Introduction

Despite therapeutic advances, many patients with multiple myeloma (MM) may relapse and develop treatment refractory disease [1, 2]. Bispecific antibodies (bsAbs) have expanded treatment options for patients with relapsed/refractory multiple myeloma (RRMM) [3, 4]. Talquetamab, a first-in-class GPRC5D (G protein-coupled receptor family C group 5 member D) and CD3 bsAb, received accelerated FDA approval in August 2023 for the treatment of adultswith RRMM after at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody [5]. Approval was based on the Phase 1/2 MonumenTAL-1 trial, which demonstrated an overall response rate (ORR) of 64% with biweekly subcutaneous dose of 0.8 mg/kg [6].

Common adverse events (AEs) in the study included cytokine release syndrome (CRS), which occurred in most patients but was primarily grade 1–2 in severity. The most frequent grade ≥3 toxicities were reversible hematologic events, typically occurring during step-up and early treatment phases. Other notable AEs included skin and nail changes, oral symptoms such as dysgeusia and dry mouth, and hypogammaglobulinemia. Talquetamab- associated dysgeusia is generally classified as grade 1 (taste changes without dietary impact) or grade 2 (taste alterations causing dietary modifications, unpleasant taste sensations, or taste loss) with no established criteria for grade 3–4 classifications. Weight loss occurred in approximately one-third of patients across both dose levels [6, 7].

While clinical trial data have established the efficacy and safety of talquetamab, real-world evidence (RWE) is essential to understand its performance in broader, more heterogeneous patient populations and treatment settings. Patients treated outside of clinical trials may have more advanced disease, comorbidities, and/or prior exposure to other immunotherapies. Additionally, real-world incidence and management of key toxicities—particularly infections and weight loss—remain poorly defined. Characterizing these patterns is critical for optimizing supportive care, mitigating AEs, and treatment delivery.

This multicenter retrospective study evaluated the real-world effectiveness and safety of talquetamab in patients with RRMM, with a focus on infections, weight changes, and survival outcomes. We also aimed to describe patterns of infections to inform clinical decision-making, guide supportive care, and improve patient counseling regarding AEs.

Methods

Study design and patient population

We conducted a multicenter, retrospective study of patients with RRMM treated with talquetamab between October 2023 and January 2025 at four academic institutions in the United States: University of Arkansas for Medical Sciences, Rutgers Cancer Institute, Columbia University Irving Medical Center, and Medical College of Wisconsin. Eligible patients had a confirmed diagnosis of RRMM and had received at least one dose of commercially available talquetamab. Data were abstracted from electronic medical records and included demographic characteristics, disease characteristics, prior therapies, talquetamab dosing patterns, AEs, treatment responses, and survival outcomes.

Ethics and inclusion statement

The study received approval from the Institutional Review Board at the coordinating institution (Medical College of Wisconsin), followed by approval from the IRBs of all participating institutions. All procedures adhered to applicable guidelines and regulations, and given the retrospective nature of this research, patient informed consent was not required.

Data collection and definitions

Baseline data included patient demographics (age, sex, race/ethnicity), disease characteristics (myeloma subtype, cytogenetic abnormalities, presence of extramedullary disease (EMD) including central nervous system (CNS) involvement, prior lines of therapy, and disease status at talquetamab initiation. High-risk cytogenetics were defined as the presence of t (4;14), t (14;16), t (14;20), del(17p), or 1q21 gain (≥3 copies).

Treatment variables included talquetamab dosing schedule, duration of treatment, administration setting (inpatient vs. outpatient), and use of prophylactic agents, including intravenous immunoglobulin (IVIG), antiviral, antibacterial, and antifungal medications. Infection prophylaxis and IVIG supplementation were at the treating physician’s discretion, following local institutional practices.

AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy consensus criteria [8]. Infections were classified by etiology (bacterial, viral, fungal, or unknown) and by severity (grade 1–5). Weight measurements were collected at baseline and tracked longitudinally during follow-up visits.

Treatment responses were assessed according to the International Myeloma Working Group (IMWG) criteria. Overall response rate (ORR) was defined as the proportion of patients achieving partial response (PR) or better. For patients with missing response data, progressive disease was coded as non-response for efficacy analysis. When response status was unclear, relapse/progression status was determined based on available clinical documentation and physician assessment.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics, treatment patterns, and AEs. Categorical variables were reported as counts and frequencies, while continuous variables were reported as medians with ranges or means with standard deviations, as appropriate.

Dosing frequency was categorized by the time between two consecutive doses as follows: Q1W (4–10 days), Q2W (11–17 days), Q3W (18–25 days), Q4W (26–31 days), and >Q4W (32 days or more). These were weighted by the inverse frequency of expected doses per month, i.e., 1/4, 1/2, 3/4, 1, and 2, respectively, to adjust for the over-representation of dosing events with a high-frequency dosing schedule and estimate the proportion of patients using each schedule.

The cumulative incidence of infections was estimated using competing risk analysis, treating death without infection as a competing event. Follow-up was censored at 60 days after the last dose of talquetamab. Infection rates were compared to historical data from 160 patients who received standard-of-care teclistamab.

For weight trajectory analysis, weight measurements were averaged within 30-day windows and labeled with the middle day (e.g., day 30 for measurements taken between days 16 and 45). Only values collected during ongoing talquetamab administration were included. Weight change from baseline was analyzed using one-sample t-tests.

Overall survival (OS) was measured from the start of talquetamab to last follow-up or death from any cause. Progression-free survival (PFS) was measured from talquetamab treatment initiation to documented disease progression, death from any cause, or last follow-up. Survival curves were estimated using the Kaplan–Meier method, and survival rates at 6 and 12 months were reported with 95% confidence intervals.

All statistical analyses were conducted using R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline characteristics

A total of 114 patients treated with talquetamab were included in the analysis. Baseline demographic and disease characteristics are summarized in Table 1. The median age was 67 years (range: 34–90 years), with 42% of patients aged 70 or older. Most patients were male (56%) and non-Hispanic White (64%). IgG myeloma was the most common subtype (59%), followed by IgA (26%) and light chain only (11%).

Table 1 Baseline demographic, disease, and treatment characteristics of patients treated with talquetamab.
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Patients were heavily pretreated with a median of 6 prior lines of therapy (range, 2–15). All patients (100%) had triple-class refractory disease, and 79% had penta-refractory disease. Notably, 65% of patients had previously received BCMA-targeted therapy. Among these patients with prior BCMA-targeted therapy, the specific agents included teclistamab (82%), CAR-T cells (75%), and belantamab mafodotin (25%). In the overall study population, this represented 53%, 49%, and 16% of all patients, respectively.

At least one high-risk cytogenetic abnormality was present in 70% of patients. Extra-osseous EMD was present in 34%, and 6.3% had CNS involvement. At the time of talquetamab initiation, 96% of patients had progressive disease.

Treatment administration and dosing patterns

The initial step-up doses (SUDs) of talquetamab were administered predominantly in the inpatient setting (88%), with only 4.4% of patients receiving all doses as outpatients. All patients underwent incremental SUD during the first week of treatment. The most common SUD pattern was administration on days 0, 2, 4, and 6 (37.7%), followed by days 0, 2, 4, and 7 (18.4%).

Following the step-up phase, dosing frequency varied over time, as shown in Fig. 1. During the first 7 days, 93% of doses were administered at ≤3-day intervals as part of step-up dosing. From days 7 to 90, dosing every 2 weeks was most common (66%). Beyond day 180, dosing every 4 weeks predominated (60%), followed by intervals of >4 weeks (33%). With a median follow-up of 6.7 months from cycle 1, day 1 for surviving patients, the median number of talquetamab doses was 5 (range, 1–24), and the median duration of treatment was 0.8 months (range, 0.0–14.3 months).

Fig. 1: Talquetamab dosing patterns.
figure 1

A Common step-up dosing sequences during the first treatment week, including Day 0/2/4/6 and Day 0/2/4/7 schedules. B Distribution of dosing intervals during maintenance therapy. Frequency distribution of dosing intervals by category: Q1W (4–10 days), Q2W (11–17 days), Q3W (18–25 days), Q4W (26–31 days), >Q4W (>32 days), and ≤3 days (initial clustered dosing). Q1W Every 1 week, Q2W Every 2 weeks, Q3W every 3 weeks, Q4W every 4 weeks.

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Clinical outcomes

Best responses to talquetamab are summarized in Table 2. Among the 98 patients with evaluable response data, the ORR was 73%, including 26% with complete response (CR), 26% with very good partial response (VGPR), and 22% with partial response (PR). Stable disease was observed in 11% of patients, and 14% had no response. Median time to best response 1.6 (range, 0.3–12.6) months.

Table 2 Best overall response to talquetamab in patients with relapsed/refractory multiple myeloma (N = 98).
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Factors associated with ORR are shown in Table 3. A trend toward higher ORR was observed in females compared to males (82% vs. 67%, p = 0.091). No significant associations were identified with age, high-risk disease status, EMD, prior lines of therapy, absolute lymphocyte count, or prior BCMA-targeted therapy overall (76% vs. 72% for no prior BCMA vs. prior BCMA therapy, p = 0.614). Among patients with prior BCMA-targeted therapy, specific subgroup analyses by therapy type (CAR-T vs. bispecific antibodies) were not performed due to overlapping exposures and small subgroup sizes.

Table 3 Clinical and demographic factors associated with response to talquetamab (N = 98).
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With a median follow-up of 6.7 months (range, 0.2–15.9 months) for survivors, the 6-month OS rate was 86% (95% CI, 80–94%), and the 12-month OS rate was 70% (95% CI, 59–83%) (Fig. 2A). Median OS was not reached. The 6-month PFS rate was 56% (95% CI, 47–67%), and the 12-month PFS rate was 45% (95% CI, 35–59%), with a median PFS of 10 months (95% CI, 5.4-NR) (Fig. 2B).

Fig. 2: Overall survival and progression free survival from talquetamab initiation.
figure 2

A Kaplan–Meier curve showing progression-free survival (PFS). B Kaplan–Meier curve showing overall survival (OS) from talquetamab initiation. Median OS was not reached; median PFS was 10 months. OS and PFS rates at 6 and 12 months are annotated with 95% confidence intervals.

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Adverse events

The most common AEs are summarized in Table 4. CRS occurred in 54% of patients, with grade 1 events in 47%, grade 2 in 6.4%, and grade 3 in 0.9%. No grade 4 or 5 CRS events were observed. ICANS was reported in 9.8% of patients, with grade ≥2 events in 5.9% and grade 3 in 2.0%. No grade 4 or 5 ICANS events occurred. Tocilizumab was administered to 41% of patients, and 18% received systemic corticosteroids for the management of CRS or ICANS. The median duration of inpatient stay for talquetamab SUD was 9 days (range, 2–54 days), and 18% of patients were readmitted within 30 days.

Table 4 Summary of key adverse events and related clinical events in patients treated with talquetamab (N = 114).
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Infections

A total of 40 infections were diagnosed in 31 patients (27%) after the first dose of talquetamab and within 60 days of the last dose. Infections occurred at a median of 23 days after treatment initiation. The characteristics of these infections are detailed in Table 5. Viral infections (59%) were more common than bacterial infections (41%), with no fungal infections reported. Most infections (85%) were confirmed both clinically and microbiologically, and 62% were grade 3 events. No grade 5 (fatal) infections were observed. More than half (55%) required hospitalization due to infection.

Table 5 Characteristics of infections following talquetamab therapy (N = 40 episodes in 31 patients).
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At 3 months after talquetamab initiation, the cumulative incidence of any infection was 26% (95% CI, 19–36%), increasing to 38% (95% CI, 27–54%) at 6 months (Fig. 3A). For grade ≥3 infections, the cumulative incidence at 3 months was 17% (95% CI: 11–26%), and 26% (95% CI, 17–42%) at 6 months (Fig. 3B).

Fig. 3: Cumulative incidence of infections with talquetamab use and risk of infections comparing talquetamab and teclistamab.
figure 3

A Cumulative incidence of grade ≥3 infections, stratified by etiology (viral vs. bacterial). B Cumulative incidence of any infection following talquetamab. C Cumulative incidence of all infections: comparison between talquetamab and teclistamab. Curves estimated using competing risk analysis; death without infection was treated as a competing event. p-values at 12 and 15 months are shown for between-group comparisons.

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Compared to teclistamab (Fig. 3C), talquetamab was associated with a significantly lower cumulative incidence of infections at all time points (p < 0.001 at 12 and 15 months) [9]. The difference was most pronounced for bacterial infections, with a 12-month cumulative incidence of 18% (95% CI, 11–29%) for talquetamab versus 52% (95% CI, 42–65%) for teclistamab (p < 0.001).

The use of infection prophylaxis was common: 90% received Pneumocystis jirovecii pneumonia (PJP) prophylaxis, 98% received herpes simplex virus/varicella zoster virus (HSV/VZV) prophylaxis, 24% received antibiotic prophylaxis, and 9.7% received antifungal prophylaxis. IVIG was administered in 61% of patients, with 50% receiving it as primary prophylaxis initiated at a median of 36 days after treatment start, before documented infection. The use of IVIG, both primary and secondary prophylaxis, was similar between teclistamab and talquetamab. Moreover, nearly 90 and 100% of patients received PJP and herpes zoster prophylaxis, respectively. Due to the limited number of patients, it may be difficult to detect differences in infection incidence based on IVIG use, as almost 60% of patients have received IVIG either as primary or secondary prophylaxis. We have recently shown that primary IVIG prophylaxis, defined as IVIG initiated before the first documented infection, may be associated with improved infection-free survival in patients who received BCMA bsAb [10].

Weight changes

Weight measurements were available for most patients and showed a progressive decline over time (Fig. 4). The mean weight loss from baseline among patients still on treatment was 1.5 kg [1.9%] at day 30 (p < 0.001), 3.6 kg [4.5%] at day 90 (p < 0.001), and 7.0 kg [8.8%] at day 180 (p = 0.014). The decline appeared to stabilize somewhat after 6 months, although follow-up beyond that point was limited.

Fig. 4: Weight change over time.
figure 4

A Absolute weight trajectory over time following talquetamab initiation, with individual patient lines in gray and mean ± SD in red. B Individual patient weight change trajectories over time with locally linearly smoothed (LOESS) mean trend and standard error bars.

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Discussion

This multicenter, retrospective analysis provides important RWE on the effectiveness and safety of talquetamab in heavily pretreated patients with RRMM. The observed ORR of 64–73%, including 23% CR rate, aligns with the findings reported in the pivotal MonumenTAL-1 trial [6, 7]. Importantly, this response rate was achieved in a heavily pretreated patient cohort with 100% triple-class refractory and 79% penta-refractory disease. Additionally, 65% of patients who had previously received BCMA-targeted therapy, highlighting talquetamab’s activity in a highly treatment-resistant setting.

In this highly refractory population, survival outcomes were favorable, with 6-month OS and PFS rates of 86 and 56%, respectively, and a median PFS of 10 months, suggesting clinically meaningful and durable responses in a real-world setting. Although direct comparisons to clinical trials are limited, these findings reinforce talquetamab’s efficacy compared to BCMA-targeted therapies like teclistamab, which reported a median PFS of 9.0 months in the MajesTEC-1 [11] in a similar patient population.

Our findings are consistent with emerging real-world data. A German multicenter study of 138 patients with RRMM reported an ORR of 65% and median PFS of 6.4 months, despite 58% of patients not meeting MonumenTAL-1 eligibility criteria and a high prevalence of adverse features such as ISS stage III (43%) and presence of EMD (37%) [12]. Similarly, a retrospective study of 68 patients with RRMM who received talquetamab reported a 71% ORR, though prior BCMA-directed therapy and EMD were associated with inferior outcomes [13]. These findings collectively reinforce the therapeutic activity of talquetamab in heavily pretreated populations, including those with high-risk features.

Our analysis of AEs highlights some important safety considerations for the clinical use of talquetamab, as AEs were frequent but manageable. The incidence of CRS (54%), was consistent with clinical trial data, and most cases were grade1-2 and managed with tocilizumab, corticosteroids, and other supportive care measures. In contrast, ICANS rate of 9.8% was slightly higher than reported in clinical trials, 6,7 which may reflect increased awareness and recognition of neurotoxicity in real-world practice and/or association with uncontrolled disease.

Weight loss emerged as a notable toxicity in our cohort, with a mean decline of 7.0 kg at 6 months. Although previously reported in clinical trials, our findings suggest weight loss may be more pronounced and progressive in real-world settings. This represents a clinically meaningful change that could impact patient quality of life, influence weight-based dosing of talquetamab, and limit treatment continuity [14]. The underlying mechanism of weight loss is not fully understood but may be related to the high incidence of taste disturbances (dysgeusia) and GPRC5D expression, resulting in mucosal toxicity [14,15,16]. In the MoumenTAL-1 study, weight loss did not resolve following dose modifications, whereas dysgeusia demonstrated improvement over the study period. These findings highlight the importance of routine nutritional monitoring, early use of supportive care measures, and proactive dose or frequency adjustment of talquetamab during treatment.

Infections remain a key concern with T-cell-redirecting therapies. In our cohort, the 3-month cumulative incidence of infections was 26%. Interestingly, viral infections were more common than bacterial infections, contrasting with the pattern typically seen in patients with MM [17, 18]. The infection rate associated with talquetamab in our study was lower than observed with teclistamab, which may reflect differences in the patient selection, disease biology, or immunomodulatory effects of targeting GPRC5D versus BCMA [17, 18]. The differential effect may be attributed to complete ablation of early B-cells by BCMA bispecific antibodies, as BCMA is expressed on both plasma cells and early B-cells, while GPRC5D expression is restricted to plasma cells. The high use of prophylactic measures, including IVIG in 61% of patients, may have also contributed to the lower infection rates with talquetamab. However, despite the lower incidence, more than half of the infections required hospitalization; notably, no infection-related mortality (grade 5 events) occurred. This real-world experience highlights the burden of infections associated with bsAbs including talquetamab.

This study has several limitations. First, as a retrospective analysis, it is subject to selection bias and incomplete data. Second, the follow-up period was relatively short for some patients, limiting assessment of long-term outcomes. Third, response assessments were not centrally reviewed, which may have introduced variability in the reported efficacy outcomes. Finally, the retrospective nature of this analysis limited our ability to systematically document the full spectrum of adverse events, including the distinctive skin and ectodermal toxicities that represent a unique safety signal associated with talquetamab.

Despite these limitations, our study provides valuable RWE on the use of talquetamab in RRMM. The findings complement clinical trial data and offer insights into efficacy, safety, and supportive care considerations for routine clinical practice.

Conclusion

In this real-world, multicenter analysis of talquetamab in heavily pretreated RRMM patients, we observed an ORR of 73% and a median PFS of 10 months, confirming the efficacy seen in clinical trials. Clinically significant AEs included CRS, infections, and progressive weight loss. While the cumulative incidence of infections was lower than those observed with use of that reported with teclistamab, over half required hospitalization, underscoring the need for vigilant monitoring and prophylactic strategies for infection prevention. Weight loss was both substantial and worsened over time, highlighting the importance of nutritional assessment, proactive talquetamab dosing adjustment, and empiric use of supportive care. These findings provide a comprehensive real-world insight into talquetamab’s therapeutic profile for RRMM and highlight the need to optimize its use in clinical practice.