The impact of reduced dosing frequency of elranatamab on patient‐reported outcomes in patients with relapsed or refractory multiple myeloma: Results from MagnetisMM‐3

Multiple myeloma (MM) is associated with a range of clinical symptoms, including bone pain, anemia, renal dysfunction, and hypercalcemia.1, 2 Given the chronic nature of MM, its symptom burden, and the side effects of its treatments, monitoring health-related quality of life (HRQOL) via patient-reported outcomes (PROs) has emerged as a critical aspect of patient care.3-5 Elranatamab, a humanized bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, has demonstrated efficacy and safety in patients with relapsed or refractory MM (RRMM) in the registrational Phase 2 MagnetisMM-3 clinical trial (NCT04649359).6-8 Patients in the MagnetisMM-3 study reported improvements in PROs, regardless of prior exposure to BCMA-directed therapy, with notable reductions in pain and disease symptoms, and improvements in patients' outlook on their future health.9 Reduction in the dosing frequency of bispecific antibodies offers convenience and flexibility to patients.10 In the MagnetisMM-3 study, patients who received weekly (QW) elranatamab for ≥6 cycles and achieved a partial response (PR) or better persisting for ≥2 months were eligible to transition to an every 2-week (Q2W) dosing schedule.7-9 While prior analyses have examined the impact of a Q2W dosing schedule on clinical outcomes,7 here we report the effect of switching from QW to Q2W elranatamab dosing on PROs among both BCMA-naive and -exposed patients from the MagnetisMM-3 study, hypothesizing that HRQOL would, at a minimum, be maintained as the incidence of TEAEs decreased after a reduction in dosing frequency while most patients maintained their response to elranatamab. MagnetisMM-3 (NCT04649359) is an open-label, multicenter, nonrandomized, Phase 2 registrational study evaluating the efficacy and safety of elranatamab monotherapy in patients with RRMM.7, 8 Eligibility criteria have been previously described.7-9 Two patient cohorts were enrolled, those without (BCMA naive) or with (BCMA exposed) prior exposure to a BCMA-directed antibody–drug conjugate and/or chimeric antigen receptor T-cell therapy. The study was conducted in accordance with the International Council for Harmonisation guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The study protocol was approved by local or independent institutional review boards or ethics committees at participating sites. All patients provided written informed consent. Patient-reported outcomes (PROs) were a prespecified exploratory endpoint of the MagnetisMM-3 study.9 All PRO measures were administered electronically on D1 and D15 of the first three cycles and D1 of each subsequent cycle through Cycle 12. Thereafter, PRO assessments were administered every three cycles. Additional information can be found in the Supporting Information. The data cutoff for this analysis was March 26, 2024, which represented a median follow-up of approximately 28 months for the overall study population. The analysis dataset included all patients who switched from QW to Q2W dosing intervals. The point at which patients switched from QW to Q2W administration was classified as their baseline (“Q2W baseline”). Of the 61 BCMA-naive patients and 22 BCMA-exposed patients who were treated with elranatamab through at least Cycle 7 in the MagnetisMM-3 study, a total of 58 and 19 patients, respectively, transitioned from QW to Q2W dosing (93%). This analysis focused exclusively on these patients. Demographic and clinical characteristics were generally similar between the two cohorts (Table S1). BCMA-naive and -exposed patients had a median age of 67.5 and 67.0 years, respectively. Differences between the BCMA-naive and -exposed cohorts, respectively, included the median number of prior lines of therapy (5.0 and 7.0) as well as the incidence of an Eastern Cooperative Oncology Group performance status of 2 (5.2% and 10.5%), Revised International Staging System disease Stage III (6.9% and 15.8%), and high-risk cytogenetics (22.4% and 15.8%). Overall QOL was assessed by the EQ-5D-5L questionnaire index score (Figure 1A,B). Scores for BCMA-naive patients remained at or near Q2W baseline levels through Month 18. A numerically greater worsening from the Q2W baseline for BCMA-exposed patients was observed at Month 18; however, again, this was based only on very small patient numbers. Global health status scores for both BCMA-naive and -exposed patients were generally stable over time compared with those reported at Q2W baseline (Figure 1C,D). In BCMA-naive patients, scores were maintained through Month 13 with a nonsignificant (95% CI overlaps with Q2W baseline) improvement at Month 16 and a nonsignificant worsening in the PRO score at Month 18. In BCMA-exposed patients, scores generally improved after Month 6, with a numerically larger improvement by Month 18 (in both cohorts, the observed scores at Month 18 may be due to small sample sizes). Similarly, QLQ-C30 scores for fatigue for both cohorts generally remained at or near Q2W baseline levels through Month 16, with nonsignificant worsening at Month 18 (Figure 1E,F). Pain scores in BCMA-naive patients remained near Q2W baseline levels through Month 7, with numerically larger worsening at Months 10, 16, and 18 (Figure 1G). However, smaller sample sizes for Month 18 may limit the interpretability of the data. Pain scores for BCMA-exposed patients showed a transient improvement relative to Q2W baseline at Month 6, then returned to and were maintained near Q2W baseline from Month 7 through Month 18 (Figure 1H). Results from the MM-specific QLQ-MY20 questionnaire revealed that scores for disease symptoms in both cohorts remained at or near Q2W baseline levels through Month 16 (Figure 2A,B). At Month 18, a numerically larger improvement was observed for BCMA-naive patients and a numerically larger worsening was observed for BCMA-exposed patients; however, small patient numbers for PROs in Month 18 may limit the interpretability of these data. QLQ-MY20 scores in the side effects domain indicated little change from Q2W baseline levels through Month 16 for BCMA-naive patients. A worsening at Month 18 may be due to the small sample size (Figure 2C). A numerically greater improvement from Q2W baseline in side effect domain scores for BCMA-exposed patients was observed at Month 7; however, domain scores stabilized near Q2W baseline levels by Month 10, improved by Month 16, and were maintained through Month 18 (Figure 2D). For BCMA-naive patients, scores for body image remained at or near Q2W baseline levels through Month 18 (Figure 2E). Numerically greater improvements in the PRO score for BCMA-exposed patients were observed at Months 10, 13, and 16 (Figure 2F). A nonsignificant worsening in the PRO score was observed at Month 18, but the sample size was quite small. Similarly, scores for future perspectives were largely consistent with Q2W baseline values through Month 18 for both cohorts (Figure 2G,H). This analysis of PROs from BCMA-naive and -exposed patients with RRMM from the MagnetisMM-3 study who transitioned to Q2W elranatamab dosing demonstrated that HRQOL was largely maintained over 18 months after this switch, including measures of fatigue, pain, disease symptoms, and overall QOL, regardless of prior exposure to BCMA-directed therapy. Numerically larger deteriorations or improvements were seen around Month 18 for some domain scores; however, small sample sizes (≤6) make any interpretation difficult. The minimal impact of the switch to less frequent dosing on patient-reported QOL and disease symptoms likely reflects the maintenance of disease control and an improved safety profile.7 Patients who switched to less frequent dosing of elranatamab did not experience a worsening in reported pain, fatigue, or disease symptoms and had largely stable side effect, QOL, body image, and future perspective domain scores. An extended dosing interval for elranatamab limits the number of contact days with a healthcare system and reduces time spent by patients coordinating treatments and visits to a healthcare facility.10 Reducing the number of contact days without compromising the efficacy or safety of bispecific antibody therapy may significantly impact a patient's QOL and influence their treatment choice. Taken together with other PROs, these findings underscore the potential benefit of tailoring dosing schedules to enhance patient satisfaction without compromising therapeutic outcomes or safety. One limitation of this analysis was self-selection population bias. In the MagnetisMM-3 study, patients were not randomized to receive elranatamab Q2W; only patients who met the dose switching criteria were eligible to transition from QW to Q2W dosing. Second, follow-up time in this analysis was variable, as it was a function of when the patient met the eligibility criteria and was transitioned to Q2W treatment. Not all patients had the opportunity to have a long follow-up period after switching to Q2W treatment, resulting in lower patient population numbers at later time points. Thus, results at later time points should be interpreted with caution. In conclusion, despite occasional transient changes in some PRO measures, the switch in elranatamab dosing schedules from QW to Q2W was not detrimental to patient QOL as assessed by measures of patient-reported functioning and symptoms. Most domain scores remained stable for well over 1 year. These data complement the findings that clinical benefit and safety are not negatively affected by a Q2W elranatamab dosing frequency10 and further support elranatamab for the treatment of patients with RRMM, regardless of prior BCMA-targeted therapy. We thank the patients who participated in the MagnetisMM-3 trial and the medical staff of participating centers. Medical writing support was provided by Robyn Roth, PhD, of Nucleus Global, an Inizio company. Nizar J. Bahlis: Conceptualization; methodology; data curation; investigation; validation; formal analysis; writing—original draft; writing—review and editing. Ajay K. Nooka: Conceptualization; methodology; data curation; formal analysis; validation; investigation; writing—original draft; writing—review and editing. Marco DiBonaventura: Conceptualization; writing—original draft; writing—review and editing; methodology; data curation; formal analysis; validation; investigation. Sharon T. Sullivan: Conceptualization; methodology; data curation; formal analysis; validation; investigation; writing—original draft; writing—review and editing. Mohammad A. Chaudhary: Methodology; conceptualization; data curation; formal analysis; validation; writing—original draft; writing—review and editing. Didem Aydin: Conceptualization; methodology; data curation; formal analysis; writing—review and editing; writing—original draft; validation. Mohamad Mohty: Conceptualization; methodology; data curation; formal analysis; validation; writing—review and editing; writing—original draft. Information on the MagnetisMM-3 study (NCT04649359) can be found at ClincialTrials.gov. Nizar J. Bahlis reports honoraria from AbbVie, Amgen, Celgene, Genentech/Roche, GSK, Janssen, Karyopharm Therapeutics, Sanofi, and Takeda; consulting or advisory roles for Amgen, Celgene, Janssen, Karyopharm Therapeutics, Pfizer, Sanofi, and Takeda; and patents, royalties, or other intellectual property from Celgene and Janssen. Ajay K. Nooka reports honoraria from Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Cellectar, Genzyme, GSK, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio, and Takeda; consulting or advisory roles for Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb, Cellectar, Genzyme, GSK, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio, and Takeda; research funding from Amgen, Arch Oncology, Bristol-Myers Squibb/Celgene, Cellectar, GSK, Janssen Oncology, Pfizer, and Takeda; and travel, accommodations, and expenses from GSK. Marco DiBonaventura, Sharon T. Sullivan, and Didem Aydin report employment and stock ownership with Pfizer. Mohammad A. Chaudhary reports employment with Pfizer. Mohamad Mohty reports honoraria from Amgen and Celgene; consulting or advisory roles for Adaptive Biotechnologies, GSK, Jazz Pharmaceuticals, MaaT Pharma, Novartis, Sanofi, and Xenikos; and speakers bureaus roles for Janssen, Jazz Pharmaceuticals, and Sanofi. This study was conducted in accordance with the International Council for Harmonisation guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The study protocol was approved by local or independent institutional review boards or ethics committees at participating sites. This study was funded by Pfizer. All the patients provided written informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified patient data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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