Patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment (RI) are considered a high-risk group frequently excluded from clinical trials. Patients with RI have a higher risk of disease progression or death compared to those without RI (relative risk (RR): 1.20 [1.003–1.431]) [ 1 ]. RI is a negative prognostic factor linked to early mortality, shorter overall survival (OS), and greater treatment-related toxicity. Only about 30% of trials clearly report the proportion of patients with RI, and eligibility criteria related to renal function are inconsistently applied, often leading to exclusion of these patients [ 2 , 3 ]. Talquetamab (Tal), a GPRC5D - targeting bispecific antibody (BsAb), received Food and Drug Administration (FDA) approval in August 2023 based on the findings from the MonumenTAL-1 clinical trial. Tal demonstrated high overall response rates (ORR) 69–74% and a manageable safety profile [ 4 ]. However, the absence of data in patients with RI means that efficacy and safety of Tal in this subgroup remain undefined.
We conducted a retrospective cohort study at our quaternary cancer center, assembling patients with RRMM who have been treated with Tal. The primary aim was to compare the safety and effectiveness in patients with and without RI, with prespecified exploratory analyses in patients with severe RI and those on dialysis. The study started on March 30, 2023, with a data cutoff date on June 25, 2025. The study protocol was reviewed and approved by the Institutional Review Board (IRB). All study procedures adhered to the ethical principles of the World Medical Association’s Declaration of Helsinki.
Study eligibility criteria included patients with RRMM who received at least one dose of Tal at our center. Tal was administered subcutaneously using an inpatient sequential escalating step-up dosing schedule to mitigate the risk of AEs (0.01 mg/kg, 0.06 mg/kg, 0.4 mg/kg, 0.8 mg/kg), followed by a bi-weekly maintenance dose of 0.8 mg/kg. Primary cohort stratification: RI cohort (creatinine clearance [CrCl] <40 mL/min; n = 12, 33.3%) vs No-RI cohort (CrCl ≥40 mL/min; n = 24, 66.7%), consistent with the exclusion criteria and definitions from the MonumenTAL-1 trial and using the Modified Diet in Renal Disease (MDRD) Formula for estimating glomerular filtration rate [ 4 , 5 ]. Two subgroups were further specified: severe RI (CrCl <30 mL/min; n = 7, 19.4%) and dialysis-dependent patients ( n = 5, 13.9%), based on previous study protocols [ 6 ].
Descriptive statistics summarize baseline patient demographics and disease characteristics. Categorical variables were compared using χ ² or Fisher’s exact tests. Continuous variables were compared using Mann–Whitney U test. Effect estimates for binary outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI) to complement p -values. Survival outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. An α of 0.05 indicates statistical significance. All analyses were performed using R (version 4.5.1) [ 7 ].
Among the total cohort of 36 patients who initiated Tal, 24 (66.7%) had no RI, and 12 (33.3%) had protocol-defined RI; of these, 7 (19.4%) had severe RI, and 5 (13.9%) were dialysis-dependent. Patients were heavily pretreated and enriched for high-risk cytogenetics per International Myeloma Society (IMS) and International Myeloma Working Group criteria (IMWG) [ 8 , 9 ]. Cytogenetic risk differed significantly by renal function ( p = 0.03). Baseline patient characteristics were comparable and evenly distributed ( Table 1 ) . Table 1 Baseline patient characteristics at talquetamab initiation. Total N = 36 (100%) RI cohort n = 12 No RI cohort n = 24 P value Patients’ demographics Age, median (IQR), years 66.5 (59.8–71) 68 (60–72.3) 0.78 a Gender, n (%) 0.5 b Male 6 (50) 15 (62.5) Female 6 (50) 9 (37.5) Year of diagnosis, median (IQR) 2020 (2018–2021) 2018 (2013–2020) 0.17 a Race, n (%) 0.35 c White 11 (91.7) 17 (70.8) Black 1 (8.3) 6 (25) Other 0 (0) 1 (4.2) Ethnicity, n (%) Hispanic 0 (0) 0 (0) Non-Hispanic 12 (100) 24 (100) Disease characteristics Cytogenetic risk, n (%) 0.03* c Standard 1 (8.3) 10 (41.7) High 8 (66.7) 5 (20.8) Double-Hit MM 3 (25) 6 (25) Triple-Hit MM 0 (0) 3 (12.5) ECOG PS, n (%) 0.53 c 0 2 (16.7) 1 (4.1) 1 5 (41.6) 10 (41.7) 2 3 (25) 10 (41.7) 3 2 (16.7) 3 (12.5) Light chain type, n (%) 0.3 b Lambda 7 (58.3) 9 (37.5) Kappa 5 (41.7) 15 (62.5) Heavy chain type, n (%) 0.86 c IgA 2 (16.7) 5 (20.8) IgG 6 (50) 13 (54.2) Non (Only light chain) 4 (33.3) 6 (25) Extramedullary disease, n (%) 2 (16.7) 4 (16.7) 1.0 b Treatment refractoriness Number of prior lines of therapy, median (IQR) 6 (5–8) 7.5 (5–9) 0.31 a Triple-class refractory, n (%) 12 (100) 23 (95.8) 1.0 b Penta-class refractory, n (%) 11 (91.7) 18 (75) 0.64 b Previous ASCT, n (%) 7 (58.3) 14 (58.3) 1.0 b Previous BCMA-directed therapy, n (%) 10 (83.3) 21 (87.5) 1.0 b RI renal impairment, ECOG PS Eastern Cooperative Oncology Group performance status, ASCT autologous stem cell transplantation, BCMA B-cell maturation antigen. a Mann–Whitney U test. b Fisher’s exact test. c Chi-square test.
Table 1
Baseline patient characteristics at talquetamab initiation.
RI renal impairment, ECOG PS Eastern Cooperative Oncology Group performance status, ASCT autologous stem cell transplantation, BCMA B-cell maturation antigen. a Mann–Whitney U test. b Fisher’s exact test. c Chi-square test.
| Total N = 36 (100%) | RI cohort n = 12 | No RI cohort n = 24 | P value |
| Patients’ demographics | |||
| Age, median (IQR), years | 66.5 (59.8–71) | 68 (60–72.3) | 0.78 a |
| Gender, n (%) | 0.5 b | ||
| Male | 6 (50) | 15 (62.5) | |
| Female | 6 (50) | 9 (37.5) | |
| Year of diagnosis, median (IQR) | 2020 (2018–2021) | 2018 (2013–2020) | 0.17 a |
| Race, n (%) | 0.35 c | ||
| White | 11 (91.7) | 17 (70.8) | |
| Black | 1 (8.3) | 6 (25) | |
| Other | 0 (0) | 1 (4.2) | |
| Ethnicity, n (%) | |||
| Hispanic | 0 (0) | 0 (0) | |
| Non-Hispanic | 12 (100) | 24 (100) | |
| Disease characteristics | |||
| Cytogenetic risk, n (%) | 0.03* c | ||
| Standard | 1 (8.3) | 10 (41.7) | |
| High | 8 (66.7) | 5 (20.8) | |
| Double-Hit MM | 3 (25) | 6 (25) | |
| Triple-Hit MM | 0 (0) | 3 (12.5) | |
| ECOG PS, n (%) | 0.53 c | ||
| 0 | 2 (16.7) | 1 (4.1) | |
| 1 | 5 (41.6) | 10 (41.7) | |
| 2 | 3 (25) | 10 (41.7) | |
| 3 | 2 (16.7) | 3 (12.5) | |
| Light chain type, n (%) | 0.3 b | ||
| Lambda | 7 (58.3) | 9 (37.5) | |
| Kappa | 5 (41.7) | 15 (62.5) | |
| Heavy chain type, n (%) | 0.86 c | ||
| IgA | 2 (16.7) | 5 (20.8) | |
| IgG | 6 (50) | 13 (54.2) | |
| Non (Only light chain) | 4 (33.3) | 6 (25) | |
| Extramedullary disease, n (%) | 2 (16.7) | 4 (16.7) | 1.0 b |
| Treatment refractoriness | |||
| Number of prior lines of therapy, median (IQR) | 6 (5–8) | 7.5 (5–9) | 0.31 a |
| Triple-class refractory, n (%) | 12 (100) | 23 (95.8) | 1.0 b |
| Penta-class refractory, n (%) | 11 (91.7) | 18 (75) | 0.64 b |
| Previous ASCT, n (%) | 7 (58.3) | 14 (58.3) | 1.0 b |
| Previous BCMA-directed therapy, n (%) | 10 (83.3) | 21 (87.5) | 1.0 b |
Regarding safety profile, comparing RI vs no-RI, respectively, cytokine release syndrome (CRS) was common and mostly low-grade, with a comparable incidence across both groups. Any-grade CRS occurred in 66.7% of patients in each group. Grade 1 CRS was reported in (58.3%) vs (45.8%) (OR: 1.66; 95% CI, 0.43–6.32). Grade ≥3 CRS was infrequent (8.3%) in each group. Recurrent CRS was uncommon (8.3%) vs (16.7%) (OR, 0.45; 95% CI, 0.05–4.59). CRS episodes were short, with a median duration of 1 day in both groups. For CRS treatment, tocilizumab was used in (66.7%) of each group, corticosteroids in (16.7%) RI vs (20.8%) no-RI, and anakinra in (8.3%) RI vs (4.2%) no-RI.
Immune effector cell-associated neurotoxicity syndrome (ICANS) was less frequent than CRS and showed no significant differences by renal function. Any-grade ICANS occurred in 16.7% with RI vs 20.8% with no-RI (OR, 0.76; 95% CI, 0.12–4.64), and grade ≥3 ICANS in 8.3% vs 12.5% (OR, 0.64; 95% CI, 0.06–6.86). ICANS duration was also brief, with a median of 2 days in both groups. ICANS treatment was used in a minority of cases and was balanced between cohorts: tocilizumab was used in 8.3% vs 20.8%, corticosteroids in 16.7% of each group, and anakinra was not used in RI vs 4.2% in no-RI group.
Infections were infrequent overall in both cohorts. Bacterial infections were observed in 8.3% with RI vs 16.7% with no-RI, viral infections in 8.3% of both cohorts, and fungal infections in 0% vs 4.2%. Dysgeusia was common, occurring in 83.3% of each group. Skin-related events were reported in 75% with RI vs 58.3% with no-RI (OR, 2.14; 95% CI, 0.46–9.98), and nail-related events in 83.3% vs 54.2% (OR, 4.23; 95% CI, 0.76–23.57). Hospital utilization metrics were likewise comparable: the inpatient length of stay during step-up dosing (first cycle) was similar (median 10 days [range 7–25] with RI vs 9 days [8–24] with no-RI), and intensive care unit admission during first cycle was uncommon (0% vs 4.2%).
Median follow-up time for the entire cohort was 7.3 months (95% CI, 4.5–10.5), with median follow-up in RI group of 11.4 months (95% CI, 4.7–18.2), 6.4 months (3.2–9.3) for those with no-RI, 4.7 months (95% CI, 3.7–10.4) in the severe RI subgroup, and 7.5 months (95% CI, 3.7–15.1) among dialysis-dependent patients. Early disease response was evident by day 30. The ORR at day 30 was 6/12 (50%) in RI vs 11/24 (45.8%) in no-RI. In the RI cohort, 30-day responses comprised complete response or better (≥CR) in 2/12 (16.7%) and very good partial response (VGPR) in 4/12 (33.3%), with no partial responses (PR), while 4/12 (33.3%) had stable disease (SD) and 2/12 (16.7%) progressive disease (PD). In the no-RI cohort at day 30, ≥CR was 1/24 (4.2%), VGPR 2/24 (8.3%), PR 8/24 (33.3%), SD 8/24 (33.3%), and PD 5/24 (20.8%). Early activity (30-day response) was also observed in the severe-RI subgroup, with VGPR in 3/7 (42.9%), and in dialysis-dependent patients, with VGPR in 3/5 (60%).
Depth of response increased by day 90 in RI and remained measurable in other groups. At day-90, ORR in RI rose to 8/12 (66.7%), including ≥CR in 4/12 (33.3%) and VGPR in 2/12 (16.7%). In contrast, the day-90 ORR in no-RI was 6/24 (25%), with ≥CR in 2/24 (8.3%), VGPR in 1/24 (4.2%), and PR in 3/24 (12.5%). Notably, 9/24 (37.5%) of patients in the no-RI cohort developed PD by this point, and 7/24 (29.2%) had a non-evaluable day-90 response. The severe-RI subgroup achieved a day-90 ORR of 4/7 (57.1%), and dialysis-dependent patients achieved an ORR of 4/5 (80%) and ≥CR in 1/5 (20%), with no PD observed in either group at this time point. The best ORR showed clinically meaningful activity across all cohorts (Fig. 1A ). Fig. 1 Efficacy and survival. A Depth of best overall response by cohort, B Survival outcomes among patients with and without renal impairment, C Survival outcomes among patients with and without severe renal impairment, D Survival outcomes among dialysis- and non-dialysis-dependent patients.
There is an observed trend toward higher OS in the RI cohort, as not reached (NR) (95% CI: 10.38–NR), compared to the no-RI group of 8.71 months (95% CI: 3.25–NR) (Fig. 1B ). However, the median progression-free survival (PFS) was significantly higher in the RI cohort of 8.48 months (95% CI: 7.49–NR) vs no-RI of 2.63 months (95% CI: 2.07–5.26) ( p = 0.006). Despite shorter survival curves in the subgroup analysis, there was no significant difference in OS while comparing patients with severe RI vs without severe RI (Fig. 1C ), but PFS was numerically longer in severe RI subgroup at 7.49 months (95% CI, 1.64–NR) compared with 3.65 months (95% CI, 2.10–7.88) in patients with no severe RI ( p = 0.22). There was also no significant difference in OS or PFS between dialysis-dependent vs non-dialysis-dependent patients (Fig. 1D ).
In this single-center, real-world analysis, Tal showed promising efficacy and manageable toxicity in heavily pretreated RRMM patients, including those with RI, severe RI, and dialysis dependence. Our findings align with the MonumenTAL-1 trial, where Tal achieved an ORR of 66–70% at doses of 0.4 mg/kg weekly or 0.8 mg/kg biweekly in patients with a median of 5 prior lines of therapy [ 4 , 10 ]. Our cohort showed early response by day 30, deepened by day 90, and clinically meaningful best ORRs without attenuation in RI cohorts. Importantly, we did not observe any limitation in efficacy among severe RI or dialysis-dependent subgroups. Our results are consistent with prior real-world data on teclistamab, a BCMA-directed bispecific, which demonstrated comparable efficacy and safety in patients with RI versus those with no RI, reinforcing the concept that BsAbs can be feasible across this population [ 11 ]. Combination BsAbs regimens (e.g., Tal plus teclistamab) show high activity but increase AEs, raising concerns about immunotoxicity in vulnerable groups like those with RI [ 12 ]. These regimens require thorough risk-benefit assessments and renal function tests before broad use adoption. Study limitations include the retrospective design, a small sample size—particularly among severe RI and dialysis patients—and a short follow-up, which limit definitive survival comparisons.
In conclusion, our findings suggest that Tal can be considered for appropriately selected patients with RI, including those with severe RI and those on dialysis, provided that multidisciplinary supportive care is in place.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Hossam M. Ali, Sandra Mazzoni.
Acknowledgements
We wish to express our sincere appreciation for the invaluable contributions of the entire Multiple Myeloma care team at the Cleveland Clinic, Taussig Cancer Center.
Author contributions
HMA, S.Mazzoni, and SR: Conceptualization, data curation, methodology. HMA: Formal analysis, software. HMA, S.Mazzoni, FA, and SR: Writing—original draft, visualization. HMA, S.Mazzoni, UG, J.Khouri, FA, LSW, DB, CJS, BMF, WVH, KH, JR, MR, J.Kissam, CS, S.Mathur, AM, TR, JB, MCP, JV, and SR: Investigation, project administration, validation, writing—review and editing, resources. All authors approved the final manuscript version.
Data availability
The datasets are available from the corresponding author on reasonable request.
Competing interests
J.Khouri has a consulting or advisory role with Janssen, Prothena, Legend Biotech, and GPCR. FA has consulting relationships with BMS, Caribou Biosciences, and received research funding (outside of this study) from Celgene, Acetylon Pharmaceuticals, Millennium, Astellas Pharma, AbbVie, Janssen, Bristol Myers Squibb, and Caribou Biosciences. B.Faiman is a consultant with Janssen, Sanofi, and BMS. S.R. received an honorarium as an advisory board member from Pfizer, Prothena Bio-sciences, and KiTE pharma, and received research funding (outside of this study) from Nexcella Inc, Poseida Therapeutics, and Janssen. S.Mazzoni has a consulting or advisory role with Janssen, Bristol Myers Squibb, Legend Biotech, Pfizer, Alexion, GSK, and received research funding from Janssen and Pfizer. MP has a consulting role with AstraZeneca. All other authors declare no competing financial interests.
Ethical
The study was reviewed and approved by the institutional review board (IRB). The requirement for informed consent was waived in accordance with institutional guidelines and ethical standards, given the retrospective design of the study, minimal risk to participants, and use of existing records. Patient confidentiality and data privacy were maintained throughout the study.
References
1. Mohyuddin GR Koehn K Shune L Aziz M Abdallah AO McClune B Renal insufficiency in multiple myeloma: a systematic review and meta-analysis of all randomized trials from 2005-2019 Leuk Lymphoma 2021 62 1386 95 10.1080/10428194.2020.1867725 33416412 Mohyuddin GR, Koehn K, Shune L, Aziz M, Abdallah AO, McClune B, et al. Renal insufficiency in multiple myeloma: a systematic review and meta-analysis of all randomized trials from 2005-2019. Leuk Lymphoma. 2021;62:1386–95. 33416412 10.1080/10428194.2020.1867725
2. Bozic B Rutner J Zheng C Ruckser R Selimi F Racz K Advances in the treatment of relapsed and refractory multiple myeloma in patients with renal insufficiency: novel agents, immunotherapies and beyond Cancers 2021 13 5036 10.3390/cancers13205036 34680184 PMC8533858 Bozic B, Rutner J, Zheng C, Ruckser R, Selimi F, Racz K, et al. Advances in the treatment of relapsed and refractory multiple myeloma in patients with renal insufficiency: novel agents, immunotherapies and beyond. Cancers. 2021;13:5036. 34680184 10.3390/cancers13205036 PMC8533858
3. Boquoi A Rings V Mohring A Savickaite I Zukovs R Strapatsas J Opportunities for participation in randomized controlled trials for patients with multiple myeloma: trial access depends on restrictive eligibility criteria and patient expectations Cancers 2022 14 2147 10.3390/cancers14092147 35565276 PMC9106039 Boquoi A, Rings V, Mohring A, Savickaite I, Zukovs R, Strapatsas J, et al. Opportunities for participation in randomized controlled trials for patients with multiple myeloma: trial access depends on restrictive eligibility criteria and patient expectations. Cancers. 2022;14:2147. 35565276 10.3390/cancers14092147 PMC9106039
4. Chari A Minnema MC Berdeja JG Oriol A van de Donk NWCJ Rodríguez-Otero P Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma N Engl J Med 2022 387 2232 44 10.1056/NEJMoa2204591 36507686 Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk NWCJ, Rodríguez-Otero P, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387:2232–44. 36507686 10.1056/NEJMoa2204591
5. Levey AS Coresh J Greene T Stevens LA Zhang YL Hendriksen S Using standardized serum creatinine values in the modification of Diet in Renal Disease study equation for estimating glomerular filtration rate Ann Intern Med 2006 145 247 54 10.7326/0003-4819-145-4-200608150-00004 16908915 Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of Diet in Renal Disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–54. 16908915 10.7326/0003-4819-145-4-200608150-00004
6. Sidana S Peres LC Hashmi H Hosoya H Ferreri C Khouri J Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment Haematologica 2024 109 777 86 10.3324/haematol.2023.283940 37731379 PMC10905101 Sidana S, Peres LC, Hashmi H, Hosoya H, Ferreri C, Khouri J, et al. Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment. Haematologica. 2024;109:777–86. 37731379 10.3324/haematol.2023.283940 PMC10905101
7. R Core Team (2025) R: a language and environment for statistical computing. R Foundation for Statistical Computing. https://www.R-project.org/ . Vienna, Austria: R Foundation for Statistical Computing; Available from: https://www.R-project.org/ .
8. Avet-Loiseau H Davies FE Samur MK Corre J D’Agostino M Kaiser MF International myeloma society/international myeloma working group consensus recommendations on the definition of high-risk multiple myeloma J Clin Oncol Off J Am Soc Clin Oncol 2025 43 2739 51 10.1200/JCO-24-01893 PMC13445576 40489728 Avet-Loiseau H, Davies FE, Samur MK, Corre J, D’Agostino M, Kaiser MF, et al. International myeloma society/international myeloma working group consensus recommendations on the definition of high-risk multiple myeloma. J Clin Oncol Off J Am Soc Clin Oncol. 2025;43:2739–51. 10.1200/JCO-24-01893 PMC13445576 40489728
9. Schavgoulidze A, Perrot A, Leleu X, Cazaubiel T, Chretien ML, Feugier P, et al. High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing. Blood. 2025:24;266–75. 10.1182/blood.2025029999 PMC13292120 40991836
10. Gong J Zhou J Yuan D Ma X Vishwamitra D Hilder B Recommended phase II doses of talquetamab in patients with relapsed/refractory multiple myeloma from monumenTAL-1: clinical pharmacology results Clin Pharmacol Ther 2025 118 954 66 10.1002/cpt.70004 40704375 PMC12439005 Gong J, Zhou J, Yuan D, Ma X, Vishwamitra D, Hilder B, et al. Recommended phase II doses of talquetamab in patients with relapsed/refractory multiple myeloma from monumenTAL-1: clinical pharmacology results. Clin Pharmacol Ther. 2025;118:954–66. 40704375 10.1002/cpt.70004 PMC12439005
11. Dima D Afrough A Goel U Grajales-Cruz AF Khouri J Julian K Teclistamab for patients with heavily pretreated relapsed/refractory multiple myeloma and renal impairment Blood Adv 2025 9 3408 17 10.1182/bloodadvances.2025016059 40198766 PMC12274829 Dima D, Afrough A, Goel U, Grajales-Cruz AF, Khouri J, Julian K, et al. Teclistamab for patients with heavily pretreated relapsed/refractory multiple myeloma and renal impairment. Blood Adv. 2025;9:3408–17. 40198766 10.1182/bloodadvances.2025016059 PMC12274829
12. Cohen YC Magen H Gatt M Sebag M Kim K Min CK Talquetamab plus teclistamab in relapsed or refractory multiple myeloma N Engl J Med 2025 392 138 49 10.1056/NEJMoa2406536 39778168 Cohen YC, Magen H, Gatt M, Sebag M, Kim K, Min CK, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392:138–49. 39778168 10.1056/NEJMoa2406536