Changes in patient‐reported distress and symptom burden during talquetamab therapy in multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy that remains incurable for most patients despite substantial therapeutic advances. Standard front-line therapy includes proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and autologous stem cell transplantation.1 After disease progression, bispecific T-cell engagers have demonstrated encouraging activity in heavily pretreated relapsed or refractory MM (RRMM).2 Bispecific antibodies redirect host T cells to malignant plasma cells through dual binding of cluster of differentiation 3 and a plasma cell surface antigen. Four bispecific antibodies have been approved by the US Food and Drug Administration for RRMM, most targeting B-cell maturation antigen.2, 3 Talquetamab (TAL) is a first-in-class bispecific antibody that targets G Protein-Coupled Receptor Class C Group 5 Member D, a receptor highly expressed on malignant plasma cells with limited, but important, off-tumour expression.4 Regulatory approval of TAL was based on the pivotal MonumenTAL-1 trial, which demonstrated overall response rates of approximately 70% in patients with RRMM, including those with prior exposure to multiple therapeutic classes.4 Based on its off-tumour expression, including keratinized tissues, TAL is associated with a distinct toxicity profile including dysgeusia, rash, skin and nail changes, weight loss and, less commonly, infections.5, 6 While clinical efficacy outcomes are well described, the impact of these toxicities on patient-reported outcomes (PROs) and distress in routine clinical practice remains underexplored.7 Growing evidence suggests a gap between patient and provider perspectives on treatment priorities, highlighting the importance of evaluating quality-of-life outcomes alongside disease control.7 To address this, we performed an institutional review board-approved retrospective, single-centre analysis of distress and symptom burden in patients receiving TAL, assessed using the National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) and problem checklist across practical social, spiritual, emotional and physical domains.8 This tool was designed for routine clinical use as a rapid screening and triage instrument, pairing a global distress score with a structured problem list to support identification of symptom domains contributing to distress during clinical visits.8 In contrast, multidimensional instruments such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, which was used in the MonumenTAL-1 trial, were developed to quantify health-related quality of life for research and clinical trial end-points rather than to guide real-time clinical decision-making.9 By leveraging a workflow-embedded screening tool, we provide real-world insight into TAL-associated symptom domains linked to worsening distress, enabling real-time clinical action. Distress assessments were collected approximately every 3 months as part of routine clinical care, with the first available post-TAL assessment used for analysis. All patients were treated with TAL between 1 January 2022 and 31 December 2024 with a starting dose of 0.01 mg/kg and treatment dose of 0.8 mg/kg. Of 47 patients who initiated therapy, 35 had paired pre- and post-treatment assessments and were included in the primary analysis. Worsening distress was defined as an increase >1 point and stable/improved distress as ≤1 point change. Demographic, disease and treatment variables were obtained from the medical record. Continuous variables were summarized as median and ranges; categorical variables as counts and percentages. Symptom prevalence was compared between pre- and post-TAL, stratified by distress trajectory (worsened versus stable/improved). Given the descriptive nature of the study, no hypothesis testing was performed. The median age at diagnosis was 65.3 years, and 57.1% were male. Most patients were non-Hispanic White (94.3%), followed by non-Hispanic Black (2.9%) and other racial/ethnic groups (2.9%). High-risk cytogenetics were present in 51.4% of patients, and 60% had International Staging System stage II/III disease. The median number of prior lines of therapy was 5 (range, 2–13). Patients remained on TAL for a median of 3.5 months (range, 0.3–18.1) and experienced a median weight change of −6.0 kg (−7.9% of body weight; Table 1). Baseline distress was low, with a median NCCN DT score of 1.0 (scale 0–10, where 0 indicates no distress and 10 indicates extreme distress). Distress increased in 51.4% of patients (18/35), while 48.6% (17/35) had stable or improved scores. Among patients with worsening distress, median DT scores rose from 1.0 to 4.5. In contrast, the stable/improved group's median decreased from 1.0 to 0.0. When all patients were analysed together, the median distress increased from 1.0 to 2.0 during treatment, reflecting a greater influence of the subgroup with worsening distress. Notably, none of the patients in the stable/improved distress subgroup had progressive disease, a factor that may have supported their more favourable experience. However, our small sample size and short follow-up limited formal correlation between disease response and distress. Turning to domain-specific PROs, practical, social and spiritual concerns remained largely unchanged. Emotional symptoms, such as worry and nervousness, generally improved, with the proportion of patients endorsing nervousness decreasing from 20.0% pre-TAL to 2.9% during therapy (Figure 1). In contrast, physical symptom burden increased overall. Fatigue rose from 37.1% to 51.4%, eating-related concerns emerged in 31.4% (previously 0%), dry/itchy skin increased from 20% to 48.6%, mouth sores from 2.9% to 14.3% and breathing difficulties from 5.7% to 11.4%. However, survivor bias is an important concern, as patients who discontinued TAL early from toxicity or disease progression may be underrepresented. Among patients whose distress increased, these physical symptoms were more pronounced: fatigue rose from 44.4% to 72.2%, dry/itchy skin from 16.7% to 61.1% and eating-related concerns from 0.0% to 38.9%. Among those who developed new eating-related concerns, 85.7% (6/7) experienced worsening distress, with median DT scores increasing by three points (from 1.0 to 4.0). Conversely, some patients reported notable weight loss or dysgeusia without a corresponding rise in distress, suggesting that certain individuals may adapt to or tolerate these physical symptoms without perceiving them as emotionally burdensome. Overall, 48.6% of patients maintained stable or improved distress despite frequent physical side effects. Only three patients (8.6%) discontinued therapy due to toxicity, two of whom were in the ‘distress increased’ group. This real-world study highlights the duality of patient experience with TAL. More than half of patients (51.4%) reported worsening global distress, with DT scores rising from 1.0 to 4.5, while 48.6% improved or remained stable (DT 1.0–0.0). Physical symptoms largely worsened, whereas emotional symptoms often remained stable or improved. Current guidance recommends continuing TAL until disease progression or unacceptable toxicity.10 Physical toxicities were the main contributors to worsening distress. Patients lost a median of 7.9% of their starting body weight, fatigue increased to 72.2% in the worsening subgroup and dermatological and eating-related concerns were common. Dysgeusia was the most frequently cited driver of distress, leading directly to nutritional compromise and weight loss.5, 6 Clinical trial data reported oral toxicities in ~70% of patients, while real-world reports suggest that nearly all patients develop some degree of taste alteration.5 In Naqvi et al.,11 dysgeusia persisted >4 months after discontinuation in some cases, suggesting a lasting impact. Similar findings in radiation-induced taste loss demonstrate parallel declines in global quality of life, with prospective studies showing impaired taste acuity and xerostomia despite preserved salivary flow, consistent with a sensory mechanism. Emerging interventions, including photobiomodulation and prophylactic strategies such as topical steroids, antifungals, zinc supplementation and dietary counselling, are under investigation.12, 13 Dermatological manifestations, including xerosis, rash and nail dystrophy, were the second most distressing physical concern.6 Beyond discomfort, these manifestations can impair sleep, dexterity and daily functioning, while cracked skin and nail changes increase infection risk.6 Proactive measures, such as regular emollient use, early dermatology referral and patient education, have demonstrated benefit and should be systematically incorporated into care.9 Interestingly, emotional distress improved, suggesting that disease control and reduced uncertainty may offset physical symptom burden. Patients with RRMM typically enter bispecific antibody therapy after exhausting multiple prior lines, often with cumulative toxicities and diminished functional reserve. In this setting, even lower grade but persistent toxicities such as dysgeusia and xerosis may disproportionately impact well-being and independence. Nutritional decline, weight loss and fatigue not only contribute to distress but may also reduce tolerance of subsequent therapies.9 These observations highlight the need to view supportive care not as adjunctive, but as central to maximizing the benefit of novel agents in a heavily pretreated population. Looking forward, therapeutic innovation must target the toxicities most relevant to patients while balancing against disease control. Our findings identify dysgeusia and weight loss as central drivers of distress, aligning with ongoing trispecific antibodies and receptor-affinity engineering efforts to reduce off-tumour effects while preserving efficacy.14 Early data also suggest that discontinuing bispecific therapy after achieving deep remission may yield durable disease control, potentially reducing long-term toxicity and distress burden.15 Integrating appropriate PRO measures into these studies will be essential to ensure that next-generation therapies deliver not only survival benefit but also capture meaningful toxicities and quality-of-life changes. In conclusion, we describe patient-reported physical symptom burden, particularly fatigue, dermatologic toxicity and eating-related concerns, associated with TAL. Yet, many patients report reduced emotional distress, reflecting the psychosocial benefits of disease response. Our analysis highlights the value of routine distress screening in identifying TAL-associated symptom domains linked to worsening distress, which may inform more targeted supportive care strategies during therapy. EA performed the research, analysed the data and drafted the manuscript. NE-M performed the research, analysed the data and contributed to manuscript revisions. AD contributed patient data, designed the study and provided critical revisions. OSA, BD, MM, RN and MCP contributed patient data and provided critical revisions. The authors thank the patients and clinical care teams whose contributions made this study possible. The authors have nothing to report. OSA reports advisory board participation with Janssen and Sanofi and consultancy with Immix Biopharma Inc. MCP reports consultancy with AstraZeneca and honoraria from Gilead. AD reports funding to institution from Abbvie, Alexion, Prothena, Janssen, Novartis, and Regeneron, IRC, DMC or Steering Committee role with Abbvie, BMS, Janssen, Prothena, advisory board role with Abbvie, BMS, Janssen, Prothena, Pfizer and Protego. This study was approved by the Medical College of Wisconsin Institutional Review Board (PRO00033723). The requirement for informed consent was waived due to the retrospective nature of the study. Patient consent not required due to the retrospective design of the study and use of de-identified data. No material from other published sources was reproduced in this manuscript; therefore, no permission was required. Not applicable; study was not part of a clinical trial. This work was presented in part at the 22nd International Myeloma Society Meeting in Toronto, Canada in September 2025. De-identified data are available from the corresponding author upon reasonable request, subject to institutional review board and institutional data-sharing policies.