Несоответствие в оценке GFR для Melphalan Dosing в нескольких пациентах Myeloma, находящихся в автономном режиме: ретроспективный анализ.

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Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of abnormal plasma cells in the bone marrow. 1 Despite advancements in treatment, high-dose chemotherapy followed by autologous stem cell transplant (ASCT) remains a cornerstone of therapy for eligible patients. 1 , 2 Melphalan is commonly used as a conditioning regimen before ASCT due to its efficacy in achieving deep remissions and improving survival outcomes. 3 Induction therapy is administered before ASCT using melphalan, an alkylating agent with myeloablative properties, to decrease tumor burden and improve disease control, then is followed by stem cell rescue. 3 , 4 Renal excretion is the major elimination pathway for melphalan and explains why decreased kidney function can increase drug exposure and increase the risk of potential side effects. Accurate dosing of melphalan is critical, as it has a relatively narrow therapeutic window and multiple toxicities. 5 , 6 Under-dosing may result in suboptimal treatment responses such as an inadequate remission response, while overdosing can lead to severe toxicity, including diarrhea (up to 97% of patients), vomiting (60%), mucositis (20%), neutropenia (60%), and AKI (10%–33%). 5 , 6 Therefore, precise assessment of renal function is paramount to ensure appropriate dosing.

In the past, 24 hours of creatinine clearance (CrCl) was the preferred index for calculating renal function to determine appropriate melphalan dosing for patients with MM undergoing ASCT per the 2010 International Myeloma Working Group (IMWG) consensus statement. 7 Several limitations exist with this method, including unreliability in patient collection and in the weight and increased age demographics of the patient population, resulting in inaccurate CrCl calculations, 8 , 9 When dosing anti-cancer drugs, including melphalan, it is acceptable for clinicians to use eGFR from serum creatinine (sCr) to determine renal function and although drug dosing was not specifically developed using eGFR. 10 In a more recent consensus statement, the IMWG recommends determination of eGFR through the CKD Epidemiology Collaboration (CKD-EPI) equation to determine appropriate dosing of melphalan for patients with MM. 11 However, sCr has several limitations, as levels can be influenced by various factors, such as age, muscle mass, diet, and medications, potentially leading to inaccurate eGFR estimations. 12 In MM patients, these limitations are further exacerbated by the disease itself, which can lead to renal dysfunction through mechanisms such as light chain cast nephropathy and hypercalcemia. 13 , 14 This variability necessitates the exploration of alternative filtration biomarkers that can provide a more reliable assessment of renal function.

Cystatin C, a 13 kDa cysteine protease inhibitor, has emerged as a promising biomarker for estimating GFR. Unlike sCr, cystatin C levels are not influenced by muscle mass, age, and sex. However, cystatin C can be influenced by corticosteroid use, including dexamethasone, which is frequently administered as part of ASCT preconditioning. 15 Corticosteroids increase cystatin C levels by promoting its production and release from tissues, independent of kidney function. Furthermore, cystatin C can be influenced by adiposity, 16 diabetes, inflammation, thyroid disease, and cardiac dysfunction. 17 It is produced at a constant rate by all nucleated cells and is freely filtered by the glomerulus, making it a potentially more accurate marker of kidney function. 15 Recent studies have demonstrated that cystatin C–based eGFR (eGFRcys) calculations may offer superior predictive value for renal dysfunction, and patients with lower eGFRcys compared with sCr-based eGFR (eGFRcr) have higher risks of adverse outcomes such as AKI and the requirement for KRT. 18 , 19 In fact, a study by Niu et al. demonstrated that utilization of the CKD-EPI-cystatin C formula was more sensitive than sCr and the CKD-EPI-stringent complete remission (sCR) formula for predicting renal impairment in newly diagnosed MM patients. 20 Given that clinicians often rely on eGFR calculations for accurate renal function assessment in melphalan dosing for MM patients undergoing ASCT in lieu of CrCl, this study aims to evaluate the efficacy of cystatin C compared with sCr in estimating eGFR. We conducted a retrospective analysis of MM patients treated with melphalan conditioning before ASCT to evaluate whether eGFRcys can provide a more reliable basis for melphalan dosing, focusing on hospitalization from melphalan toxicity within 30 days of ASCT with the goal of reducing treatment-related toxicity. Another outcome was to assess IMWG response criteria at 12 months among patients with discordant melphalan dosing as well as 12-month mortality rate.

Methods

Study Design and Inclusion Criteria

This was a retrospective cohort study including all patients at the Medical University of South Carolina diagnosed with MM for which they underwent ASCT during the years 2021–2023. The providers were not blind to this protocol. We screened all patients undergoing ASCT and applied an exclusion criteria, including treatment with corticosteroids within 2 weeks of melphalan treatment and/or had an AKI at the time of baseline laboratory chemistries or during ASCT, ultimately resulting in a final cohort of 84 patients included in our study ( Supplemental Figure 1 ). AKI in this setting was diagnosed by the 2012 Kidney Disease Improving Global Outcomes criteria. 21

Melphalan dosing in our patients was based on pretransplant eGFR calculated from sCr: • 200 mg/m 2 for eGFR >50 ml/min. • 140 mg/m 2 for eGFR <50 ml/min.

There is variability in dosage of melphalan conditioning therapy for ASCT, with the 2023 IMWG consensus statement recommending dose reduction to 140 mg/m 2 at eGFR <60 ml/min. 11 However, dosing thresholds vary between centers, with dose reduction to 140 mg/m 2 implemented for patients perceived to have increased risk of toxicity due to comorbidities including impaired renal function. We consider dose reduction for patients based on review of several risk factors for toxicity including age, comorbidity index, and renal function, and each case is presented weekly for physician consensus.

eGFR was calculated using both sCr and cystatin C levels for all patients included in our study The 2021 CKD-EPI equation was used to estimate eGFR from sCr, and the 2012 CKD-EPI equation was used to estimate eGFR from cystatin C. We compared actual melphalan dosing patients received based on eGFRcr to expected melphalan dosing patients would have received if cystatin eGFRcys was instead used, to determine concordant and discordant dosing (as described below) and investigate clinical outcomes.

Definitions

We defined appropriate melphalan dosing (concordant patients) as any patient who received either the 200 mg melphalan dose based on eGFRcr calculated as >50 ml/min and had eGFR >50 ml/min through eGFRcys calculation or any patient who received the 140 mg melphalan dose based on a eGFRcr calculated <50 ml/min and also had eGFR calculated as <50 ml/min through eGFRcys calculation (Table 1 ). Inappropriate (discordant patients) melphalan dose was defined as any patient who received 200 mg melphalan dose based on an eGFRcr calculated as >50 ml/min and had an eGFR calculated as <50 ml/min through cystatin C–based calculation (Table 1 ).

Hospitalization in this study was ascertained through manual chart review and defined as presentation to an emergency department for a chief complaint directly related to melphalan toxicity within 30 days of melphalan dosing. Included melphalan toxicities/symptoms were mucositis, AKI, hypokalemia, fever, and/or diarrhea. 22 , 23 This excluded presentations for causes not directly related to melphalan.

Disease statuses were designated by oncology using the IMWG response criteria as progressive disease, partial remission, very good partial remission, complete remission (CR), and sCR. 24

Statistical Analyses

Continuous data were reported as median and interquartile range (IQR). Comparison of qualitative data were performed through chi-square or Fisher exact test where appropriate. Quantitative data were compared through Mann–Whitney U test or Kruskal–Wallis test, where appropriate. P value of <0.05 was used as the cutoff to determine significance.

Study End Points

The primary end points of this study were to compare the incidence and nature of hospitalizations within 30 days of melphalan dosing and 30-day patient mortality in patients with concordant melphalan dosing compared with discordant melphalan dosing. Secondary end points included IMWG–defined disease status at 3 and 12 months and 12-month survival.

Results

Our study included 76 patients, with baseline patient characteristics in Table 2 . There was a significant difference in age between groups ( P = 0.024); the average age of discordant patients was 71.1 years, and the average age of concordant patients was 64.6 years. There were no significant differences in other variables analyzed including sex, race, weight, MM subtype, or IMWG diagnosis at the time of transplant between the discordant and concordant patient groups.

We determined eGFR for each patient in our study using both the CKD-EPI sCr and CKD-EPI cystatin C equations to determine the corresponding melphalan dosing and subsequently determined whether the patient's dosing was concordant or discordant (Figure 1 A). Overall, the median CKD-EPI eGFRcr value was 93.5 ml/min per 1.73 m 2 (IQR, 40 ml/min per 1.73 m 2 ), and the median CKD-EPI eGFRcys value was 88.5 ml/min per 1.73 m 2 (IQR, 56 ml/min per 1.73 m 2 ; P = 0.525). We performed a subgroup analysis only including the discordant patients ( n =13; Figure 1 B). The median CKD-EPI eGFRcr in the discordant group was 59 ml/min per 1.73 m 2 (IQR, 22.5 ml/min per 1.73 m 2 ), while the median CKD-EPI eGFRcys in the same patient group was 45 ml/min per 1.73 m 2 (5.0 ml/min per 1.73 m 2 ; P < 0.001).Comparing eGFR and subsequent melphalan dosing using CKD-EPI sCr compared with CKD-EPI cystatin C, 13 patients (17%) were identified as having discordant dosing, having received a higher melphalan dose (200 mg/m 2 ) than what would have been administered if eGFR was determined by CKD-EPI eGFRcys (140 mg/m 2 ; Table 1 ). One hundred percent of the patients receiving discordant dosing were hospitalized within 30 days of conditioning chemotherapy with melphalan (Figure 2 ) due to melphalan toxicity including mucositis, AKI, hypokalemia, fever, and diarrhea. In comparison, patients with concordant dosing had a 30-day hospitalization rate of 60% ( P = 0.006). Furthermore, the median hospitalization duration in discordant patients was 7 days (IQR, 8 days) compared with 2.5 days (IQR, 5 days) in patients with concordant dosing ( P = 0.0014; Figure 3 ).

In addition, there were a total of three deaths, in our patient cohort, two (15%) of which were patients with discordant dosing ( P = 0.074). All deaths occurred after the 12-month follow-up. In the discordant group, one patient died from complications of progressive disease in hospice care (autopsy was not pursued) and one patient died due to complications of sepsis. The one death in the concordant group occurred due to cardiac arrest.

Furthermore, we compared the number of patients who fell below and above the melphalan dosing threshold (50 ml/min per 1.73 m 2 ) using eGFRcr to both sCr-cystatin C–based eGFR (eGFRcrcys) and to eGFRcys (Table 1 ). Significantly more patients would have received a reduced melphalan dose (eGFR <50 ml/min per 1.73 m 2 ) using cystatin C–based eGFR compared with eGFRcr ( P = 0.002); however, no significant differences were identified when comparing the combine CKD-EPI eGFRcrcys to eGFRcr (Table 3 ).

IMWG response criteria were compared from time of transplant to 3 and 12 months post-transplant among patients with discordant melphalan dosing ( n =13) and concordant melphalan dosing ( n =63; Table 4 ). In both patient groups, the median change in IMWG response criteria was no change at 3 months post-transplant but was improved by one category at 12 months post-transplant. Subanalysis was performed looking at percent of patients with IMWG of CR or sCR at baseline and 12 months. Fifteen percent of discordant patients met these criteria at baseline with an increase to 62% of discordant patients at 12 months ( P = 0.044), and 17% of concordant patients met these criteria at baseline with an increase to 49% at 12 months ( P < 0.001). There was no significant change in the percentage of patients achieving sCR or CR between discordant and concordant groups ( P = 0.438).

Discussion

Accurate and timely eGFR assessment is critical to guiding drug eligibility, dosing of cancer therapy including chemotherapies, and minimizing the risks of both toxicity and undertreatment in patients living with malignancy. A statement from the American Society of Onco-Nephrology in 2022 advocated for the use of validated GFR estimating equations incorporating both sCr and cystatin C in patients with cancer. 25 However, data assessing the individual performance of these GFR estimating equations in particular cohorts of patients with cancer, such as MM patients undergoing ASCT, are lacking. Furthermore, linking the performance of the eGFR estimating equation to patient-centered outcomes such as chemotherapy-related toxicity and hospitalization needs further evaluation. There is very little evidence for the role of cystatin and its performance in dosing melphalan in MM patients undergoing ASCT, and many centers still rely on sCr to estimate eGFR premelphalan dosing before ASCT. Cystatin C levels are increased by corticosteroid exposure and inflammation, and its utility in MM patients is not standard of care, although in most patients, dosing of chemotherapy using eGFR estimating equations occurs before corticosteroid exposure.

Our study highlights that that reliance on sCr alone may lead to an overestimation of eGFR which can result in higher-than-intended doses of melphalan in approximately one in five adult patients undergoing ASCT. These patients were identified as being older patients (median age, 71.1 years) and living with CKD (median eGFR, 58 ml/min per 1.72 m 2 ). This is not surprising as patients with CKD are at high risk for adverse safety events because of the complexity of their care and impaired renal function. 26 Notably, 13 patients (17%) in our cohort received a 200 mg/m 2 dose of melphalan instead of the more appropriate 140 mg/m 2 when eGFR was estimated using sCr rather than cystatin C. All (100%) the patients in this discordant group were hospitalized within 30 days of chemotherapy administration from melphalan related toxicities, significantly exceeding the median hospitalization rate by 4.5 days compared with those who were dosed appropriately. The 13 discordant patients who received a higher-than-intended melphalan dose had a significantly higher average duration of hospitalization as compared with patients with appropriate melphalan dosing These data are significant even in light of the fact that one patient in the appropriate dosing group was hospitalized for 26 days due to a seemingly unrelated complicated dental abscess.

CKD alone did not explain the high baseline level of melphalan toxicity seen in the concordant cohort. Up to 60% of patients with a median GFR of 97 ml/min experienced some degree of melphalan toxicity resulting in hospitalization consistent with other incidence reports of melphalan toxicity. 27

eGFR was further recalculated in our study using the 2021 combined CKD-EPI eGFRcrcys equation as per American Society of Onco-Nephrology expert group recommendation, and hospitalization outcomes were then compared between all three calculations (Table 3 ). More patients were calculated to have eGFR <50 ml/min requiring melphalan dose reduction using CKD-EPI eGFRcys compared with CKD-EPI eGFRcrcys ( P = 0.002). There was no significant difference in the number of patients requiring melphalan dose reduction using CKD-EPI eGFRcr compared with CKD-EPI eGFRcrcys ( P = 0.24). There were 50% more patients hospitalized with melphalan related toxicity at 30 days using CKD-EPI cystatin C eGFR compared with the CKD-EPI eGFRcrcys equation; however, this difference was not statistically significant (Table 3 ). This was unexpected as previous studies have found that in large cohorts, combining creatinine with cystatin C to calculate eGFR results in higher accuracy and precision as compared with either creatinine or cystatin C alone. 28 , 29 Hospital course was longer for the discordant group, but the patients in this group were older, and we are unsure if there were any barriers to discharge which may also have affected this clinical outcome. There was no significant statistical differences in race and gender between the two groups. Furthermore, the use of the combined CKD-EPI equation has been demonstrated to be superior to either equation alone in elderly patients. 30 – 32 However, our study's relatively small sample size may have limited the statistical power. Cystatin C was also demonstrated to be superior in estimating true renal function in the setting of prolonged critical illness. 26

We theorize several factors may cause creatinine-based equations to overestimate renal function in these patients. MM is often associated with significant muscle wasting and reduced muscle mass, which leads to lower creatinine production. 1 , 12 In elderly patients, who may already have reduced muscle mass due to aging, the presence of MM exacerbates declining muscle mass, which can result in overestimation of GFR when using creatinine-based equations, as these equations assume a certain level of creatinine production that is not met in these patients. 31 In addition, MM can cause renal impairment through mechanisms, such as light chain deposition disease, cast nephropathy, and hypercalcemia, which can further complicate the accurate estimation of GFR. 1 These renal pathologies do not necessarily affect cystatin C levels in the same way they affect creatinine levels, as cystatin C is produced at a constant rate by all nucleated cells and is less influenced by muscle mass, making it more reliable in conditions where muscle mass is significantly affected. 18 , 20 Fu et al. demonstrated that sCr and cystatin C (sCr×eGFRcys) could be effectively used to assess the degree of sarcopenia in patients with advanced cancer and that there was a stronger correlation with muscle mass compared with the sCr/cystatin C ratio alone, suggesting cystatin C's utility as an objective biomarker for these patients. 33 The findings of our study suggest that incorporating cystatin C into routine clinical practice for eGFR calculation could significantly improve the safety and efficacy of melphalan conditioning regimens. Accurate dosing is essential to balance the therapeutic benefits of melphalan with its potential toxicities. By reducing the incidence of dose-related complications, cystatin C–based dosing could enhance patient outcomes, reduce health care resource utilization, and improve the overall quality of life for MM patients undergoing ASCT. Future research should focus on larger patient population sizes with an emphasis on melphalan related toxicities resulting in hospitalization to confirm the advantages of cystatin C in melphalan dosing for ASCT. Investigation of alternative dose reduction strategies should also be performed, as institution specific protocols for eGFR threshold exist. Furthermore, these data highlight the need for measurement of GFR through exogenous filtration markers to be considered in patients with cancer for whom eGFR results in borderline eligibility for chemotherapy dosing or clinical trials. A promising technique using transdermal fluorescence detection of fluorescent GFR tracer markers may be of additional benefit to these patients and recently received US Food and Drug Administration approval to assess kidney function (MediBeacon Transdermal GFR System). 27 Future prospective studies are needed comparing GFR and subsequent melphalan dosing through combined eGFRcrcys equation to GFR determined using filtration markers.

Limitations of our study include the relatively small sample size, the retrospective nature of the study design, and the patient population only representative of a single center. A key limitation of our work is that we relied on the discrepancy between creatinine and eGFRcys equations rather than validation against measured GFR (mGFR). In addition, it was not feasible to directly measure GFR in our study. Although mGFR is the gold standard for determining GFR and ideally be used, we were limited to determining an eGFR due to the complexity and cost of the available mGFR methods, no such device was US Food and Drug Administration approved at the time of study initiation. Dose reduction of melphalan for patients based on review of several risk factors for toxicity including age and comorbidity index can create possible effect of errors in the dosing of melphalan. Finally, non-GFR determinants related to eGFRcys may also be determining the increased risk of adverse events and was not discussed here.

In conclusion, this study identified a subset of MM patients undergoing ASCT treated with melphalan condition therapy, with incongruity identified between sCr and eGFRcys resulting in discrepancy of melphalan dosing. This was subsequently associated with adverse outcomes. These findings highlight the clinical relevance of recognizing discordance among eGFR metrics. While direct measurement of GFR was not performed in our study and thus limits conclusions regarding accuracy of measurement in renal function between metrics, our results may be interpreted as hypothesis-generating and serve as a foundation for future prospective, multicenter studies that compare combined creatinine and cystatin C filtration markers to measured GFR to clarify whether integrating these methods meaningfully enhances drug dosing of melphalan and diminish toxicity in our ASCT population.

Supplementary Material

Acknowledgments

Dialysis Clinic, Inc. has supplied funds outside of this work.

B.T. and A.L.G. contributed equally to this work.

See related editorial, “Mind the Gap: eGFR Discordancy and Melphalan Toxicity in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant,” on pages 705–707.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B538 .

Author Contributions

Conceptualization: Hamza Hashmi, Blaithin A. McMahon.

Data curation: James Davis, Ashley L. Golbus, Elaine Park, Benjamin Teruel.

Formal analysis: Ashley L. Golbus, Blaithin A. McMahon.

Investigation: Hamza Hashmi, Blaithin A. McMahon, Elaine Park, Benjamin Teruel.

Methodology: Ashley L. Golbus, Blaithin A. McMahon.

Project administration: Blaithin A. McMahon, Benjamin Teruel.

Supervision: Blaithin A. McMahon, Patrick T. Murray.

Validation: Blaithin A. McMahon.

Writing – original draft: Ashley L. Golbus, Blaithin A. McMahon, Benjamin Teruel.

Writing – review & editing: James Davis, Hamza Hashmi, Blaithin A. McMahon, Patrick T. Murray, Benjamin Teruel.

Funding

None.

Declarative Statements

This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. The need to obtain informed patient consent was waived.

Data Availability Statements

Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Health Care Data. Reason for Restricted Access: I would have to modify the Instituition Review Board application to be able to share the dataset.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/B539 .

Supplemental Figure 1 . Patient inclusion and exclusion criteria.

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