Teclistamab for patients with heavily pretreated relapsed/refractory multiple myeloma and renal impairment Open Access

The introduction of B-cell maturation antigen (BCMA)–directed bispecific antibodies into clinical practice has revolutionized the treatment paradigm of relapsed/refractory multiple myeloma (RRMM).^1-6 Teclistamab was the first anti-BCMA bispecific antibody to receive US Food and Drug Administration approval in October 2022 for the treatment of patients with RRMM who have received ≥4 previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This approval was based on the phase 1/2 MajesTEC-1 trial, which evaluated 165 patients with a median of 5 prior lines of therapy, most of whom (78%) were triple-class refractory.¹ 

In MajesTEC-1, teclistamab yielded an overall response rate (ORR) of 63%, with 40% of patients achieving a complete response (CR) or better. After a median follow-up time of 14 months, the median progression-free survival (PFS) and overall survival (OS) were 11.3 and 18.3 months, respectively.¹ Cytokine release syndrome (CRS) and neurotoxicity, including immune effector cell–associated neurotoxicity syndrome (ICANS), were found in 72% and 14.5%, respectively; however, grade ≥3 CRS or ICANS events were rare (<1%).¹ 

Given its high efficacy and favorable safety profile, teclistamab has been established as an important therapeutic option for patients with RRMM. However, similar to many pivotal registration trials, the MajesTEC-1 trial excluded patients with renal impairment (RI). Specifically, patients with a creatinine clearance (CrCl) of <40 mL/min were not trial-eligible. As a result, the efficacy and safety of teclistamab in this patient population are unknown.

Renal dysfunction is a common phenomenon in both newly diagnosed and RRMM,^7-10 and the etiology can be multifactorial: for example, direct cast nephropathy from monoclonal light chains or toxicities of multiple treatments during the disease course.¹¹ As patients progress through lines of therapy, existing RI often worsens, and recovery of renal function is less likely in patients with RRMM compared to those with newly diagnosed disease.^10,12 Overall, the presence of RI has been associated with a significantly worse prognosis, especially if severe.¹³ The goal of this multicenter retrospective analysis was to evaluate the outcomes of patients with RRMM and RI treated with standard-of-care (SOC) teclistamab.

This retrospective analysis evaluated patients with RRMM who received teclistamab under a commercial US Food and Drug Administration label. Data were collected from 13 academic centers participating in the US MM Immunotherapy Consortium. The study was conducted in compliance with the Declaration of Helsinki. Each center obtained institutional review board approval in accordance with institutional requirements.

Consistent with the current dosing guidelines outlined in the package insert, patients received subcutaneous teclistamab in step-up doses of 0.06 and 0.3 mg/kg, followed by a full dose of 1.5 mg/kg; subsequent dosing frequency was according to the treating physician’s discretion. Step-up dosing protocols were implemented according to each center’s standard of care. For patients on dialysis, if teclistamab dosing was scheduled on a dialysis day, it was administered after dialysis. The data cutoff date for the safety and efficacy analyses was 30 April 2024.

On the basis of the exclusion criterion for the MajesTEC-1 trial, RI was defined as CrCl of <40 mL/min at the time of teclistamab initiation.¹ As done previously, CrCl of <30 mL/min or being on dialysis was defined as severe RI.¹⁴ CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria.¹⁵ Hematologic toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 5.0. Infectious prophylaxis, use of growth colony-stimulating factor, and management of CRS and ICANS were according to institutional guidelines.^16,17 Although there were some differences between practices based on specific institutional protocols, infection management guidelines were overall consistent with previously published guidelines.¹⁸ 

Therapeutic responses were assessed using the International Myeloma Working Group criteria.¹⁹ However, because of the retrospective nature of the study, confirmatory testing and imaging to verify CR in patients with extramedullary disease (EMD) were not mandated. EMD in this study was defined as bone-independent–only tumors of plasma cells growing at anatomic sites outside of the bone marrow before teclistamab initiation. Bone-dependent and paraskeletal plasmacytomas were not considered EMD. High-risk cytogenetics were defined as the presence of deletion 17p, t(4;14), t(14;16), and/or gain/amplification 1q on fluorescence in situ hybridization (FISH) testing at any time point before teclistamab initiation. PFS was defined as the time from treatment initiation to disease progression or death from any cause, whichever occurred first. OS was defined as the time from treatment initiation to death from any cause.

Baseline characteristics and outcomes related to safety and efficacy were outlined with descriptive statistics. Differences between groups were evaluated using χ² or Fisher exact tests for categorical variables or Kruskal-Wallis rank sum tests for continuous variables. PFS and OS were estimated using the Kaplan-Meier method, and survival outcomes between subgroups were compared using log-rank test. Multivariable Cox proportional hazard regression models were used to analyze the association of RI with PFS and OS while adjusting for the selected characteristics. The probability of non-relapse mortality was estimated using cumulative incidence curves while accounting for death due to disease progression as a competing risk. Predictors of response and survival with teclistamab were assessed using univariable and multivariable logistic regression models. All statistical analyses were conducted in R (version 4.4.2). All statistical tests were 2 sided, and a P value of <.05 was considered statistically significant.

A total of 384 consecutive patients were included in this study, of whom 81 (21%) had RI (CrCl <40 mL/min) at tecistamab initiation. Among these, 45 (18%) had severe RI, including 18 (5%) who were on dialysis. The median age of the entire cohort was 68 years (range, 61-74); 34% of the patients were non-White; and 37% were penta-class refractory. In addition, 26% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, 55% had high-risk FISH findings, and 26% had EMD before teclistamab initiation. The median time from diagnosis to teclistamab initiation was 70.3 months (interquartile range, 42.4-112). Baseline patient characteristics are summarized in Table 1 stratified by the cohort with RI (n = 81) vs those without RI (n = 303).

Most patients with RI received teclistamab ramp-up in the inpatient setting rather than outpatient (82% vs 18%). In the RI cohort, 28% of the patients had ECOG PS ≥2, 59% had high-risk cytogenetics by FISH, 22% had EMD at teclistamab initiation, and 38% were penta-class refractory. Of the 81 patients with RI, 36 (44%) had documented history of cast nephropathy (either clinically diagnosed or with biopsy) before teclistamab initiation. Patients with RI were older (median age, 71 vs 67 years; P = .002) and had a higher median number of prior lines of therapy (7 vs 6; P = .04). There was no difference in the proportion of patients with penta-class refractory disease (38% vs 37%; P = .97) or exposure to a previous BCMA-directed therapy (46% vs 51%; P = .45). At baseline, patients with RI had higher rates of anemia and thrombocytopenia compared with the normal renal function group.

CRS of any grade was seen at comparable rates among patients with and without RI (51% vs 59%; P = .23), including grade ≥3 CRS events (1.2% vs 1%; P = .9). Likewise, ICANS of any grade was observed at similar rates in patients with and without RI (16% vs 13%; P = .6), including grade ≥3 ICANS events (2.5% vs 2.6%; P = .9). Adverse events for both cohorts are summarized in Table 2. For the subgroup of patients with severe RI (n = 45), any grade (grade ≥3) CRS and any grade (grade ≥3) ICANS were 60% (2%) and 18% (4%), respectively. For the subset of patients who were on dialysis only (n = 18), any grade (grade ≥3) CRS and any grade (grade ≥3) ICANS were 55.5% (0%) and 17% (5.5%), respectively (supplemental Table 1).

Patients with RI had a similar hospital length of stay compared with those without RI (median 8 days for both groups, P = .75). Tocilizumab, steroid, and anakinra use for either CRS or ICANS was similar between the 2 groups. No delayed neurotoxicity or immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome were seen in patients with RI.

Infections were found in 33% vs 46% of patients with and without RI (P = .06), whereas severe infections occurred in 20% vs 19% (P = .9), respectively. At day 30, incidence of grade ≥3 thrombocytopenia was higher in patients with RI (17% vs 6%; P = .002). Patients with RI also had a trend toward higher rates of grade ≥3 anemia at day 30 compared with those without RI (11% vs 6%; P = .1). Despite the significant difference in severe thrombocytopenia, the use of thrombopoietin receptor agonists was similar between patients with and without RI (2.5% vs 2.6%; P >.9), as was the use of granulocyte colony-stimulating factor (12% vs 17%; P = .3). Intravenous (IV) immunoglobulin use was also similar between the 2 groups.

Of the 18 patients who were on dialysis at teclistamab initiation, 2 had progressed, and another 2 had died from myeloma progression by day 30, while 14 were alive and remained dialysis dependent. Of the remaining 63 patients with CrCl of <40 mL/min at teclistamab initiation, 14 (22%) had either progressed or died by day 30, 35 (56%) remained in the same range of CrCl, 11 (17.5%) improved to CrCl ≥40 mL/min, while only 2 (3%) had notable drop in their CrCl from >30 mL/min to <20 mL/min without requiring dialysis. Of note, CrCl at day 30 was not available for 1 patient. Among the 303 patients with baseline CrCl ≥40 mL/min at teclistamab initiation, 73 (24%) had either progressed or died by day 30, 214 (71%) remained in the same range of CrCl ≥40 mL/min, and 9 (3%) experienced worsening of their CrCl to <40 mL/min by day 30. Of note, CrCl at day 30 was not available for 7 patients.

Patients with and without RI had similar response rates, as shown in Figure 1. ORR was 52% vs 56% (P = .61), with very good partial response or better rates being 47% vs 46% (P = .92) and CR or better rates being 20% vs 24% (P = .53) in patients with and without RI, respectively. Univariable and multivariable analyses for ORR and CR or better rate are presented in supplemental Tables 2 and 3.

The median follow-up of the entire cohort was 9.9 months (95% confidence interval [CI], 9.5-10.6). The estimated median PFS for patients with and without RI was 4.6 months (95% CI, 2.9-10.7) vs 6.5 months (95% CI, 5.5-8.7), respectively (P = .62; Figure 2A). On multivariable analysis, the presence of RI was not independently associated with PFS (hazard ratio, 1.2; 95% CI, 0.85-1.6; P = .31; Table 3). The estimated median OS for patients with RI was not reached (NR; 95% CI, 9.41 to NR) vs 16.1 months (95% CI, 14 to NR) for those without RI (P = .77; Figure 2B).

When analyzing renal function as severe RI (CrCl of <30 mL/min or dialysis dependence) vs no severe RI (CrCl ≥30 mL/min), we observed similar results with no significant difference in PFS and OS among the 2 groups (Figure 3). In detail, the median PFS for the severe RI cohort was 7.8 months (95% CI, 4.3 to NR) vs 5.9 months (95% CI, 4.4-8.1) for the cohort without severe RI (P = .43), and the median OS was NR (95% CI, NR to NR) vs 16.1 months (95% CI, 14 to NR), respectively (P = .6)

At data cutoff, 137 patients who received commercial teclistamab had died, 108 (36%) with RI and 29 (36%) without. The causes of death and early death are summarized in supplemental Tables 4 and 5. The cumulative incidence of death due to non-relapsed mortality did not differ for the groups with and without RI (14% vs 12%, respectively; P = .26).

To our knowledge, this is the largest study evaluating the outcomes of patients with RRMM and renal dysfunction treated with SOC teclistamab. Such patients were excluded from the pivotal MajesTEC-1; thus, the safety and efficacy of BCMA-targeting bispecific antibodies in this population are unclear. Our cohort with RI consisted of heavily pretreated patients with a median of 7 prior lines of therapy, of whom 38% were penta-drug refractory with aggressive disease features, including 59% with high-risk cytogenetics and 22% with EMD. Overall, our findings suggest that administration of teclistamab is feasible in patients with RI, with efficacy and safety comparable to patients with normal renal function.

With regard to safety, the incidence and severity of CRS and ICANS were comparable in patients with and without RI, including in patients with severe RI. Management of CRS and neurotoxicity was generally similar, with no differences in rates of tocilizumab, steroid, or anakinra use. As found with a similar RI-focused analysis in BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy previously conducted by our group, short-term cytopenias were also worse in the RI cohort receiving teclistamab.¹⁴ The mechanism for this difference is unclear, but unlike with CAR-T therapy, it cannot be attributed to the pharmacokinetics of lymphodepleting chemotherapy, which is not used with teclistamab. In both the previous study and ours, patients with RI had received more prior lines of therapy. As such, baseline and short-term cytopenias after treatment initiation may be sequelae of patients with RI being more heavily pretreated before CAR-T or teclistamab was considered as options.¹⁴ However, unlike with the previous CAR-T study, hospital lengths of stay were similar between the RI and non-RI groups in this analysis. The rate of infections was not significantly different between the 2 cohorts, although it was numerically higher in patients without RI. However, the rates of severe infections were comparable between the 2 groups. It is not clear why patients without RI had numerically higher rates of infections, but this could be explained by the less rigorous monitoring of real-world patients, leading to failure to capture infections, especially if these are non-severe and resolve without any intervention. Another potential explanation is that patients on dialysis or with severe RI may have blunted febrile responses as a consequence of uremia, potentially leading to underrecognition of infections (supplemental Table 6).

In terms of efficacy, it is important to emphasize that response rates and survival outcomes with teclistamab were similar in patients with and without RI, including patients with severe RI. In addition, we did not observe increased non-relapse mortality in the RI group. Moreover, it was encouraging to see that some patients experienced an improvement in their renal function after teclistamab initiation, and renal function did not deteriorate outside of the context of disease progression. Similar findings of comparable efficacy in patients with and without RI have also been reported with the use of other SOC BCMA-targeted therapies, including the CAR-T product idecabtagene vicleucel, as described previously.¹⁴ 

Prior to this report, available data on the use of teclistamab in patients with RI were sparse and limited to case series. Joiner et al²⁰ reported their center's experience with teclistamab in 7 patients with severe RI, including 4 patients with end-stage renal disease on dialysis at the time of teclistamab initiation, all of whom had an ECOG PS ≥2, and all, except 1, were penta-class refractory. Of the 7 patients, 5 achieved very good partial response, whereas the remaining 2 progressed without achieving response, both of whom had EMD.²⁰ Most patients developed CRS of grade 1-2, with only 1 experiencing CRS grade 3; however, none of the patients experienced ICANS. Notably, 1 patient with acute RI related to myeloma progression had substantial renal improvement.²⁰ A case series of 15 patients on dialysis from France reported an ORR of >90% and a median PFS of NR after 5.4 months of median follow-up.²¹ Furthermore, 11 of 15 patients developed grade 1-2 CRS, and 1 patient developed grade 2 ICANS, but none of the patients experienced grade ≥3 CRS or ICANS events.²¹ The infection rate was 53%, most of which were severe. Another small case series of patients on dialysis receiving teclistamab²² reported similar response and toxicity rates that overall align with our findings, supporting the feasibility and efficacy of teclistamab in patients with RI without any new or unexpected red flags or excessive toxicities. Taken together all the above-mentioned and our results, it seems that CRS events are mainly of grades 1 to 2, occasionally grade 3, but resolve with prompt intervention. ICANS is less frequent, and when present, it is usually mild. Infections, as expected, remain an ongoing issue generally in patients receiving BCMA-directed bispecific antibodies irrespective of renal function, suggesting the potential benefit of implementing intensifying prophylactic strategies, such as preemptive monthly IV immunoglobulin replacement. IV immunoglobulin does not require dose reduction in RI; however, adjustments such as reducing the infusion rate or increasing the dosing interval are common practices in patients with RI or those on dialysis.²³ 

The main strengths of our study include its multi-institutional nature and the large size of our patient cohort treated with teclistamab. In addition, we included all patients with RRMM and RI treated with teclistamab, not just those on dialysis. Moreover, it is important to highlight that this study includes patients otherwise ineligible for clinical trials; thus, it is practice informing for treating physicians. Limitations of our study include its retrospective design and heterogeneity in institutional protocols for toxicity management. Response assessments were determined by individual investigators without an independent review committee, and confirmatory testing and imaging to verify CR were not mandatory given the study’s retrospective design. Moreover, dose interruptions and delays were according to institutional standards and/or at the discretion of each treating physician. Given the multicenter and retrospective nature of this study, there were no universal criteria for dose interruptions/delays, making it challenging to capture these data in a uniform manner. Furthermore, because of the multifactorial nature of RI and the lack of biopsy in most patients, determining its precise etiology was difficult. As a result, information on RI etiology, aside from history of cast nephropathy, was not reported. Last, data on blood transfusion requirements and bleeding events were not available. Despite the limitations, our data provide the basis for further investigation of the role of bispecific antibodies in patients with RRMM and RI, the management of whom remains a critical unmet need in real-world practice.

In conclusion, our study reveals that treatment with teclistamab is feasible, safe, and effective in patients with RRMM and RI; thus, the presence of RI should not be a barrier to receiving BCMA-targeted bispecific antibodies as SOC interventions. We encourage the inclusion of these patients in future clinical trials evaluating bispecific antibodies in MM to increase the accessibility of novel agents to this large subset of patients.

The authors acknowledge the patients who participated in this study and the research personnel at all study sites.

Contribution: D.D., A.A., U.G., and S.P.S.-A. wrote the first draft of the manuscript; D.D. and U.G. analyzed the data; and all authors contributed patients to this analysis, provided critical feedback, edited and wrote the manuscript, and approved the final manuscript.

Conflict-of-interest disclosure: R.B. reports consulting for Adaptive Biotechnologies, Bristol Myers Squibb (BMS), Caribou Biosciences, Genentech, Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures; and receiving research support from AbbVie, BMS, Janssen, Novartis, Pack Health, Prothena, and Sanofi. D.D. reports consulting for Karyopharm. G.K. reports consulting for BMS, Arcellx, Sanofi, Janssen, Cellectar, Pfizer, and Kedrion; and receiving research support from BMS, Janssen, and AbbVie. S.S. reports receiving research support from Magenta Therapeutics, BMS, Allogene, Janssen, Novartis, and AbbVie; and serving on the advisory board/providing consultancy for BMS, Janssen, Sanofi, Oncopeptides, Takeda, Regeneron, AbbVie, Pfizer, BioLineRx, Legend, and Kite. J.A.D. reports providing consultancy for BMS and Janssen; and serving on the speaker’s bureau for Janssen. S. Richard reports receiving honoraria from Janssen, BMS, Genentech, Karyopharm Therapeutics, and MJH Life Sciences; serving on the steering committees of Gracell Therapeutics and BMS; receiving research support from Janssen, BMS, C4 Therapeutics, Gracell Therapeutics, and Heidelberg Pharma; and consulting for Genentech, Janssen, BMS, and Karyopharm Therapeutics. L.S. reports consulting for BMS. J.K. reports consulting for GPCR Therapeutics, Janssen, Prothena, and Legend Biotech; and receiving research support from Prothena, Ascentage, Janssen, Karyopharm, and GPCR Therapeutics. H.C.L. reports consulting for BMS, Pfizer, Janssen, Regeneron, GlaxoSmithKline (GSK), Sanofi, AbbVie, Takeda Pharmaceuticals, Allogene Therapeutics, Menarini, and Alexion Pharmaceuticals; and receiving research funding from Amgen, BMS, Janssen, GSK, Regeneron, and Takeda Pharmaceuticals. K.K.P. reports consulting for BMS, Janssen, AstraZeneca, Legend Biotech, Kite, Genentech, AbbVie, Sanofi, Caribou, Takeda, Regeneron, Poseida, Novartis, and Oricell. D.K.H. reports receiving research funding from BMS, Janssen, Karyopharm, Kite Pharma, and Adaptive Biotechnologies; and serving in a consulting or advisory role for BMS, Janssen, Legend Biotech, Pfizer, Kite Pharma, AstraZeneca, and Karyopharm. A.A. reports receiving research funding from AbbVie, Adaptive Biotechnologies, K36 Therapeutics, Johnson & Johnson, and Regeneron Pharmaceuticals; and serving in an advisory role for Karyopharm, BMS, Sanofi, Johnson & Johnson, and Pfizer. C.J.F. reports consulting for Janssen; receiving research support from Janssen and Regeneron; and ownership of publicly traded stock in Affimed. Y.L. reports consulting for Janssen, Legend, Celgene, Sanofi, BMS, Pfizer, Regeneron, Genentech, NexImmune, and Caribou; and receiving research funding from Janssen, Celgene, and BMS. A.J.C. reports consulting for AbbVie, Adaptive Biotechnologies, BMS, HopeAI, Janssen, Sebia, and Sanofi; and receiving research funding from AbbVie, Adaptive Biotechnologies, Caelum, Harpoon, Nektar, BMS, Janssen, Sanofi, OpnaBio, IgM Biosciences, and Regeneron. L.D.A. Jr reports consulting for Janssen, Celgene, BMS, Amgen, GSK, AbbVie, BeiGene, Cellectar, Sanofi, and Prothena; and receiving research support from BMS, Celgene, GSK, Janssen, and AbbVie. A.L.G. reports research funding from Johnson & Johnson, Novartis, Tmunity, and CRISPR Therapeutics; consulting for Johnson & Johnson, Gracell, BMS, GSK, Regeneron, AbbVie, and Smart Immune; and serving on data and safety monitoring board for Johnson & Johnson. S.P.S.-A. reports providing consultancy for Sanofi. H.H. reports consulting for Janssen; and speaker bureaus for Janssen and Karyopharm. F.A. reports serving as an adviser and speaker for BMS, Celgene, and Caribou Biosciences; and receiving research funding from Allogene Therapeutic, Celgene, GSK, BMS, and Caribou Biosciences. S. Raza reports serving on the advisory board of Pfizer, Prothena Biosciences, and Kite Pharma; and receiving research funding from Poseida, Therapeutics, Nexcella Inc, and Janssen. A.R. reports providing consultancy for Adaptive, BMS, Janssen, Karyopharm, and Sanofi. S.A. reports receiving research funding from GSK, Amgen, and Karyopharm; and honoraria from Janssen. D.W.S. reports consulting for Sanofi, Janssen, Pfizer, BMS, GSK, Legend Biotech, Bioline, AstraZeneca, Arcellx, Opna Bio, and AbbVie. R.C.B. reports receiving research funding from AbbVie, BMS, Celgene, Karyopharm Therapeutics, Regeneron, and Janssen; and serving on the advisory board of Cellectar, Janssen, and Pfizer. A.F.G.-C. reports serving on the advisory board for Cellectar Biosciences, Janssen, and Pfizer; receiving honoraria from Cellectar Biosciences, Janssen, Sanofi, Amgen, and Pfizer; and receiving research funding from Cellectar Biosciences. O.C. reports providing consultancy for Janssen, BMS, and Legend Biotech; and receiving honoraria from BMS for speaker bureau. P.M.V. reports providing consultancy for AbbVie, AstraZeneca, BMS, Karyopharm, Lava Therapeutics, Sanofi, Regeneron, Janssen, and GSK; and receiving research funding from AbbVie, GSK, Janssen, and Regeneron. L.M. reports serving on the advisory board of Legend Biotech and BioLineRx. M.R.G. reports serving on the advisory board of BMS and Arcellx. K.J. reports serving as advisory board consultant for Janssen, Pfizer, and BioLineRx. The remaining authors declare no competing financial interests.

Correspondence: Danai Dima, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA 98109; email: danaid@uw.edu.