Introduction
Survival in patients with multiple myeloma (MM) has improved significantly in the last 10 years, with advances in treatment such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies [
1‐
6]. However, MM remains incurable, and most patients relapse, requiring multiple rounds of treatment [
7‐
9]. Patients with MM who have received IMiDs, PIs, and anti-CD38 monoclonal antibodies [i.e., triple-class exposed (TCE)] have a poor prognosis and limited treatment options, with a low likelihood of response to subsequent therapy [
10]. Therefore, there is an urgent requirement for new, more efficacious therapy options to delay progression, prolong survival, and improve quality of life in these patients [
10‐
12].
Teclistamab is an off-the-shelf, T-cell-redirecting, B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells [
13,
14]. The safety and efficacy of teclistamab has been investigated in MajesTEC-1, a single-arm, open-label, multicohort, phase 1/2 study in patients with triple-class exposed relapsed/refractory MM (TCE-RRMM) who previously received ≥ 3 lines of therapy (LOTs). Initial results from the cohort with no previous exposure to anti-BCMA therapy demonstrated that weekly teclistamab at the recommended phase 2 dose of 1.5 mg/kg was well tolerated, with an overall response rate of 63% [
15]. In the absence of a control arm in MajesTEC-1, indirect adjusted treatment comparisons can be performed to assess the benefits of treatment relative to regimens used in clinical practice [
16]. LocoMMotion was the first prospective study of real-world physician’s choice of therapy (RWPC) in patients with TCE-RRMM [
17], which created an external real-world control arm for comparison with MajesTEC-1. In the study reported here, individual patient data (IPD) from MajesTEC-1 and LocoMMotion were analyzed to assess the comparative effectiveness of teclistamab versus currently available RWPC in patients with TCE-RRMM.
Discussion
Despite recent advances, outcomes for many patients with TCE-RRMM remain poor, and there is an urgent need for novel therapies in this population. Teclistamab, an off-the-shelf, BCMA × CD3 bispecific antibody, has demonstrated deep and durable clinical responses and a predictable safety profile in MajesTEC-1 in patients with heavily pre-treated RRMM. MajesTEC-1 was performed as a single-arm study, because a randomized controlled trial was not feasible as there was no established standard of care and a lack of clinical equipoise. When direct comparisons are not feasible, indirect treatment comparisons can be performed between different treatment regimens using statistical methods that control for baseline differences in patient characteristics between populations [
20]. The adjusted comparisons presented here represent high-quality evidence to inform the comparative effectiveness of teclistamab relative to RWPC.
Data for RWPC were obtained from LocoMMotion, which includes patients from nine European countries and the United States and is therefore representative of RWPC across different settings. A key advantage of LocoMMotion was the availability of a wide range of clinically relevant baseline risk factors and outcomes consistent with those captured in MajesTEC-1, which allowed generation of robust comparative analyses on all relevant endpoints, including response and survival outcomes, with proper adjustment for confounding bias due to imbalance in prognostic baseline characteristics.
Our analyses demonstrated clinically and statistically significant advantages in response and survival outcomes with teclistamab over RWPC in patients with triple-class-exposed RRMM who received ≥ 3 previous LOTs. Patients treated with teclistamab were 2.3-fold, 5.2-fold, and 148.3-fold more likely to achieve a response (ORR), ≥ VGPR, and ≥ CR, respectively, versus RWPC. The superior depth of response is demonstrated by the fact that, within the responding teclistamab patients, nearly all reached ≥ VGPR (94%) and the majority (63%) reached ≥ CR, while the majority (58%) of the RWPC responders only reached PR as best response, and only 1.5% reached ≥ CR. The significantly higher rate of ≥ CR with teclistamab is particularly important, given that ≥ CR rate is a common measure of depth of response and associated with prolonged remission [
21]. This is also related to the substantially longer DOR for teclistamab, with a 68% reduction in the risk of progression or death since onset of response compared to the responders in the RWPC-cohort. Patients on teclistamab also had significantly better PFS and numerically better OS compared with RWPC. Additionally, the benefit of teclistamab in improving PFS and OS was observed beyond 3 months of treatment initiation (Fig.
2). The main findings were consistent with those from sensitivity analyses conducted to assess the effect of varying the statistical methods and covariates used.
There are some limitations to our study. As in any non-randomized study, residual confounding cannot be excluded. However, the prospective nature of the LocoMMotion study allowed all patient characteristics as captured in MajesTEC-1 to be collected at baseline, which enabled data analyses to adjust for clinically important prognostic factors. The list of clinically important prognostic factors to be adjusted for was identified a priori based on a review of the literature and consultations with clinical experts, and was further validated by the prognostic strength of these factors in the MajesTEC-1 and RWPC cohorts. Clinical experts were consulted at multiple stages of the analysis to ensure clinical validity of the chosen covariates. Imbalances between cohorts on all these risk factors were minimal after ATT-weighting, strengthening the validity of the adjusted comparisons. Cytogenetic risk was not included in the reported analyses, due to high missingness, which reflects that this is not routinely captured in real-world practice. Also, race was not included, due to low numbers for non-White RWPC patients. However, sensitivity analyses (not reported here) additionally including both factors did not show any major impact on the comparative results.
A further limitation is that there were no restrictions on treatment types used in LocoMMotion, thereby allowing physicians to prescribe based on clinical judgement. Although comparison of teclistamab to individual therapies was not possible due to the highly varied and individualized therapies selected by physicians for their patients, the comparator group was representative of regimens that are widely available to clinicians for use in clinical practice.
Another limitation was the limited availability of newer treatments in the RWCP cohort. Although new therapies for treatment of patients with TCE-RRMM have recently emerged, including selinexor, belantamab mafodotin, ide-cel, and cilta-cel, their use has been largely limited to participants in clinical trials [
22‐
25]. During recruitment for LocoMMotion, selinexor was only available in the United States, and belantamab mafodotin was approved in the United States and the European Union for 3 months during the LocoMMotion recruitment period, so both agents were received by only a few patients in the study in the treatment line initiated at baseline. No patients initiated CAR-T treatment (ide-cel or cilta-cel), as these were not approved at time of enrollment in LocoMMotion. However, of all the RWPC patients who received subsequent treatment after the treatment line initiated at baseline, 46% were treated with at least one novel agent, indicating that OS observed for RWPC may reflect the benefit of other novel agents.
Acknowledgements
We thank all patients who participated in the MajesTEC-1 and LocoMMotion studies and the families and caregivers, physicians, and nurses who cared for the patients and supported the studies. We also thank the staff members at the MajesTEC-1 and LocoMMotion sites involved in data collection, data analysis, and interpretation, and acknowledge the contributions of Nichola Erler-Yates and Jedelyn Cabrieto (Janssen) to the data analyses.
Author Contributions
Philippe Moreau, Aurore Perrot, Rachel Kobos, Jennifer Smit, and Maria-Victoria Mateos: Conceptualization, Investigation, Visualization, Writing-Reviewing and Editing Niels W. C. J. van de Donk, Michel Delforge, Hermann Einsele, Valerio De Stefano, Britta Besemer, Charlotte Pawlyn, Lionel Karlin, Salomon Manier, Xavier Leleu, Katja Weisel, and Ahmed Elsada: Conceptualization, Investigation, Writing-Reviewing and Editing Francesca Ghilotti: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing original draft, Writing-Reviewing and Editing Joris Diels: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing original draft, Writing-Reviewing and Editing Raul Morano and Mary Slavcev: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing-Reviewing and Editing Vadim Strulev: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Visualization, Writing original draft, Writing-Reviewing and Editing Lixia Pei: Conceptualization, Investigation, Methodology, Writing-Reviewing and Editing.
Disclosures
Philippe Moreau has held a consulting or advisory role for AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, and Sanofi; and received honoraria from AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. Niels W. C. J. van de Donk has received honoraria from Celgene; held a consulting or advisory role for Amgen, Bayer, Celgene, Janssen, Novartis, Roche, Servier, and Takeda; and received research funding from Amgen, BMS, Cellectis, and Janssen. Michel Delforge has held a consulting or advisory role for Amgen, Celgene, and Janssen; and received honoraria from Amgen, Celgene, and Janssen. Hermann Einsele has held a consulting or advisory role for Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda; received travel, accommodations, and/or expenses from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Takeda; received honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda; and received research funding from Amgen, Bristol Myers Squibb, Celgene, and Janssen. Valerio De Stefano has received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, and Takeda. Aurore Perrot has received honoraria from AbbVie, Amgen, Celgene, Janssen-Cilag, GlaxoSmithKline, Sanofi, and Takeda. Britta Besemer has received travel, accommodations, and/or expenses from Janssen-Cilag; and received honoraria from Janssen-Cilag. Charlotte Pawlyn has received honoraria from Amgen, Celgene/Bristol Myers Squibb, Janssen, Sanofi, and Takeda. Lionel Karlin reports employment (family member) by Aguettant; has received honoraria from AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda; has held a consulting or advisory role for AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda; and has received travel, accommodations, and/or expenses from Amgen, Janssen, Sanofi, and Takeda. Salomon Manier has received research funding from AbbVie, Celgene/Bristol Myers Squibb, Janssen, Novartis, and Takeda. Xavier Leleu has held a consulting or advisory role for AbbVie, Amgen, Bristol Myers Squibb, CARsgen Therapeutics, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Karyopharm Therapeutics, Merck, Novartis, Oncopeptides, Roche, and Takeda; received travel, accommodations, and/or expenses from Takeda; and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, CARsgen Therapeutics, Celgene, GlaxoSmithKline, Janssen-Cilag, Karyopharm Therapeutics, Merck, Novartis, Oncopeptides, Roche, Sanofi, and Takeda. Katja Weisel has held a consulting or advisory role for Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, Karyopharm Therapeutics, Oncopeptides, Roche, Sanofi, and Takeda; has received travel, accommodations, and/or expenses from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, and Takeda; received honoraria from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche/Genentech, Sanofi, and Takeda; and has received research funding from Amgen, Bristol Myers Squibb/Celgene, Celgene, GlaxoSmithKline, Janssen-Cilag, and Sanofi. Francesca Ghilotti is employed by Janssen. Joris Diels is employed by and has stock/other ownership interests in Janssen. Ahmed Elsada was employed by Janssen-Cilag during the conduct of the research and publication development; he is currently an employee of Bristol-Myers Squibb. Raul Morano is employed by Janssen. Vadim Strulev is employed by and has stock/other ownership interests in Janssen. Lixia Pei is employed by and has stock/other ownership interests in Janssen. Rachel Kobos is employed by and has stock/other ownership interests in Janssen. Jennifer Smit is employed by, has stock/other ownership interests in, and has received travel, accommodations, and/or expenses from Johnson & Johnson/Janssen. Mary Slavcev is employed by and has stock/other ownership interests in Janssen. Maria-Victoria Mateos has held a consulting or advisory role for AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Regeneron, Roche/Genentech, and Takeda; and received honoraria from AbbVie/Genentech, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, and Takeda.