Связанное со здоровьем качество жизни с лечением linvoseltamb в случае рецидива/извлечения нескольких миелом LINKER-MM1.

Introduction

Although new treatment modalities for multiple myeloma (MM) have improved survival, 1 patients often experience multiple relapses and can become refractory to treatment (relapsed/refractory MM [R/RMM]). 2 , 3 Patients with R/RMM have poor health-related quality of life (HRQoL) that deteriorates with disease progression or with increasing lines of therapy. 1 , 4 Pain, fatigue, and decreased physical function are among the most common symptoms/impacts contributing to reduced HRQoL in patients with MM, 5 with symptoms including constipation, nausea, insomnia, and appetite loss. 6 , 7

In patients with MM, the high B-cell maturation antigen (BCMA) expression in malignant plasma cells makes it an ideal therapeutic target, 8 resulting in the development and subsequent US and EU approval of the BCMA-directed bispecific antibodies (bsAbs) teclistamab, 9 , 10 , 11 elranatamab, 12 , 13 , 14 and linvoseltamab. 15 , 16 , 17 Linvoseltamab is a human BCMA × CD3 bsAb that activates contact-dependent cytolytic killing of BCMA-expressing MM plasma cells by CD3 + effector T cells. 18 LINKER-MM1 is an ongoing open-label, multicenter phase 1/2 dose-escalation and dose-expansion trial evaluating linvoseltamab for patients with R/RMM. 15 , 19 Clinical efficacy results showed an objective response rate of 71% among 117 patients over a median follow-up of 21.3 months; 52% achieved a complete response or better, and 63% achieved at least a very good partial response. 19 Linvoseltamab demonstrated a generally manageable safety profile; the most common adverse events of any grade included cytokine release syndrome (46.2%); neutropenia (43.6%); and anemia, diarrhea, and cough (all 40.2%). 19 Linvoseltamab is approved in the EU for patients with R/RMM who have received ≥3 previous therapies and in the US for patients who have received ≥4 previous lines of therapy. 16 , 17

Patient-reported outcomes (PROs) can provide further insight for providers and patients into the benefits of treatment. Additionally, use of PROs to contextualize therapeutic benefits and risks from the patient’s perspective is advocated by regulatory agencies, 20 , 21 with assessment of symptoms, symptomatic adverse events, and physical and role functions recommended as core PROs in cancer clinical trials. 20 Limited aspects of HRQoL have been suggested to be improved or maintained in patients with R/RMM treated with teclistamab and elranatamab. 22 , 23 As PRO measures for assessing HRQoL were predefined secondary endpoints in LINKER-MM1, this analysis evaluates HRQoL in patients with R/RMM while receiving linvoseltamab.

Methods

Study design and population

LINKER-MM1 ( ClinicalTrials.gov identifier: NCT03761108 ) is being conducted in accordance with the Declaration of Helsinki; patients provided written informed consent before participation, and the study was approved by the institutional review board or independent ethics committee at each participating site. Study design and clinical efficacy and safety results as of the 6 January 2024 data cutoff were previously published, 15 and longer-term clinical results (23 July 2024 data cutoff) have been presented previously. 19 This analysis provides results on patient-reported HRQoL outcomes as of the 23 July 2024 data cutoff.

The trial population consists of adults (aged ≥18 years) with active MM; measurable serum or urine markers as defined by the International Myeloma Working Group (IMWG) 24 ; an Eastern Cooperative Oncology Group performance status of 0 or 1; and exposure to ≥3 previous lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Alternatively, phase 1 patients could have triple-class exposed, double-class refractory disease (an immunomodulatory drug and a proteasome inhibitor), and phase 2 patients could have triple-class refractory disease (an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody), if exposed to <3 previous lines of therapy. Key exclusion criteria were the presence of primary systemic light chain amyloidosis, known central nervous system involvement by MM, history of a neurodegenerative condition or central nervous system movement disorder, and previous treatment with BCMA-directed immunotherapies, excluding BCMA antibody-drug conjugates.

Treatment

Linvoseltamab was administered by intravenous infusion at weeks 1 (5 mg), 2 (25 mg), and 3 (200 mg), followed by once-weekly 200 mg dosing through week 14 (phase 2) or week 16 (phase 1), then 200 mg dosing every 2 weeks until disease progression or discontinuation. Patients in phase 2 who achieved and maintained a very good partial response at or after week 24 and received ≥17 doses of linvoseltamab 200 mg could transition to dosing every 4 weeks.

PROs

Patient-reported HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), 25 the EORTC 20-item MM module (QLQ-MY20), 26 and the EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). 27

The QLQ-C30, a 30-item general oncology questionnaire, consists of a Global Health Status/QoL (GHS/QoL) scale, 5 functional scales (physical, role, cognitive, emotional, and social), and scales/items for symptoms of fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. 25 The GHS/QoL, physical and role functioning, and fatigue and pain symptom scales are considered especially relevant to patients with R/RMM, 5 and physical and role functions are included in the US Food and Drug Administration recommendations for core PROs in cancer clinical trials. 20 The recall period is during the past week except for physical functioning. Scores are transformed to a 0 to 100 scale; higher scores on GHS/QoL and functional scales and lower scores on symptom scales indicate better outcomes. A score change of ≥10 points in absolute value was considered to be clinically meaningful. 28

The QLQ-MY20 assesses HRQoL relevant to MM on domains of disease symptoms (DS), side effects of treatment (SE), body image (BI), and future perspective (FP) over the past week. 26 Transformed scores range from 0 to 100; higher DS and SE scores reflect more symptomatology or problems, and higher BI and FP scores represent better outcomes. A previous report suggests clinically meaningful thresholds for change of −16 points or less for improvement in and +11 or more points for worsening of DS, −6 or less points for improvement in and +9 or more points for worsening of SE, +33 or more points for improvement in and −33 or less for worsening of BI, and +11 or more points for improvement in and −11 or less points for worsening of FP. 29

The EQ-5D-3L is a generic measure of HRQoL that includes a visual analog scale (VAS) for assessing self-perceived health state at time of questionnaire completion, with end points of 0 “worst health you can imagine” and 100 “best health you can imagine.” 27 A ≥12-point change on the VAS was considered clinically meaningful. 30

Statistical analysis

PROs were administered at baseline, at week 4, and every 4 weeks thereafter. Completion rates for PROs were calculated as the number of patients with minimum requirements for scoring divided by the number of patients with an expected PRO assessment; minimum requirements for scoring were defined as having nonmissing values for ≥1 scale. Analyses were conducted on the full analysis set of patients who received any study drug within the 5-25-200 mg dosing regimen during phase 1 (n = 12) and phase 2 (n = 105), with data cutoff of 23 July 2024. Mixed models for repeated measures (MMRM) analyses were used to estimate least squares (LS) mean change from baseline, with 95% confidence intervals (CIs), at each time point and overall change from baseline across all study assessments. In contrast to other R/RMM clinical trials that used the QLQ-C30 and focused on scales considered relevant in R/RMM, 22 , 23 , 31 , 32 , 33 , 34 all QLQ-C30 scales except financial difficulties are presented. The MMRM used all available data for patients with a baseline and ≥1 postbaseline assessment, and assumed that missing data were missing at random. Model covariates were baseline PRO score, time point, and baseline PRO score-by-time-point interaction; assessment time points were included if there were ≥10 patients.

The proportions of patients with clinically meaningful improvement or worsening or maintenance from baseline in PROs at weeks 12, 24, 52, and 104 were determined by analyzing patients with nonmissing data. Clinically meaningful changes were predefined using the aforementioned thresholds; maintenance was any change not reaching the threshold.

An MMRM analysis for overall change from baseline across study assessments was also conducted based on stratification by objective response status of treatment responders and nonresponders. Treatment responders were those with the best overall response using the IMWG international uniform response criteria, 35 determined by an independent review committee. These responses are defined as partial response, very good partial response, complete response, and stringent response (complete response + normal free light chain ratio and absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence).

Kaplan–Meier curves assessed time to definitive deterioration (TTDD) excluding death, defined from the first treatment dose to the first clinically meaningful worsening, based on the aforementioned thresholds and seen at all later time points or if there were no subsequent assessments. Patients with a nonmissing baseline assessment who did not experience a definitive, meaningful deterioration were censored at the last available PRO assessment. Patients with no baseline assessment, no postbaseline assessments, or whose baseline scores did not allow further deterioration were censored at the first dose. The LS mean change from baseline was considered statistically significant if the 95% CI did not cross 0. Because no adjustment for multiplicity was performed, all statistical significance is nominal. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Patient population

In total, 117 patients treated at the full 200 mg dose were evaluated, with a median follow-up of 21.3 months. This population was 54.7% male and 70.9% White, with a median age of 70 years ( Table 1 ; 200 mg group). Overall, 82.1% had triple-class refractory disease, 76.9% were penta-exposed, and 39.3% had high-risk cytogenetics ( Table 1 ).

PRO completion rates and baseline scores

PRO completion rates were >80% through week 80 and decreased to 52% at week 104 for all PRO instruments. These rates do not account for dose delays during the period immediately preceding data cutoff because patients who were scheduled to receive the study drug but had a dose delay were counted as having missed their PRO assessments.

At baseline, patients reported greater pain, indicated by a substantially higher mean score on the QLQ-C30 pain scale ( supplemental Table 1 ), than a general cancer population. 36 Values on the QLQ-C30 functional and symptom scales were generally similar to, or slightly worse than, a general cancer population and slightly better than a reference myeloma population ( supplemental Table 1 ). 36 On the QLQ-MY20, patients reported a substantial impact on DS and a greater impact on SE ( supplemental Table 1 ). The mean EQ-5D-3L VAS score (60.9 [standard deviation, 24.7]) was lower than general-population norms (range, 71.1-83.7), 37 indicating impaired HRQoL.

Change from baseline

QLQ-C30

The overall change from baseline across all assessments indicated improvements of nominal statistical significance on all QLQ-C30 scales ( Table 2 ). On the GHS/QoL, physical functioning, and role functioning scales, LS mean changes were 7.0 (95% CI, 5.4-8.6), 4.5 (95% CI, 2.5-6.6), and 7.0 (95% CI, 4.7-9.3), respectively. Of the functional scales, the greatest overall improvement was observed for social functioning (LS mean change, 10.4; 95% CI, 7.1-13.8) and was clinically meaningful. Nominal statistically significant LS mean improvements in fatigue (−7.4; 95% CI, −10.0 to −4.9) and pain (−10.2; 95% CI, −13.8 to −6.6) were observed, with the latter being clinically meaningful ( Table 2 ). Improvements on the other QLQ-C30 symptom scales, including insomnia and appetite loss, were all of nominal statistical significance ( Table 2 ). None of the overall changes showed a nominal statistically significant worsening or reached the threshold for clinically meaningful worsening.

In evaluating changes from baseline at each assessment, nominal statistically significant improvements were observed as early as week 12 for GHS/QoL and week 20 for physical and role functioning scales ( Figure 1 ); improvements were generally maintained at subsequent assessments, with some assessments in role functioning reaching the threshold for clinically meaningful change ( Figure 1 B). Improvements from baseline were observed on the other functional scales ( supplemental Figure 1 ), especially social functioning, which showed nominal statistical significance vs baseline starting at week 12 and reached the clinically meaningful threshold at several assessments ( supplemental Figure 1 C).

Nominal statistically significant improvements observed at week 16 for fatigue and pain were maintained at most subsequent assessments ( Figure 1 C). The clinically meaningful improvement threshold reached on the pain scale at week 20 was maintained at most subsequent assessments; fatigue reached the threshold at weeks 68 to 76 and weeks 100 to 104. Nominal statistically significant improvements were also observed on the other QLQ-C30 symptom scales ( supplemental Figure 2 ), with insomnia and appetite loss approaching or reaching the threshold considered clinically meaningful at multiple assessments. None of the QLQ-C30 scales reached the threshold for clinically meaningful worsening at any assessment.

QLQ-MY20

Improvements from baseline of nominal statistical significance were observed on all QLQ-MY20 scales overall ( Table 2 ) and at most assessments ( Figure 2 ). Overall change on the FP scale reached the clinically meaningful threshold at most assessments starting at week 20 ( Figure 2 B). No QLQ-MY20 scale had a nominal statistically significant worsening overall or reached the threshold for clinically meaningful worsening.

EQ-5D-3L VAS

The overall LS mean change from baseline was 8.0 (95% CI, 5.0-11.0). Improvements of nominal statistical significance were observed at most assessments, starting at week 20 ( supplemental Figure 3 ).

Proportions of patients with clinically meaningful improvement or maintenance

Clinically meaningful improvement or maintenance on all QLQ-C30 scales was reported by 70% to 94% of patients at week 12 (13%-42% for improvement and 28%-77% for maintenance) and remained relatively stable at weeks 24, 52, and 104 ( Figure 3 A), although sample sizes at week 104 were limited. In particular, 33% to 58% and 42% to 67% of patients reported clinically meaningful improvement in pain and fatigue, respectively.

On the QLQ-MY20 scales, 73% to 100% of patients had clinically meaningful improvement or maintenance across week 12, 24, 52, and 104 assessments (18%-64% for improvement and 18%-72% for maintenance; Figure 3 B). Similarly, 83% to 98% of the patients had clinically meaningful improvement or maintenance from baseline on the EQ-5D-3L VAS ( Figure 3 C).

TTDD

Median TTDD was not reached by 104 weeks on the QLQ-C30 GHS/QoL scale ( Figure 4 ) nor on any of the PRO scales (data not shown). Median TTDD was reached only on the QLQ-MY20 FP scale (37.8 months; 95% CI, 27.6 to not reached) and EQ-5D-3L VAS (37.8 months; 95% CI, 37.8 to not reached), although the number of patients after 24 months was low (≤10).

Treatment responders

Based on the IMWG response definition of best overall response of partial response or better, there were 83 treatment responders (70.9%) and 34 nonresponders (29.1%). Baseline PRO values were generally similar in responders and nonresponders who had baseline and ≥1 postbaseline assessment ( supplemental Table 2 ). Among responders, overall changes from baseline indicated improvement in nominal statistical significance on all scales ( Table 3 ). As with the results for the entire cohort, the greatest overall improvements in responders on the QLQ-C30 functional and symptom scales were for social functioning (LS mean change, 10.9; 95% CI, 7.6-14.3) and pain (LS mean change, −11.6; 95% CI, −15.3 to −7.8), respectively, both of which were clinically meaningful. On the QLQ-MY20, improvement in FP score among responders was clinically meaningful (LS mean change, 11.9; 95% CI, 10.0-13.9; Table 3 ).

Changes among responders contrasted with nonresponders, who reported numerical worsening on most scales, including the QLQ-C30 fatigue scale and EQ-5D-3L VAS, both of which were of nominal statistical significance and approached clinically meaningful thresholds for worsening ( Table 3 ).

Discussion

Despite the availability of novel therapies in R/RMM, treatment remains challenging, particularly because the disease is incurable and patients have already received multiple therapies. All patients in this study were triple-class exposed, and 82% were at least triple-class refractory, including more than three-quarters who were penta-exposed, of whom approximately one-third were penta-refractory. In such a population, it is especially important to determine whether clinical benefits observed with new treatments are accompanied by benefits from the patient’s perspective, as endorsed by regulatory agencies as part of oncology clinical trials. 20 , 21 These results, using PRO measures that capture disease-related and generic HRQoL as well as symptoms and domains relevant to R/RMM, show that linvoseltamab provides patient-reported benefits in HRQoL that track with clinical response. Patient-reported benefits were reported on all QLQ-C30 and QLQ-MY20 scales as well as the EQ-5D-3L VAS and were observed over the full treatment period. These results are generally consistent with those of recent trials of other BCMA bsAbs for R/RMM 22 , 23 but expand upon the outcomes by reporting a more comprehensive set of PROs through 2 years.

Completion rates for all PRO measures were generally as expected based on other studies in R/RMM. 22 , 32 , 38 The apparent reduction in completion rates at later assessments may be because of PRO measures being scheduled during visits when linvoseltamab was also administered; dose delays close to the data cutoff date resulted in some patients who remained on treatment being included in the denominator despite not having the expected PRO completed for these scheduled visits. In such cases, these scheduled assessments were flagged as missing because dose delays were not flagged until the delayed dose was administered (ie, after data cutoff).

Except for higher baseline pain scores, QLQ-C30 scores at baseline were similar to or only slightly better than those of a reference MM population. The more severe baseline pain score supports the importance of this symptom; pain has been significantly associated with overall HRQoL as well as with functioning domains in patients with MM. 31 Baseline scores on the QLQ-MY20 further highlight the substantial disease-specific burden borne by these patients, especially for SE, which may not be surprising given that over three-quarters of patients were penta-exposed. In most of these patients, treatment with linvoseltamab resulted in improvement or maintenance in HRQoL without adding to the symptom burden among patients remaining on treatment. Durability of response was further suggested by the observation that median TTDD was not reached on any of the scales over 2 years.

Improvements that were of nominal statistical significance and/or clinically meaningful were observed in QLQ-C30 outcomes relevant to R/RMM, including pain, fatigue, physical functioning, and role functioning. Pain and fatigue had higher proportions of patients experiencing clinically meaningful improvement relative to other symptom scales. Pain has previously been suggested to be associated with a higher fatigue burden and decrements in physical and role functioning, 39 and thus improvements in pain may have contributed to improvements in these other outcomes. In contrast to pain, fatigue is a complex symptom with multiple underlying causes and has been reported as the primary driver of QLQ-C30–assessed HRQoL in patients with cancer. 40 Our observed effects of linvoseltamab on fatigue are consistent with teclistamab 22 ; fatigue change from baseline (ie, treatment initiation) was not reported in an evaluation of elranatamab. 23

Role functioning showed a greater magnitude of improvement than physical functioning and surpassed thresholds for clinically meaningful changes at several assessments. This difference between role and physical functioning may reflect not only the broader scope of role functioning, which encompasses participatory domains of work and daily activities, 25 but also its slightly poorer baseline score. Although patients had a high baseline level of physical functioning, maintenance of physical functioning remains an important outcome. Similarly, social functioning had changes from baseline that were of nominal statistical significance and clinically meaningful at several assessments. These changes in role and social functioning suggest that linvoseltamab treatment provides benefits beyond physical effects by improving daily and social activities. Notably, this is, to our knowledge, the first clinical trial of a BCMA bsAb to report nominal statistically significant changes from baseline in physical, role, and social functioning scales; these scales did not significantly improve from baseline with teclistamab 22 and were not reported with elranatamab. 23 We also observed a trend toward improvement in insomnia and appetite loss, symptoms that affect patients’ daily lives but have been infrequently reported in MM clinical trials. Both symptoms showed improvements from baseline of greater magnitude than seen for most other symptom scales; they were not only of nominal statistical significance but also approached or reached the clinically meaningful threshold at multiple assessments.

On all scales, most patients reported clinically meaningful improvement or maintenance of baseline scores at week 12, and these proportions remained stable at weeks 24, 52, and 104, further supporting the durability of HRQoL benefits. The substantial proportions of patients with clinically meaningful improvements in the MM-relevant scales of pain (33%-58%) and fatigue (42%-67%) likely contributed to the clinically meaningful improvement in GHS/QoL (33%-43%).

On the QLQ-MY20, both DS and SE scales showed improvements of nominal statistical significance, with at least one-third having clinically meaningful improvements on SE at defined assessments. Importantly, these scales confirm the benefits of linvoseltamab on symptomatic disease without adding to the burden of assessed treatment-related side effects. The FP scale showed the greatest magnitude of benefits in terms of changes from baseline as well as proportion of patients with clinically meaningful improvement, suggesting treatment benefits on emotional health that are further supported by the very low proportion of patients who had meaningful worsening on the QLQ-C30 emotional functioning scale. Because emotional health in MM has been associated with patient perceptions of disease control, 41 these results suggest that patients treated with linvoseltamab may perceive control of their disease in a positive light and have a more favorable perspective on their future health.

Of additional clinical relevance is that overall improvements of nominal statistical significance relative to baseline were observed among treatment responders (ie, those with a best response of partial response or better) on all scales, reaching the clinically meaningful threshold for improvement on the QLQ-C30 social functioning and pain scales and the QLQ-MY20 FP scale. In contrast, nonresponders generally showed numerical worsening, with nominal statistically significant worsening on the QLQ-C30 fatigue and EQ-5D-3L VAS scales. Although these results should be interpreted judiciously because nonresponders had fewer assessments than responders, findings support PRO benefits with linvoseltamab that appear to be associated with the achievement of clinical response.

Similar effects on patient-reported HRQoL-related outcomes were observed in triple-class exposed and multi-refractory patients with R/RMM treated with new therapies in clinical trials, 22 , 32 , 33 , 34 , 38 , 42 although heterogeneity in data collection, PRO measures, and analysis, including application of different clinically meaningful thresholds, precludes comparisons across studies. This heterogeneity, especially in the PRO scales reported, also manifested in 2 trials of other BCMA bsAbs 22 , 23 and highlights the need for more comprehensive and standardized assessment. Nevertheless, those 2 studies, combined with the current encouraging results with linvoseltamab, contribute to the growing body of literature on the effects of BCMA bsAbs on PROs and can help inform treatment decisions in patients with R/RMM and limited treatment options.

Several study limitations should be considered, including that this was a single-arm, nonrandomized, open-label study and that the evaluable cohort in this ongoing trial decreased over time, causing a reduction in sample size that may have contributed to the large variability in scores at later assessments. Analyses using MMRM inherently assume missing assessments are missing at random; however, patients who discontinue because of progression may have an HRQoL trajectory (ie, worsening) that is different from that of those who do not experience progression. As such, results should be considered only within the context of patients who remain on linvoseltamab treatment. Furthermore, patients were marked as having missed PRO assessments when there was a dose delay, which, depending on the reason for the delay, might lead to a missed signal of a decrement in HRQoL. Nevertheless, our analysis showed that those with a favorable treatment response generally continue to see benefits in PROs longitudinally. A final limitation is that there remains a lack of consensus about the thresholds that represent meaningful changes in these patients; anchor-based analyses to derive meaningful changes within the trial population were not conducted. However, meaningful changes were based on published thresholds, 26 , 28 , 29 some of which reflect conservative estimates.

In summary, patient-reported benefits on domains affecting HRQoL among patients treated with linvoseltamab for up to 2 years were consistent with observed clinical outcomes. 15 Patients with R/RMM, on average, improved or maintained HRQoL and functioning while on treatment without meaningful worsening of their symptom burden.

Although improvements were especially noted in outcomes specifically relevant to R/RMM, including pain and fatigue, role functioning, and side effects of treatment, other observed benefits were seen in insomnia, appetite loss, social functioning, and emotional health. Improvements in these key symptoms and functioning likely contributed to the improvement in cancer-related and overall HRQoL, as indicated by changes from baseline in QLQ-C30 GHS/QoL and EQ-5D-3L VAS, respectively. These results paralleled the clinical response, with responders having a greater magnitude of benefit than nonresponders. Combined with previously reported clinical efficacy and safety data, 15 , 19 these HRQoL findings support a favorable benefit-risk profile of linvoseltamab for the treatment of patients with R/RMM.

Conflict-of-interest disclosure: N.B. reports an advisory/consultant role with Janssen. J.R. reports advisory/consultant roles with AbbVie, Bristol Myers Squibb, Forus, Genentech, Janssen, Karyopharm, Menarini, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Sanofi, and Takeda Pharmaceuticals; and participated in speakers bureaus for Adaptive Biotechnologies, Bristol Myers Squibb, Janssen, and Sanofi. M.V.D. reports advisory/consultant roles for Bristol Myers Squibb, Janssen, Lava Therapeutics, and Sanofi. H.C.L. reports advisory/consultant roles with Alexion Pharmaceuticals, Allogene Therapeutics, Bristol Myers Squibb, GSK, Janssen, Menarini, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, and Takeda Pharmaceuticals; and reports research funding from Amgen, Bristol Myers Squibb, GSK, Janssen, Regeneron Pharmaceuticals, Inc., and Takeda Pharmaceuticals. A.S. reports advisory/consulting roles with Janssen Oncology and GSK; research funding from Janssen Oncology (institutional), GSK (institutional), Bristol Myers Squibb (institutional), Regeneron Pharmaceuticals, Inc. (institutional), Genentech (institutional); and patents, royalties, and other intellectual property for a novel bone anabolic agent in the treatment of cancer bone metastasis (institutional). J.A.Z. reports employment with Bristol Myers Squibb/Celgene (spouse); advisory/consulting roles with Takeda Pharmaceuticals, Sanofi, Regeneron Pharmaceuticals, Inc., and Alexion; and research funding from Bristol Myers Squibb (institutional), Janssen Oncology, and RLL Bio LLC. M.R.S. reports advisory/consulting roles with Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb Foundation, Janssen Oncology, and Pfizer; reports research funding from Janssen (institutional), Bristol Myers Squibb Foundation (institutional), Regeneron Pharmaceuticals, Inc. (institutional), and AbbVie (institutional); and served as a speaker for Johnson and Johnson and Regeneron Pharmaceuticals, Inc. R.B. reports honoraria from Hikma Pharmaceuticals; reports advisory/consulting role with Bristol Myers Squibb, Sanofi, Janssen, and Pfizer; reports research funding from Karyopharm Therapeutics (institutional), AbbVie (institutional), Janssen (institutional), Bristol Myers Squibb (institutional), Daiichi Sankyo/Lilly, Seagen, Regeneron Pharmaceuticals, Inc., Zymeworks, Arvinas, Marker Therapeutics, Pionyr, and Quantum Leap Healthcare Collaborative; and reports other relationship for GSK. T.J.I., M.D., K.R.L., G.S.K., L.C., J.H., and Q.M. hold stock or stock options for, and are employees of, Regeneron Pharmaceuticals, Inc. T.J.I. also holds stock in AbbVie and Eli Lilly & Co. J.H. also holds stock in Pfizer Inc. K.K. was an employee of Regeneron Pharmaceuticals, Inc. at the time of the study. C.I. is an employee of IQVIA. S.J. reports advisory/consulting roles with Bristol Myers Squibb, Janssen, Genmab, GSK, Legend Biotech, Takeda Pharmaceuticals, Sanofi, Regeneron Pharmaceuticals, Inc., and Caribou Biosciences; and reports travel, accommodation, and expense funds from Bristol Myers Squibb, Janssen Biotech, and Regeneron Pharmaceuticals, Inc. J.E.H. and J.J.M. declare no competing financial interests.

Acknowledgments

A list of study investigators can be found in Appendix (Table A1) in the primary publication ( https://doi.org/10.1200/JCO.24.01008 ). This study was designed by employees of Regeneron Pharmaceuticals, Inc., in collaboration with the investigators. The authors thank the patients, their families, all other investigators, and all investigational site members involved in this study. Medical writing support was provided by E. Jay Bienen, PhD, and was funded by Regeneron Pharmaceuticals, Inc. Editorial support was provided by Poppie Cooper, MSc, of Oberon, a division of OPEN Health Communications, funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines.

Authorship

Contribution: T.J.I., M.D., C.I., K.R.L., G.S.K., L.C., J.H., and Q.M. contributed to the design and implementation of the analysis, including reporting and interpretation of data; K.K. was involved in the reporting and interpretation of data; J.E.H., N.B., J.R., M.V.D., H.C.L., A.S., J.A.Z., J.J.M., M.R.S., R.B., and S.J. were principal investigators in the LINKER-MM1 trial and, in addition to the provision of study materials or patients, aided in the collection and assembly of data and the interpretation of study results. All authors reviewed the manuscript during its preparation and approved the final draft.

Footnotes

At the time of the study.

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and the statistical analysis plan) that support the methods and findings reported in this study. Individual anonymized participant data will be considered for sharing (1) once the product and indication has been approved by major health authorities (eg, US Food and Drug Administration, European Medicines Agency, Pharmaceuticals and Medical Devices Agency, etc.) or development of the product has been discontinued globally for all indications on, or after, April 2020, and there are no plans for future development; (2) if there is legal authority to share the data; and (3) there is not a reasonable likelihood of participant reidentification. Submit requests to https://vivli.org/ .

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Figures and Tables

References

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