Impact of Kidney Histology and Choice of Treatment on Survival in Patients with Multiple Myeloma

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Abstract

Key Points

• Kidney involvement in patients with multiple myeloma has many different findings in kidney histology.

• Persistent dialysis requirement is a major cause of mortality.

• The rapid initiation of modern myeloma therapy is essential to prevent the need for dialysis and reduce mortality.

Background

Acute or CKD affects 20%–40% of patients with multiple myeloma (MM). While the negative prognostic effect of kidney involvement is established, the specific effect of different histological patterns remains poorly understood. We aimed to characterize the clinical outcomes associated with distinct kidney histologies in patients with MM.

Methods

We retrospectively analyzed 193 patients with MM who underwent kidney biopsy, comparing outcomes with 62 patients with MM without kidney disease. Patients were categorized by histological findings: cast nephropathy (CN, n=120), lightchain (AL) amyloidosis (n=19), monoclonal Ig deposition disease (MIDD, n=8), and other renal disease (n=46). We evaluated kidney function, dialysis requirements, treatment responses, and survival across histological subtypes and treatment modalities (conventional therapy versus modern agents including proteasome inhibitors, CD38 antibodies, and autologous stem cell transplantation).

Results

The CN and MIDD groups had the lowest median eGFR at biopsy (13.0 and 25.5 ml/min per 1.73 m², respectively). Nephrotic-range proteinuria (>3.5 g/24 hours per Kidney Disease Improving Global Outcomes) was observed in the AL amyloidosis group (median 3910 mg/24 hours). KRT was initiated in 42.5% of patients. The proportion achieving KRT independence was 42.4% in the CN group and 50% in the other renal disease group, whereas none in the AL amyloidosis or MIDD groups recovered sufficient native kidney function. Modern combination therapy significantly improved renal outcomes, with 100% of patients receiving triple therapy showing renal response. KRT dependency was the strongest predictor of mortality: Patients remaining on KRT had significantly shorter survival compared with those never requiring KRT (12.7 versus 56.2 months, P < 0.001). The extent of improvement in kidney function did not influence survival; only dialysis status was prognostically relevant.

Conclusions

Kidney histology determines distinct clinical trajectories in patients with MM, with CN showing potential for dialysis reversibility. Modern combination therapies significantly improve renal outcomes. The requirement for ongoing KRT was the primary predictor of overall survival.

Introduction

Acute or CKD affects 20%–40% of patients with multiple myeloma (MM) at diagnosis and represents the most prognostically significant calcium, renal impairment, anemia, bone criterion, with kidney failure being the second leading cause of death after infections.^1–3 While cast nephropathy (CN) with creatinine >2 mg/dl defines myeloma-related kidney disease, other paraprotein-mediated pathologies, including lightchain (AL) amyloidosis and monoclonal Ig deposition disease (MIDD), also cause significant morbidity.^4–6

Modern therapies including proteasome inhibitor (PI), CD38 antibodies (CD38), and autologous stem cell transplantation (ASCT) have transformed MM outcomes, yet patients with renal involvement continue to experience inferior survival.^7–9 Critical knowledge gaps persist regarding which patients achieve dialysis independence, whether specific renal histologies respond differentially to modern therapies, and how renal pathology influences treatment outcomes. The specific effect of different renal histologies on disease trajectory remains poorly characterized, with previous studies focusing primarily on functional parameters and providing limited systematic evaluation of histological patterns and their distinct clinical courses.

To address these questions, we conducted a comprehensive analysis of patients with MM with histologically confirmed kidney involvement, comparing outcomes across different pathological subtypes and evaluating factors predicting KRT reversibility and survival. This study represents one of the largest systematic evaluations of biopsy-proven kidney disease in MM, providing novel insights into the heterogeneous nature of myeloma-associated kidney pathology and informing evidence-based treatment strategies.

Methods

Study Design and Patient Selection

We conducted a retrospective multicenter analysis of patients who underwent kidney biopsy in the context of MM at four centers between September 1999 and July 2023. Kidney biopsy indications at the participating centers were based on established clinical practice guidelines. For patients with confirmed or suspected MM or monoclonal gammopathy of undetermined significance, biopsy was performed when patients presented with (1) GFR lower than age-appropriate norms, (2) proteinuria >500 mg/d, (3) excretion of light chains, or (4) abnormal urine sediment. These criteria align with contemporary recommendations for kidney biopsy in monoclonal gammopathies and aim to establish a definitive histological diagnosis to guide therapeutic decisions. The indication for kidney biopsy was made in an interdisciplinary manner between nephrologists and hematologists.

Both light chain myeloma and MM with complete Ig were included in the analysis. A control cohort of MM patients without renal involvement was established using data from the respective institutional information systems. These patients were diagnosed between February 2004 and August 2020. To ensure comparability, control patients were matched for age (±5 years), sex, and International Staging System stage with the renal involvement cohort. Only patients with Revised International Staging System stage 3 myeloma were included to create a homogeneous comparison group. Patients with only a short KRT duration (e.g., because of volume overload) were not included. KRT had to be performed for at least 4 weeks (three times per week) to be considered dialysis-dependent.

MM Diagnosis and Staging

MM diagnosis and staging were performed according to International Myeloma Working Group (IMWG) criteria. Staging included assessment of serum β2-microglobulin, albumin, and lactate dehydrogenase. Patient characteristics recorded included age at kidney biopsy, sex, KRT status (never required, ongoing, or discontinued), and time from initial myeloma diagnosis to kidney failure.

Laboratory Methods

All laboratory analyses were performed at local institutional laboratories using standardized methods. Kidney function was assessed by serum creatinine and eGFR calculated using the CKD Epidemiology Collaboration formula. Proteinuria was quantified in 24-hour urine collections using automated turbidimetric assay (Architect ci 8200, Abbott GmbH, Wiesbaden, Germany).

Immunofixation electrophoresis was performed using HydraGel-IF kits (Sebia Labordiagnostische Systeme GmbH, Fulda, Germany) to detect Bence-Jones proteinuria. Serum free light chains were quantified using the Freelite Assay (Bindingsite GmbH, Schwetzingen, Germany). Normal serum free light chain ratios were defined as 0.26–1.65. Urine and serum light chains were measured nephelometrically using BN ProSpec (Siemens Health care GmbH, Erlangen, Germany).

Kidney Biopsy Procedures

All kidney biopsies were performed under inpatient conditions with minimum 24-hour monitoring to ensure adequate treatment and monitoring of potential complications. Preprocedural coagulation studies were mandatory to minimize bleeding risk, and international normalized ratio and platelet count were optimized before biopsy if necessary. BP was closely monitored on the day of biopsy and maintained below 150/90 mm Hg when necessary. Patients with elevated BP were monitored overnight in the intermediate care unit after the procedure.

Histological Classification

Histological results were classified into four categories: CN, MIDD, AL amyloidosis, and other renal disease (ORD). The ORD category included acute tubular necrosis, acute interstitial nephritis, diabetic nephropathy, and other non-myeloma–related kidney pathologies.

Nephropathological processing followed a standardized protocol using 1 μm thin hematoxylin-eosin and periodic acid-Schiff stains. Immunohistochemistry was performed using antibodies against IgA, IgG, IgM, kappa light chain, lambda light chain, C1q, and C3. Congo red staining was performed when amyloidosis was suspected. All biopsies were examined by experienced kidney pathologists.

Treatment Assessment

First-line myeloma therapy was classified according to the presence of (1) PI, (2) CD38, and (3) high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). Treatment decisions were made by institutional multidisciplinary teams considering patient age, comorbidities, kidney function, and disease characteristics.

Best response after first-line therapy was assessed according to current IMWG criteria. For patients receiving ASCT, response was evaluated post-transplantation. When response could not be determined from medical records, complete response (CR) and stringent CR were defined on the basis of negative immunofixation in serum and urine and normalized free light chain ratio. Bone marrow evaluation was not systematically performed in all patients because of the retrospective nature of the study.

For patients developing kidney function impairment during myeloma therapy, postbiopsy treatment and response were assessed separately.

Renal Response Evaluation

Renal response was evaluated using IMWG renal response criteria. Response categories included: CR (baseline eGFR <50 ml/min per 1.73 m² increasing to >60 ml/min per 1.73 m²), partial response (baseline eGFR <15 ml/min per 1.73 m² increasing to 30–59 ml/min per 1.73 m²), minor response (baseline eGFR <15 ml/min per 1.73 m² increasing to 15–29 ml/min per 1.73 m² or baseline eGFR 15–29 ml/min per 1.73 m² increasing to 30–59 ml/min per 1.73 m²), and no change.

KRT independence was considered the strongest indicator of renal response, regardless of eGFR improvement. Owing to the retrospective nature and varying data availability, renal response was evaluated at three time points: 1 month, after first-line therapy completion, and at 1 year.

Statistical Analyses

Continuous variables were assessed for differences between groups (CN, light chain deposition disease, AL-Amyloidosis, ORD, and No kidney involvement) using the Kruskal–Wallis test. When the Kruskal–Wallis test indicated significant differences between groups (P < 0.05), post hoc pairwise comparisons were performed using the Wilcoxon rank-sum test with Bonferroni correction for multiple comparisons to identify which specific group pairs differed significantly. Time-to-event analyses were performed using Kaplan–Meier estimates to evaluate overall survival (OS) and KRT-free survival across groups. Median survival times were defined as the time point at which 50% of the study population remained event-free. Survival analyses were stratified by treatment regimen (categorized as no modern drugs, one drug, two drugs, or three drugs including PI, CD38, and ASCT), KRT status (ongoing, discontinued, or never required), and kidney involvement (absent versus present and myeloma-related versus other causes versus none). For KRT analyses, patients were stratified by kidney histology (CN, MIDD, AL amyloidosis, or ORD), with patients without renal involvement excluded. Group comparisons were conducted using the log-rank test. Right censoring was applied to patients lost to follow-up or who had not reached the end point at last contact.

Cox proportional hazards regression analyses were performed to evaluate factors influencing survival and KRT probability. For survival analyses, patients with and without kidney involvement were first compared, with no renal involvement as the reference category. Subsequently, analyses were restricted to patients with kidney involvement, evaluating the effects of eGFR, KRT requirement (no KRT as reference), and age both independently and in combined models.

For KRT risk analyses, only patients with kidney involvement were included, with evaluation of eGFR, histological subtype (CN as reference), and age in independent and combined models.

P values < 0.05 were considered statistically significant. All analyses were conducted using R Statistical Software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria) with tidyverse (Wickham) and survminer (Kassambra) packages.

Results

The study cohort comprised 255 patients with balanced gender distribution and a median follow-up of 25.9 months (range, 0.1–233 month). Kidney involvement was documented in 193 patients (75.7%), including CN (n=120), AL amyloidosis (n=19), MIDD (n=8), and ORD (n=46), while 62 patients (24.3%) showed no kidney involvement. Patients with MIDD were significantly younger (mean age, 60.5±9.7 years) than all other patient groups (mean age, 71.1±10.9 years, P = 0.015). Patient characteristics are summarized in Table 1. The time between initial diagnosis of MM and kidney biopsy was not significantly different between the individual groups and ranged in median between 0.2 months (CN) and 0.9 months (ORD; P = 0.2).

Table 1.

Patients' demographics and clinical factors

Demographics and Clinical Factors	CN	AL-Amyloidosis	MIDD	ORD	No Kidney Involvement	P Value
N	120	19	8	46	62
Sex (female/male)	59/61	8/11	4/4	19/27	27/35
Median age (yr±SD)	70.7±10.9	70.4±9.0	60.5±9.7	73.3±8.4	71.8±12.7	MIDD versus all other groups P = 0.015
Creatinine (mg/dl), median (IQR)	4.5 (2.6–6.7)	1.9 (1.3–2.8)	2.4 (1.9–4.0)	1.7 (1.1–2.8)	0.9 (0.8–1.15)	CN versus AL-amyloidosis/ORD/no kidney involvement: P < 0.001 No kidney involvement versus all other groups: P < 0.001
eGFR (ml/min per 1.73 m2), median (IQR)	13.0 (7.3–21.9)	28.8 (20.1–50.6)	25.5 (13.5–33.1)	36.2 (19.9–53.1)	66.1 (56.1–77.6)	No kidney involvement versus all other groups: P < 0.001 CN versus Al-amyloidosis: P < 0.001; CN or MIDD versus ORD: P < 0.001
Proteinuria (mg/24 h), median (IQR)	2742 (1283–4877)	3910(2182–8966)	1727(1379–2325)	1130 (553–2574)	174 (93–287)	AL-amyloidosis versus all other groups: P < 0.001 CN versus ORD P < 0.001 CN versus no kidney involvement: P < 0.001 ORD versus no kidney involvement: P < 0.001
Requiring KRT (n=82)	66	5	1	10	0
KRT ended (n=33)	28	0	0	5	0

AL, lightchain; CN, cast nephropathy; IQR, interquartile range; MIDD, monoclonal Ig deposition diseases; ORD, other renal disease.

Kidney Function and Involvement

Kidney involvement was present in 193 patients (75.7%). Patients with CN showed the most severe kidney function impairment with a median eGFR of 13.0 ml/min (interquartile range [IQR], 7.3–21.9 ml/min), followed by patients with MIDD with 25.5 ml/min (IQR, 13.5–33.7 ml/min). The difference between these groups was not statistically significant (P = 0.55). Patients with AL-amyloidosis had a median eGFR of 28.8 ml/min (IQR, 20.1–50.6 ml/min), significantly higher than patients with CN (P < 0.001). Patients with ORD had the least impaired kidney function with a median eGFR of 36.2 ml/min (IQR, 19.9–53.1 ml/min), significantly better than both CN and MIDD groups (P < 0.001).

Patients without kidney involvement (n=62, 24.3%) had a median eGFR of 66.1 ml/min (IQR, 56.1–77.6 ml/min) and median serum creatinine of 0.9 mg/dl (IQR, 0.8–1.15 mg/dl).

Proteinuria

Proteinuria was highest in patients with AL-amyloidosis (median, 3910 mg/24 hours; IQR, 2182–8966 mg/24 hours), compared with CN (median, 2742 mg/24 hours; IQR, 1283–4877 mg/24 hours), MIDD (median, 1727 mg/24 hours; IQR, 1379–2325 mg/24 hours), and ORD (median, 1130 mg/24 hours; IQR, 553–2574 mg/24 hours). Patients with AL-amyloidosis had significantly higher proteinuria than all other groups with kidney involvement (P < 0.001 for all comparisons). Patients without kidney involvement had median a proteinuria of 174 mg/24 hours (IQR, 93–287 mg/24 hours), significantly lower than all patients with kidney involvement (P < 0.001).

KRT Requirement

Of patients with kidney involvement, 42.5% (n=82) required KRT at least temporarily. Patients with CN had the highest KRT requirement (55.0%, n=66), followed by AL-amyloidosis (26.3%, n=5), ORD (21.7%, n=10), and MIDD (12.5%, n=1 patients).

KRT independence was achieved in 42.4% of patients with CN (28/66) and 50.0% of patients with ORD (five out of ten). No patients with AL-amyloidosis or MIDD achieved KRT independence during follow-up.

Time to KRT initiation varied significantly between groups: Patients with CN required KRT after a median of 0.9 months, compared with 32.4 months for MIDD (P < 0.001), 15.4 months for AL-amyloidosis, and 17.1 months for patients with ORD (see Figure 1).

Figure 1.

Time to KRT separated by kidney histology. AL, lightchain; CN, cast nephropathy; MIDD, monoclonal Ig deposition disease; ORD, other renal disease.

OS

Patients without kidney involvement had significantly longer median OS compared with those with kidney involvement (73.4 [95% confidence interval (CI), 51.2 to not estimable] versus 40.5 [31.2 to 57.6] months, P = 0.027). Among kidney involvement subgroups, median OS was CN 39.3 months (30.3 to 62.7), AL-amyloidosis 57.6 (5.0 to not estimable) months, and ORD 45.9 (27.0 to 89.7) months, while the median OS of MIDD was not reached. No significant difference was observed between myeloma-associated kidney diseases and ORD (P = 0.79; see Figures 2 and 3).

Figure 2.

Survival depending on kidney involvement.

Figure 3.

Survival depending on the type of renal involvement (renal insufficiency due to myeloma, renal insufficiency due to other etiologies) compared with patients without renal involvement.

KRT status significantly affected survival. Patients never requiring KRT had a median OS of 56.2 (42.9 to 87.3) months, compared with 12.7 (5.3 to 30.6) months for those continuously requiring KRT (P < 0.001). Patients achieving KRT independence had median OS of 40.9 (30.8 to not estimable) months, not significantly different from those never requiring KRT (P=0.80; see Figure 4).

Figure 4.

Survival according to status of KRT dependence (never, ongoing, discontinued).

Hematological Response

Data on treatment were available for 218 patients (see Table 2). PI therapy was used in 73.4% of cases, a CD38 in 22.9%, and ASCT in 28.9%. When adjusted for approval dates, utilization rates were 80.3% for bortezomib and 68.3% for daratumumab.

Table 2.

First-line treatments

Regime	No (%)
No therapy	16 (6.3)
Chemotherapy	31 (11.3)
Unknown	37 (15.3)
Dara-VTD	17 (6.7)
Dara-VRD	2 (0.8)
DRD	5. (2.0)
Dara-VMP	19 (7.5)
DVD	2 (0.8)
Dara-Pom-D	1 (0.4)
Isa-VRD	4 (1.6)
Elotuzumab-RD	1 (0.4)
VMP	11 (4.3)
VCD	60 (23.5)
VRD	3 (1.2)
VD	28 (11.0)
VTD	8 (3.1)
RD	5 (2.0)
KRD	1 (0.4)
TD	1 (0.4)
Pomalidomide dexamethasone	1 (0.4)
Bortezomib bendamustine dexamethasone	2 (0.8)

Dara, daratumumab; D, dexamethasone; DRD, daratumumab, revlimid and dexamethason; DVD, daratumumab, velcade, and dexamethason; Isa, isatuximab; K, Kyprolis (trade name for carfilzomib); KRD, kyprolis, revlimid, and dexamethason; M, melphalan; P, prednisone; Pom, pomalidomide; R, Revlimid (trade name for Lenalidomide); T, thalidomide; V, Velcade (trade name for bortezomib); VCD, velcade, cyclophosphamid, and dexamethason; VMP, velcade, melphalan, and prednison; VRD: velcade, revlimid, and dexamethason; VTD, velcade, thalidomid, and dexamethason.

Patients without modern therapy achieved a very good partial remission (VGPR) or better in 35.6% of cases (complete remission 10.3%, VGPR 23.0%, partial remission 39.1%). Primary refractory disease occurred in 25.3%.

Patients with ASCT were significantly younger (mean age 60.5±7.7 years) than non-ASCT patients (73.1±10.1 years, P < 0.001). Patients with ASCT achieved VGPR or better in 81.0% of cases (complete remission 36.2%, VGPR 27.6%, partial remission 17.2%) with only 1.7% showing progressive disease.

Patients receiving all three treatment modalities (PI, CD38, ASCT) achieved the highest response rates: 88.9% VGPR or better (stringent complete remission 33.3%, complete remission 27.8%, VGPR 27.8%, partial remission 5.6%).

Treatment Response and Survival

Treatment intensity correlated with survival outcomes. Patients receiving PI, CD38, or ASCT had a median OS of 58.5 (40.5 to 87.3) months compared with 11.9 (4.5 to 33.7) months for those receiving none of these therapies (P = 0.002). Combination of two treatment modalities yielded a median OS of 100.8 (62.7 to not estimable) months. Median OS for patients receiving all three modalities was not reached (see Figure 5).

Figure 5.

Survival according to treatment. ASCT, autologous stem cell transplantation; CD38, CD38 antibody; PI, proteasome inhibitor.

Treatment Response and Renal Response

Renal response data were available for 122 patients, assessed at 1 month, after completion of first-line therapy, and at 1 year. Renal response was reached only by patients achieving hematological response. Patients with hematological progression showed no renal response.

Patients having received conventional therapy showed minimal change in kidney function (after first line: minor response 9.0%, partial response 14.1%, CR 12.8%). Patients with ASCT demonstrated significant kidney function improvement. The proportion of patients achieving at least a minor renal response increased from 48% to 72% after high-dose chemotherapy.

Among patients receiving PI, CD38, and ASCT in first line, 43% showed no renal response at 1 month, but 100% demonstrated response after ASCT (86% CR, 14% PR).

Risk Factor Analysis

Cox proportional hazard analysis revealed that kidney involvement increased the risk of mortality (hazard ratio [HR], 1.63; 95% CI, 1.05 to 2.53). Among patients with kidney involvement, every ml/min increase in eGFR reduced the mortality rate by 0.91% (HR, 0.99; 95% CI, 0.98 to 0.99). Persistent KRT dependency carried an HR of 2.39 (95% CI, 1.58 to 3.62).

In combined analysis, ongoing KRT requirement (HR, 1.77; 95% CI, 1.14 to 2.69) and age (HR, 1.04; 95% CI, 1.02 to 1.07) were primary mortality risk factors.

For KRT risk, compared with patients with CN: Patients with ORD had an 80% lower risk (HR, 0.20; 95% CI, 0.09 to 0.44; P < 0.001), patients with MIDD had an 84% lower risk (HR, 0.16; 95% CI, 0.02 to 1.13; P = 0.066), and patients with AL-amyloidosis had a 64% lower risk (HR, 0.36; 95% CI, 0.15 to 0.91; P = 0.03).

In multivariate analyses, only ORD maintained a significantly reduced KRT risk compared with CN (HR, 0.42; 95% CI, 0.19 to 0.95). GFR (HR, 0.95; 95% CI, 0.92 to 0.97) remained significant independent predictors (see Figure 6).

Figure 6.

Forest plots showing the devastating impact of persistent dialysis dependency on survival and the increased risk of dialysis dependency in patients with cast nephropathy. Hazard ratios of factors associated with (A) mortality and (B) progression to dialysis. *P < 0.05; ***P < 0.005. AIC, akaike information criterion.

Discussion

Kidney involvement in patients with MM represents a complex clinical challenge that can significantly affect both, treatment options and patient outcomes.^1,2,10 Our study demonstrates that kidney complications substantially influence survival, with patients having kidney involvement showing 63% higher mortality risk compared with those without kidney disease. Moreover, the underlying kidney histology not only determines the severity of kidney dysfunction but also implies distinct disease trajectories, with different patterns of progression, KRT requirements, and potential for recovery that have profound implications for patient management and prognosis.

The most significant finding of our study is the dramatic improvement in renal outcomes with modern therapeutic approaches. Patients receiving combination therapy with PI, CD38, and ASCT achieved superior renal responses, with 100% of patients showing renal improvement after ASCT compared with only 26.1% with conventional therapy achieving complete or partial renal response after 1 year. This supports previous reports demonstrating that modern MM therapies can reverse the historically poor prognosis associated with renal involvement.^7,8,10–13

Our data confirm that renal response is contingent upon achieving hematological response with no patient experiencing improvement in kidney function in the absence of systemic disease control. This underscores the importance of effective systemic therapy in managing MM-associated kidney disease.^14,15

A key strength of our study is the systematic histological characterization of kidney involvement, revealing distinct patterns across different pathologies. Patients with CN and MIDD presented with the most severe kidney impairment (eGFR 13.0 and 25.5 ml/min, respectively), yet showed markedly different clinical trajectories. While patients with CN required KRT rapidly (median 0.9 months), patients with MIDD maintained kidney function for significantly longer (median 32.4 months), despite similar initial eGFR values.

This temporal difference may reflect distinct pathophysiological mechanisms: CN involves acute tubular obstruction by light chain casts leading to rapid functional decline, while MIDD represents a more indolent process of light chain deposition with gradual functional deterioration. Understanding these kinetics could inform monitoring strategies and timing of therapeutic interventions.

The irreversibility of KRT dependence in patients with AL amyloidosis and MIDD contrasts sharply with the potential for renal recovery in CN (42.4%) and ORD (50.0%). This finding has critical implications for patient counseling and treatment planning. The inability to achieve KRT independence in AL amyloidosis may relate to irreversible tissue damage from amyloid fibril deposition, while the crystalline deposits in MIDD may similarly cause permanent structural alterations. Future research should explore whether earlier intervention with modern therapies could prevent this irreversible damage.

Our analysis reveals that KRT dependency, rather than the degree of kidney impairment per se, serves as the primary prognostic determinant. Patients requiring ongoing KRT had a 139% higher mortality risk (HR, 2.39), while those achieving KRT independence showed survival comparable with patients never requiring KRT (56.2 versus 40.9 months, P = 0.80).

This finding suggests that KRT dependency may serve as a surrogate marker for more advanced disease or treatment resistance rather than simply reflecting kidney dysfunction. Alternatively, KRT-related complications, including infections, cardiovascular stress, and treatment delays, may contribute to increased mortality. The correct dosage of some MM medications (e.g., Lenalidomide) is also difficult when KRT is required.

Importantly, factors traditionally associated with KRT outcomes—including age, proteinuria levels, and pre-KRT eGFR—did not predict KRT reversibility in our cohort.^16,17

This suggests that MM-associated kidney disease follows different recovery patterns compared with other causes of AKI, possibly because the systemic nature of the underlying malignancy.

Our findings contrast with earlier reports showing uniformly poor outcomes for patients with MM with kidney involvement. Decourt et al. reported significantly shorter survival for KRT-dependent patients across all histological subtypes, with patients with AL amyloidosis surviving 28.9 months compared with 16 months for patients with CN.¹⁸ Our study shows no significant differences in survival between histological subtypes, likely reflecting the effect of modern therapeutic approaches unavailable during the earlier study period (2002–2011).

The evolution of treatment paradigms over our study period (spanning the introduction of novel agents) may have differentially benefited certain patient subgroups. Future studies should examine whether specific histological patterns show preferential responses to particular therapeutic approaches.

Our Cox proportional hazard analysis identified eGFR as the strongest predictor of both survival and KRT risk, with each 1 ml/min increase reducing mortality risk by approximately 1%. Among histological subtypes, patients with ORD showed the lowest KRT risk even after adjusting for baseline kidney function, suggesting inherent differences in disease biology.

These findings support the development of risk stratification models incorporating both functional and histological parameters. Such models could guide treatment intensity decisions and inform discussions about prognosis and goals of care.

Our results have several important clinical implications. First, aggressive pursuit of systemic disease control with modern therapeutic combinations is justified even in patients with severe kidney function impairment, given the potential for meaningful renal recovery. Second, histological characterization through kidney biopsy provides valuable prognostic information that extends beyond traditional functional assessments.

Future research priorities should include (1) prospective validation of our findings in larger, multicenter cohorts; (2) investigation of optimal treatment sequencing in renally impaired patients; (3) development of biomarkers to predict KRT reversibility; (4) examination of quality of life outcomes in patients achieving KRT independence; and (5) cost-effectiveness analyses of intensive treatment approaches in this population.

Several limitations warrant consideration. The retrospective design and extended observation period (spanning significant changes in MM treatment) may introduce temporal bias, although we attempted to address this through treatment era stratification. The lack of standardized protocols for kidney biopsy timing and KRT initiation across the study period may have influenced our results. Cytogenetic risk stratification data were unavailable, preventing assessment of this important prognostic factor. In addition, we could not analyze the optimal duration of KRT support or factors influencing the timing of KRT discontinuation.

Another important limitation is the absence of systematic comorbidity data because our 24-year data collection period preceded standardized electronic documentation, and all participating centers underwent multiple transitions in clinical information systems. While comorbidity assessment would have provided valuable additional information, the quality and completeness of retrospectively available data did not meet standards necessary for rigorous analysis.

Missing data on treatment-related toxicities and dose modifications in renally impaired patients limits our ability to assess the safety-efficacy balance of intensive therapeutic approaches. Future studies should systematically capture these important clinical parameters.

CKD in MM significantly affects patient outcomes, but modern therapeutic approaches have substantially improved the prognosis for these patients. The achievement of KRT independence, rather than the degree of kidney improvement, serves as the primary determinant of survival benefit. Histological characterization provides valuable prognostic information and should guide treatment decisions. Our findings support aggressive systemic therapy even in patients with severe kidney impairment, particularly for those with CN and other reversible causes of kidney dysfunction. The dramatic improvements observed with modern combination therapies suggest that historical nihilistic approaches to patients with MM with kidney involvement should be abandoned in favor of aggressive, multidisciplinary management strategies aimed at achieving both hematological and renal responses. Importantly, kidney biopsies in patients with MM provide critical diagnostic and prognostic information; we strongly advocate for their routine use in patients with MM presenting with AKI after exclusion of obstructive and prerenal causes.

Ethics Committee of the State Medical Association of Rhineland-Palatinate No.: 2024-17889-retrospektiv.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B520.

Author Contributions

Conceptualization: Raoul Bergner, David Klank.

Data curation: Raoul Bergner, Clara Daschner, Julian Friedrich, David Klank, Lina Rüsing.

Formal analysis: Raoul Bergner, Julian Friedrich, David Klank.

Validation: David Klank.

Writing – original draft: Raoul Bergner, David Klank.

Writing – review & editing: Clara Daschner, Julian Friedrich, Christian Löffler, Peter Paschka, Stefan Porubsky, Lina Rüsing.

Funding

None.

Declarative Statements

This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. All patients provided written informed consent. This study includes clinical experimentation and complies with the Declaration of Helsinki.

Data Availability Statements

Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Observational Data.