A U-Shaped Association: The First-Year eGFR Slope and Mortality Risk in Multiple Myeloma.

Introduction

Multiple myeloma (MM) is incurable and the second most prevalent hematologic malignancy [ 1 ]. Renal impairment (RI) is a prominent characteristic of MM, affecting up to 50% of patients, and necessitating dialysis in 2%–4% [ 2 , 3 ]. RI has been associated with inferior overall survival, increased early mortality risk and a greater relative risk of disease progression for patients with MM [ 4 , 5 ].

With the advent of novel therapeutic agents, many MM patients with RI achieved renal function recovery and prolonged survival following treatment [ 5 , 6 ]. Nevertheless, patients who present with RI continue to face a higher mortality risk than those without RI, even after renal recovery [ 5 ]. Recognizing the prognostic significance of RI, the International Myeloma Working Group (IMWG) has issued specific recommendations for the management of RI in MM, underscoring its pivotal role during disease progression [ 2 ]. Of note, RI is defined by the IMWG as serum creatinine > 2 mg/dL or creatinine clearance < 40 mL/min/1.73 m 2 —thresholds that represent relatively advanced renal dysfunction [ 2 ]. Given that early identification and prompt management of RI at diagnosis and at relapse are critical to optimizing patient outcomes [ 2 , 7 ], there is an urgent need to explore early predictive indicators of renal compromise.

The estimated glomerular filtration rate (eGFR) slope, defined as the annual change in eGFR, is an early parameter that captures longitudinal renal function dynamics. Prior studies have linked eGFR slope to adverse clinical outcomes, including cardiovascular events [ 8 ], end‐stage renal diseases [ 9 ], and all‐cause mortality [ 10 , 11 ]. However, in the MM field, most researches primarily focused on RI at baseline or at specific time points during MM progression, largely overlooking the prognostic implications of early renal function trajectories. For example, some patients exhibit a rapid eGFR decline without fulfilling the diagnostic criteria for RI; whether this subclinical decline confers excess mortality remains unknown.

To address this knowledge gap, we retrospectively enrolled MM patients admitted to our hospital from 2008 to 2022, and dynamically monitored creatinine and eGFR levels. Our primary objectives were to elucidate the prognostic impact of renal function kinetics and evaluate its early predictive value to all‐cause mortality in patients with MM.

Materials and Methods

Ethics

The ethics committee of the West China Hospital, Sichuan University approved the study protocol (approval number: 1783). This study was registered by the Chinese Clinical Trial Registry (ChiCTR2400081476, https://www.chictr.org.cn ). The individual information of the patients included in this database was anonymous, and the need for informed consent was waived.

Study Design and Participants

This retrospective longitudinal study investigated the correlations between the first‐year eGFR change rate (eGFR slope) and mortality risk in patients with MM. The study cohort comprised patients with MM admitted to our Hospital from July 1, 2008, to August 30, 2022. This study included patients (1) newly diagnosed MM (NDMM) according to the IMWG criteria [ 12 ], (2) aged ≥ 18 years, and (3) with more than three creatinine measurements (including the measurement at baseline) spaced at least 4 weeks apart.

Patients who (1) had a follow‐up time of < 12 months, (2) underwent continuous or temporary dialysis during the study period, (3) had missing baseline data or (4) had a history of kidney diseases before MM diagnosis were excluded from the study. The baseline was the date of the patients' first MM diagnosis at West China Hospital and the availability of creatinine measurement. Creatinine levels were monitored every 3 months in the first year, every 6 months in the second year, and annually thereafter. Missing data at a certain point would be replaced with the nearest available data within a 3‐month timeframe. Baseline data, including demographics (age, sex, and body mass index), clinical information, laboratory tests, medication prescription history, and comorbid conditions were collected. Patient follow‐up included hospital electronic databases, phone calls, and interviews. All patients were followed until death, last contact, or the end‐date follow‐up of the study on December 30, 2024.

RI was indicated as serum creatinine levels of > 2 mg/dL or impaired creatinine clearance of < 40 mL/min/1.73 m 2 [ 13 ].

Exposure and Control

The CKD‐EPI equation using creatinine measurements was utilized to estimate the eGFR [ 14 ]. The first‐year eGFR slope, representing the average annual rate of change, was derived for each participant by applying the least‐squares regression to all eGFR values recorded within the first year following MM diagnosis [ 10 ].

Study Outcomes and Follow‐Up

The study outcome was all‐cause mortality. Patients' living status was determined from their hospital records and practitioner interviews.

The response to anti‐MM treatment was classified as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD), progressive disease (PD), and relapse according to IMWG response criteria [ 15 ].

Statistical Analysis

All analyses were performed using R 4.3.0. Continuous variables were presented as mean and standard deviation or median and interquartile ranges (IQRs), while categorical variables were demonstrated as frequency ( n ) and percentage (%). The Chi‐square or Fisher's exact tests were used to analyze categorical variables. The one‐way ANOVA analysis and the Wilcoxon–Mann–Whitney rank‐sum tests were used to analyze normally distributed data and continuous skewed variables, respectively.

Kaplan–Meier survival analysis with the log‐rank test was used to compare survival outcomes. Cox proportional hazards regression was performed, with modeling the first‐year eGFR slope as the primary exposure with restricted cubic splines (RCS) (knots at 5th, 27.5th, 50th, 72.5th, and 95th percentiles), the model was adjusted by gender, age, ISS stage, hypertension, diabetes mellitus, baseline creatinine, first‐line therapy and the first‐year response to anti‐MM therapy. The multicollinearity was assessed using variance inflation factors (VIFs).

Subgroup Analysis

The treatment response was closely associated with the incidence and recovery of renal impairment [ 13 ]. Patients were divided into two groups based on their first‐year response: (1) less than PR group: those who did not reach PR or better response within the first year; (2) PR or better group: those who maintained PR or better response throughout the first year. Association of first‐year eGFR slope with mortality was then evaluated within each of these response‐based subgroups. Additionally, because baseline eGFR is also strongly correlated with eGFR slope [ 4 , 5 ], patients were further stratified into three groups according to the baseline renal function: eGFR of < 40 mL/min/1.73 m 2 , 40 ≤ eGFR < 90 mL/min/1.73 m 2 , and eGFR ≥ 90 mL/min/1.73 m 2 . The same analysis was performed across these baseline eGFR subgroups.

Results

Patients' Characteristics

From 2008 to 2022, 4918 patients were diagnosed with MM at West China Hospital, of which 4342 participants had complete baseline data. The final cohort comprised 974 NDMM patients after excluding patients with no follow‐up ( n = 728), having history of kidney disease before MM diagnosis ( n = 90), not NDMM ( n = 648), less than three creatinine measurements ( n = 2118), undergoing temporary or persistent dialysis ( n = 252), death within 12 months ( n = 433) and follow‐up time < 12 months ( n = 78) (Figure 1 ). A total of 6662 creatinine determinations were investigated for these 974 patients during the follow‐up period. The median follow‐up duration was 40 months (IQR: 26 to 67 months), with a median of six creatinine measurements per patient. Table 1 presented the study population's baseline characteristics.

Longitudinal eGFR Changes During the Disease Course of Myeloma

The changes of eGFR were monitored dynamically throughout the disease course.

The overall trend of eGFR changes was shown in Figure 2A , eGFR levels showed a substantial increase following the first‐line therapy in the majority of patients. Over the entire clinical progression of MM, patients classified as ISS stage III at baseline exhibited the lowest eGFR values, while those in ISS stage I maintained the highest eGFR levels (Figure 2B ). Similarly, eGFR was also significantly lower in MM patients aged 60 years or older compared to those under 60 years of age (Figure 2C ). The trend of eGFR change showed no significant difference between males and females (Figure 2D ).

First‐Year eGFR Slope Was a Significant Predictor to All‐Cause Mortality in MM Patients

As shown in Figure 2 , the eGFR had a quickly increased stage following first‐line therapy. Therefore, we selected 12 months, a time point at which eGFR has stabilized relatively, as the landmark for analysis to investigate whether eGFR changes within the first year after diagnosis could predict mortality risk in MM patients. Of the included 974 patients, the median 1‐year eGFR slope was 3.69 mL/min/1.73 m 2 /year (IQR −4.9 to 16.6 mL/min/1.73 m 2 /year). The association between the first‐year eGFR slope and mortality risk exhibited a U‐shaped pattern (p for nonlinear trend = 0.0145) after adjusted by gender, age, ISS stage, hypertension, diabetes mellitus, baseline creatinine, first‐line therapy and first year treatment response (Figure 3A ). The nadir of risk corresponded to a slope of 4.09 mL/min/1.73 m 2 /year (HR 1.00, 95% CI 0.99–1.01) (Figure 3A ). The VIF of all included variables were lower than 5, indicating no multicollinearity existed (Table S1 ). In terms of survival outcomes, patients were divided into three groups according to the tertile of first‐year eGFR slope, the average times of creatinine measurements were 6.8, 7.2, 6.7 in lower (first‐year eGFR slope ≤ −2.3 mL/min/1.73 m 2 /year, n = 325), middle (first‐year eGFR slope was from −2.3 to 10.8 mL/min/1.73 m 2 /year, n = 325) and higher (first‐year eGFR slope > 10.8 mL/min/1.73 m 2 /year, n = 324) tertile group, respectively. The change of eGFR of the three groups during the first year was shown in Figure S1 , individuals in the upper tertile of first‐year eGFR slope had lower baseline eGFR and were more likely to be those with RI. Patients in the middle tertile (median follow up: 45 months) demonstrated the longest median survival time of 119 months, which was notably longer than that of patients in the lower tertile (119 vs. 102 months, p = 0.025, median follow up of 38 months) and the higher tertile (119 vs. 76 months, p < 0.001, median follow up of 37 months) (Figure 3B ). These results further validated the “U” shaped relationship between first‐year eGFR slope and mortality risk in MM patients.

Subgroup Analysis

During the first year of the included 974 NDMM patients, 756 (77.6%) achieved PR or better response to anti‐MM treatment. The incidence of renal dysfunction in PR or better group (25%) was significantly lower than that in the less than PR group (33.9%) (P 0.028, Table S2 ). Changes of eGFR during first year in the two group was shown in Figure 4A , patients in the PR or better group had higher eGFR compared to less than PR group. Notably, in the PR or better group, an increase of first year eGFR slope was associated with a higher mortality risk, with the mortality HR exceeding 1 when the annual eGFR increase surpassed 4.3 mL/min/1.73 m 2 (Figure 4B ). In contrast, in the less than PR group, a decline in eGFR slope correlated with higher mortality risk, particularly when the eGFR slope fell below 1.18 mL/min/1.73 m 2 /year (HR for mortality > 1) (Figure 4C ).

Subgroup analysis was further conducted based on baseline renal function. Patients were stratified into three groups based on their baseline eGFR: eGFR < 40 mL/min/1.73 m 2 ( n = 158), 40 ≤ eGFR < 90 mL/min/1.73 m 2 ( n = 448) and eGFR ≥ 90 mL/min/1.73 m 2 ( n = 368) groups. Figure 5A illustrated the first‐year eGFR changes across the three groups. In the eGFR < 40 mL/min/1.73 m 2 group, the HR for mortality fell below one when the first‐year eGFR slope ranged from 1.56 to 15.5 mL/min/1.73 m 2 /year, and rose sharply outside this interval (Figure 5B ), indicating that an appropriate increase of eGFR during the first‐year after MM diagnosis was associated with lower mortality risk. For patients with a baseline eGFR between 40 and 90 mL/min/1.73 m 2 , the HR for mortality dropped below one when the first‐year eGFR slope fell within the range of −8.25 to 8.03 mL/min/1.73 m 2 /year (Figure 5C ). Patients with a baseline eGFR > 90 mL/min/1.73 m 2 appeared to be more sensitive to eGFR increases. In this subgroup, when the annual eGFR increment exceeded 6.91 mL/min/1.73 m 2 /year, the mortality risk progressively increased with further rises in the eGFR slope; and when the increment surpassed 14.86 mL/min/1.73 m 2 /year, the HR for mortality exceeded one, suggesting that an excessive increase in eGFR during the first year may not confer a long‐term survival benefit in this patient subgroup (Figure 5D ).

Discussion

In this large retrospective longitudinal cohort of 974 NDMM patients, we identified a robust U‐shaped association between the first‐year eGFR slope and all‐cause mortality. Beyond this overall pattern, however, the most striking and clinically counterintuitive finding is that an excessive rise in eGFR—a change that would conventionally be interpreted as renal recovery—was paradoxically associated with heightened mortality, particularly in patients who achieved a favorable treatment response. This observation challenges the long‐held assumption that “rising eGFR” uniformly signifies benign renal outcomes and underscores the need for a more nuanced, response‐stratified interpretation of eGFR dynamics.

Dynamic eGFR change is an important kidney function indicator [ 16 , 17 ]. An eGFR range of 0.5–1.00 mL/min/1.73 m 2 per year had a 96% probability of predicting chronic kidney disease (CKD) progression as previously reported [ 18 ]. Additionally, several studies have identified the eGFR slope as a primary outcome, for its relative accurate reflection of kidney function kinetics and the good predict value for prognosis [ 19 , 20 ]. Many studies have demonstrated the association of decreased eGFR with increased mortality risk in various diseases, such as CKD [ 21 , 22 ], diabetes mellitus [ 11 ], and rheumatoid arthritis [ 23 ]. However, the relationship between eGFR change over time and MM prognosis remains unknown. Previous studies only focused on MM patients with RI or acute kidney injury (AKI), which indicate the relative late stage of renal failure [ 2 ]. After a median follow‐up of 40 months in 974 patients with MM, our cohorts indicated that patients with baseline eGFR < 90 mL/min/1.73 m 2 experienced significantly elevated mortality when the first‐year slope fell below specific thresholds (−8.25 mL/min/1.73 m 2 /year for the 40–90 group, and below 1.56 for the < 40 group).

Several mechanisms may explain the association between eGFR decline and mortality. First, a decrease in eGFR may signal a deterioration in renal function, which likely reflects a high burden of MM disease activity [ 24 ]. Additionally, kidney function decline may induce oxidative stress, vascular damage, and a higher risk of cardiovascular events [ 25 , 26 ]. It can also contribute to loss of appetite, diminished physical function, and overall frailty [ 10 ]. Collectively, these factors are likely to exacerbate the burden on patients with MM and may indirectly or directly increase the mortality risk.

More intriguingly, our study revealed a paradoxical yet consistent finding: excessive eGFR increases during the first year were also associated with heightened mortality, challenging the conventional notion that “rising eGFR” uniformly signifies renal recovery. Similar results have been observed in previous studies [ 10 , 23 , 25 ]. For example, Turin et al. noted the highest mortality rate among individuals with increased eGFR of ≥ 5 mL/min/1.73 m 2 per year (HR: 2.2, 95% CI: 2.10–2.31) compared to the stable group in a community‐based cohort [ 10 ]. Similarly, the ARIC study revealed that participants with stage 3 CKD who had increased eGFR also experienced a twofold mortality increase [ 25 ]. In the MM setting, improper eGFR rise (≥ 15.5 mL/min/1.73 m 2 per year in baseline eGFR < 40 mL/min/1.73 m 2 group, ≥ 14.86 mL/min/1.73 m 2 per year in eGFR > 90 mL/min/1.73 m 2 group, and ≥ 8.03 mL/min/1.73 m 2 per year in 40 ≤ baseline eGFR < 90 mL/min/1.73 m 2 group) appears detrimental, and results in an increased mortality risk. This seemingly counterintuitive phenomenon may be explained by a reduction in serum creatinine due to muscle wasting, malnutrition, or hemodilution—common sequelae of a heavy MM burden—rather than an actual improvement in glomerular filtration [ 23 ]. Thus, an “artificially” elevated eGFR in normo‐filtering patients may serve as a surrogate for a catabolic state or poor overall health, rather than a benign renal outcome. The underlying mechanism requires further investigation.

The heterogeneity in eGFR slope‐mortality associations across treatment response strata further substantiates this mechanistic interpretation and, importantly, reveals the specific clinical context in which the paradoxical eGFR‐rise phenomenon becomes most apparent. Firstly, patients maintaining PR or better response to anti‐MM therapy during the first year were more sensitive to increments in eGFR slope, once the annual change surpassed 4.3 mL/min/1.73 m 2 , further rises were accompanied by a considerably elevated mortality hazard. Notably, it is precisely in this “favorable responder” group—where renal function is generally well preserved—that the paradoxical harm of eGFR increase emerges most clearly. Conversely, among those who did not reach PR, vulnerability shifts toward eGFR slope decrements, with mortality risk increasing progressively as the eGFR slope declines (Figure 4C ). This divergence may be attributable to disparities in the propensity for RI: poor responders are more prone to occur RI (33.9% in less than PR group vs. 25% in PR or better group, p 0.028, Table S2 ), in this context, eGFR decreases signify worsening renal function and thus higher mortality. In contrast, positive responders have lower RI risk and generally maintain normal or elevated eGFR‐a profile resembling that of the eGFR ≥ 90 subgroup; in these patients, RI is infrequent, and any excessive upward drift in eGFR likely reflects non‐renal factors such as sarcopenia or comorbidity‐related creatinine dilution rather than genuine renal benefit.

Collectively, these findings have important clinical implications. Previously, only RI and AKI were determined as risk factors for mortality in MM [ 27 , 28 , 29 ]. However, RI and AKI frequently appear transiently in patients with MM, and capture only advanced or established renal failure. Our results advocate for a paradigm shift from static, dichotomous RI classification toward dynamic, continuous eGFR trajectory monitoring. This approach enables earlier identification of high‐risk individuals—especially those who do not yet meet the conventional criteria for RI but are already exhibiting unfavorable slope trends—thus providing a critical window for timely therapeutic adjustments, such as intensifying anti‐myeloma regimens, optimizing hydration, or nephroprotective interventions.

Our study is strengthened by its novelty and large sample size. We are the first to report a U‐shaped association between the first‐year eGFR slope and mortality risk in MM, and to validate its significant predictive value for mortality. Secondly, the large sample size enabled us to adjust for multiple risk factors and conduct a wide range of subgroup analyses, further enhancing the credibility of our result. Additionally, our study data is quite comprehensive, with 6662 creatinine measurements performed on 974 patients. On average, six creatinine tests were performed per patient, which surpasses the number reported in many previous studies [ 11 , 21 , 22 , 23 , 30 ]. The large participant pool and multiple measurements per patient improved the accuracy of eGFR change calculations and the reliability of the results. Several limitations should also be acknowledged. First, the single‐center retrospective design with prospective follow‐up may introduce selection bias, and the generalizability of our findings requires external validation. Second, by requiring a follow‐up of at least 12 months and multiple creatinine measurements, we inherently excluded patients who died or lost follow‐up within the first year, meaning our conclusions are specifically applicable to long‐term survivors and may not fully capture the prognostic value of eGFR slope in the most critically ill subset.

In conclusion, first‐year eGFR slope is a practical and valuable early prognostic marker for mortality in MM. The U‐shaped relationship underscores that both declines and increases in eGFR are detrimental, albeit through distinct mechanisms. Notably, an eGFR rise—especially in treatment‐responsive patients—should prompt caution rather than be automatically interpreted as renal recovery.

Author Contributions

Mingjing Guan: conceptualization, writing – original draft, investigation, methodology, formal analysis, data curation, visualization, validation, writing – review and editing. Lian Li: conceptualization, methodology, software, data curation, investigation, validation, formal analysis, supervision, visualization, resources, writing – original draft, writing – review and editing. Xiang Liu: conceptualization, investigation, funding acquisition, writing – review and editing, visualization, validation, methodology, software, formal analysis, project administration, resources, supervision, data curation, writing – original draft. He Li: conceptualization, investigation, methodology, formal analysis, visualization, writing – original draft, data curation. Ting Niu: conceptualization, supervision, project administration, writing – review and editing, validation, funding acquisition. Wenjiao Tang: data curation, conceptualization, writing – review and editing, supervision, resources, validation, methodology, investigation.

Funding

This work was supported by “Qimingxing” Research Fund for Young Talents (HXQMX0156), 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21007), Key Research and Development Program of Sichuan Province (No. 2023YFS0031), National Key Research and Development Program of China (Nos. 2022YFC2502600 and 2022YFC2502603), Postdoctoral Research Fund, West China Hospital, Sichuan University (2024HXBH073).

Ethics Statement

The ethics committee of the West China Hospital, Sichuan University approved the study. The individual information of the patients included in this database was anonymous, and the need for informed consent was waived.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: The change of mean eGFR over time in the lower, middle and higher tertile of first‐year eGFR slope.

Table S1: Variance inflation factor (VIF) results.

Table S2: The association of first year treatment response and incidence of RI.

Acknowledgments

The authors would like to thank Enago ( www.enago.cn ) for the language editing services for this manuscript.

Data Availability Statement

The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.

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