Estimation of benefit to bispecific antibodies in US patients with lymphoma and multiple myeloma Open Access

TO THE EDITOR:

Bispecific antibodies (BsAbs) have gained momentum during the last several years in the treatment of hematological malignancies, as their novel mechanism of action has led to improved outcomes in patients with relapsed/refractory (R/R) hematological malignancies, after conventional therapies. This progress has culminated in 7 regulatory approvals of BsAbs by the US Food and Drug Association (FDA) to treat hematological malignancies.¹ Excluding blinatumomab, the remaining 6 have gained accelerated approval through phase 2 trials to treat R/R non-Hodgkin lymphoma (NHL) (mosunetuzumab,² epcoritamab,³ and glofitamab⁴), and R/R multiple myeloma (MM) (teclistamab,⁵ elranatamab,⁶ and talquetamab⁷). Although these agents are associated with overall response rates (ORRs) of >50% in heavily-treated patients,^2-7 an estimate of real-world eligibility and response to these therapies in the United States is not known.

We sought to estimate the current and future proportion of US patients with NHL and MM who would be eligible for and might respond to FDA-approved BsAbs for R/R NHL and MM in a given year, based on their current FDA-approved indication, as was previously done for chimeric antigen receptor (CAR) T-cell therapy⁸ and immune checkpoint inhibitors.⁹ A patient was eligible for treatment with a BsAb if they had the tumor type eligible for trial enrollment in the pivotal studies. We selected all BsAbs that were approved by the FDA for NHL and MM through December 2024. For each drug and year for which the drug was approved, the approved indication and ORR were extracted from the FDA label and registrational study, respectively. We used the incidence rate of NHL and MM from American Cancer Society's Cancer Facts and Figures during each year starting from the initial BsAb regulatory approval.¹⁰ Our study is reported according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines for cross-sectional studies. Institutional Review Board approval was waived because the study did not involve health care records and data are publicly available.

Six BsAbs were approved in the United States since 2022 to treat NLH and MM: epcoritamab and glofitamab in 2023 to treat R/R diffuse large B-cell lymphoma (DLBCL) and other mature B-cell neoplasms; mosunetuzumab in 2022 and epcoritamab in 2024 to treat R/R grade 1 to 3A follicular lymphoma (FL); and teclistamab in 2022 and elranatamab and talquetamab in 2023 for MM. All of them were authorized via accelerated approval pathway after a phase 2 trial (Table 1).

To determine the proportion of patients who are potential candidates for a BsAb, we used the annual incidence rates and made assumptions in effective attrition rates between lines of therapy based on published literature (ie, number of patients eligible for BsAb). For NHL, we assumed 30% of NHL diagnoses are DLBCL,¹¹ whereas 20% are FL.¹² Of all newly diagnosed patients with DLBCL, we assumed that 30% (10% primary refractory and 20% in relapse) would receive a second-line therapy; of these patients, we assumed that 50% would be eligible to receive a BsAb as third-line therapy.¹¹ We assumed that 75% of the newly diagnosed patients with FL are grade 1 to 3A; of these, 85% will require first-line treatment, 50% will require second-line treatment, and 13% will be eligible to receive a BsAb as third-line therapy.^12,13 For MM, we assumed that 15% of newly diagnosed patients with MM will be eligible to receive BsAbs as fifth line of therapy.¹⁴ 

To estimate the population who would potentially benefit from these therapies per year, the estimated number of patients eligible was multiplied by the ORR reported in the trial that led to the BsAb approval for each year a therapy had an approval, using the highest reported response, if >1 BsAbs were approved for that histology.

In 2023, the total number of new NHL cases was 80 550, in 2024 it was 80 620, and in 2025 it was projected to be 80 350. Of these, we estimated 3624 patients with DLBCL would be potentially eligible to receive BsAbs in 2023, 3628 in 2024, and 3615 projected in 2025. We estimated 1366 patients with FL to be potentially eligible to receive BsAbs in 2023, 1367 in 2024, and 1363 in 2025. The percentage of patients per year that were potentially eligible for BsAbs was 15% for DLBCL (4.5% of all NHL cases) and 8.5% for FL (1.7% of all NHL cases). Based on the best reported response rates from registration trials, we estimated that 9% of patients with DLBCL (2% of all NHL) and 5% of those with FL (1% of all NHL) would benefit from BsAbs every year.

In 2022, the total number of new MM cases was 35 730, in 2023 it was 35 730, in 2024 it was 35 780, and in 2025 it was projected to be 36 110. The percentage of patients per year that were potentially eligible for BsAbs was 15% for newly diagnosed MM. We estimated 5340 newly diagnosed patients with MM are potentially eligible to receive BsAbs in 2022, 5340 in 2023, 5367 in 2024, and 5417 in 2025. Based on the best response rates from registration trials, we estimated that 10.5% of the patients with MM would benefit from BsAbs every year.

To address potential future indication changes, we projected the estimated benefit, should the FDA label expand, to allow the use of BsAb in the second-line setting for MM or NHL. Under such conditions using the same effective attrition rates, in 2025 a total of 12 353 patients with NHL would be eligible for BsAb therapy (15%, an increase of 150%), and assuming 47% of newly diagnosed patients with MM will receive a second-line treatment,¹⁴ a total of 16 972 patients would be eligible for BsAb therapy (47%, an increase of >3 times; supplemental Figure 1).

Despite reasonably high ORR of BsAbs in heavily-pretreated patients enrolled in registrational trials, we found the percentage of patients with NHL and MM who would potentially be eligible and respond to these therapies under the current FDA indication, to be quite low (approximately only 1/10 per year). These are likely due to multiple factors: death from disease progression before receiving BsAb, poor performance status and comorbidities that would preclude the use of BsAb, or travel and financial constraints that may limit access to academic centers, if prescribing ability is limited in community settings.

As death due to progression is the most important cause of attrition,¹⁴ exposing patients to BsAbs in earlier lines of therapy would increase the estimated benefit from these drugs. Although this analysis addresses current FDA-labeled indications, the therapeutic landscape of NHL and MM is rapidly evolving and several trials are evaluating BsAbs in earlier lines of therapy and/or in combination with other agents, showing promising results. Examples include the recently published STARGLO trial (NCT04408638) evaluating glofitamab in combination with chemotherapy as first salvage therapy for patients with DLBCL, and preliminary data from MonumenTAL-3 (NCT05455320), which evaluated talquetamab in combination with daratumumab with or without pomalidomide in patients with MM, with at least 1 prior line of therapy.

Important limitations to our analysis should be noted. Response rates to B-cell maturation antigen BsAbs may be lower in patients with MM who were previously exposed to B-cell maturation antigen CAR T-cell therapy,¹⁵ which differs from the ORR reported in the clinical trials that led to the approval of these drugs. Similarly, although CD20 targeting BsAbs are active in patients with NHL previously exposed to CD19 CAR T-cell therapy,^16,17 real-world analyses show lower response rates.¹⁸ As such, our estimates may overstate the real-world efficacy of these agents in certain patient populations. Furthermore, our effective attrition rate assumptions come from either multinational clinical trials or retrospective database studies and may not be generalized to the US population treated in community sites. At instances where multiple attrition rate estimates were available in the literature, we used the average rate in our calculations.

Although BsAbs represent an important advancement in the therapeutic landscape, our findings emphasize the need for continued evaluation of their real-world impact, as access and utilization remain limited by clinical eligibility, number of prior therapies, and most importantly attrition. Future research should focus on optimizing patient selection, moving BsAbs to earlier lines of therapy, utilizing combination treatments, and expanding access to these therapies in community settings.

Acknowledgments: This research is partly supported by National Cancer Institute grant U01CA271410.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Contribution: T.H. finalized the manuscript and provided supervision; and all authors had a role in conceiving, analyzing, writing, and editing the manuscript.

Conflict-of-interest disclosure: T.H. reports research funding (to institution) from BeiGene and Bristol Myers Squibb; and is on the consulting or advisory board of BeiGene. F.A.R.-O. declares no competing financial interests.

Correspondence: Talal Hilal, Division of Hematology and Oncology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix 85054, AZ; email: hilal.talal@mayo.edu.