnosed patients with MM who presented with AKI, were hospitalized, and treated with daratumumab-based induction therapy without using plasmapheresis. Treatment with daratumumab combinations demonstrated rapid and significant reductions in sFLCs and high renal response rates, and these findings compare favorably with outcomes from older regimens. These findings highlight the efficacy of early use of daratumumab in patients with MM and AKI and provide an approach without plasmapheresis.

The authors acknowledge the care and input from pharmacy and nursing for the special care of these patients.

Contribution: E.B.K. and A.J.Y. designed the study and analyzed the data; J.E.M., M.L., S.S.H., and C.W.M. collected and organized the data; A.R.B., E.K.O., D.C., N.S.R., and A.J.Y. cared for the patients; and all authors were involved in drafting, contributing to, and approving the manuscript.

Conflict-of-interest disclosure: M.L. reports consulting for BTG Therapeutics, AstraZeneca, Genentech, Genmab, and MJH Life Sciences. E.K.O. reports consulting for Janssen, Bristol Myers Squibb (BMS), Sanofi, Pfizer, Exact Sciences, and Grail; and steering committee fees from Natera. D.C. reports consulting for Sanofi. N.S.R. reports consulting for AbbVie, Amgen, BMS, Janssen, Pfizer, Immuneel, GlaxoSmithKline (GSK), K36 Therapeutics, Sanofi, and AstraZeneca; and research funding from Pfizer. A.J.Y. reports consulting for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Johnson & Johnson (Janssen), Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda; and research funding to institution from Amgen, BMS, GSK, Johnson & Johnson (Janssen), and Sanofi. The remaining authors declare no competing financial interests.

The current affiliation for E.K.O. is Dana-Farber Cancer Institute, Boston, MA.

Correspondence: Andrew J. Yee, Massachusetts General Hospital Cancer Center Boston, 55 Fruit St, Boston, MA 02114; email: ayee1@mgh.harvard.edu.