Bispecific Antibodies and BiTEs in Blood Cancers: Expanding Options for an Aging Veteran Population

NEW ORLEANS — As the veteran population continues to age, bispecific antibodies (BsAbs) and bispecific T-cell engagers (BiTEs) are emerging as an important therapeutic class for blood cancers that disproportionately affect older adults and especially older veterans.

Hematologic malignancies are highly associated with military service. For veterans exposed to burn pits, presumptive conditions include lymphoma of any type, as well as other hematologic and lymphatic cancers. The VA considers Hodgkin’s disease, chronic B-cell leukemia, multiple myeloma, and non-Hodgkin lymphoma presumptive conditions for veterans exposed to Agent Orange, while Hodgkin’s disease and leukemia are considered presumptive for any veteran who develops the disease within one year of separation from active duty. Many of these malignancies are also diseases of aging, placing veterans at the intersection of exposure-related risk and demographic vulnerability.

More than half of veterans receiving VA care are 65 or older, the age range in which multiple myeloma and aggressive lymphomas are most commonly diagnosed. Historically, advanced age, frailty, and comorbidities have limited access to intensive therapies for these cancers, but data emerging from real-world and multicenter studies suggest that bispecific antibodies could expand access to treatment to older and frail veterans.

Bispecifics in Multiple Myeloma: Efficacy Beyond Younger Trial Populations

Multiple myeloma offers a prime example. Although bispecific antibodies targeting B-cell maturation antigen (BCMA) were initially approved based on clinical trials enrolling relatively few elderly patients, subsequent real-world analyses have focused specifically on outcomes in older adults.

In the pivotal phase I/II MajesTEC-1 trial supporting approval of the BCMA-directed bispecific antibody teclistamab for relapsed or refractory multiple myeloma, only 15% of patients were age 75 or older. To better understand safety and efficacy in older patients, investigators from the U.S. Multiple Myeloma Immunotherapy Consortium conducted a multicenter study examining age-related outcomes in 385 patients treated with teclistamab.¹

Of those patients, 83 (22%) were age 75 or older. Researchers reported no significant differences between older and younger patients in response rates or survival outcomes or, notably, in the primary adverse events associated with bispecifics, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome (ICANS). Outcomes appeared to favor the older patients, possibly as a result of selection bias, with overall response rates of 62% in patients age 75 or older and 53% in younger patients, while progression-free survival was 10.7 months and 5.2 months, respectively. The older cohort also had fewer adverse baseline disease characteristics, including lower rates of high-risk cytogenetics and extramedullary disease, underscoring the heterogeneity of aging patients and the need for individualized assessment rather than age-based exclusion, the researchers said.

“Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration,” the investigators concluded.

Frailty and Comorbidity: Real-World Data From BCMA-directed Bispecifics

Frailty, rather than age alone, is often a defining challenge in the VA population. A single-center retrospective study evaluated outcomes in patients with relapsed or refractory multiple myeloma treated with BCMA-directed bispecific antibodies (BsAbs), stratified by a simplified frailty index incorporating age, ECOG performance status, and comorbidities.²

Among 102 patients ranging from age 40 to 88, 39% were classified as frail. Despite worse baseline characteristics, including older age and poorer performance status, frail patients experienced similar rates of cytokine release syndrome, neurotoxicity, and treatment-related mortality compared with nonfrail patients. Best overall response rates were 80% in frail patients and 73% in non-frail patients, with no statistically significant differences in progression-free or overall survival.²

Based on these findings, investigators concluded that bispecific antibodies were safe and effective, even in older and frail patients with relapsed or refractory disease.

A second analysis examined outcomes in 99 patients with multiple myeloma, ages 65 to 89 years, who initiated bispecific antibody therapy at the Mayo Clinic, including both approved (teclistamab or talquetamab) in 45 and investigational agents in 54 patients. Nearly 70% were aged 70 or older, and 71% met criteria for frailty. Once again, frailty was not associated with inferior efficacy or increased toxicity. Overall response rates, progression-free survival, overall survival, hospitalization burden, and rates of cytokine release syndrome and neurotoxicity were similar between frail and nonfrail patients.³

Investigators found that poor performance status, rather than age or comorbidity burden alone, predicted worse outcomes. “Frailty, defined using the simplified frailty index, was not significantly associated with inferior efficacy or increased toxicity with BsAb therapy among older patients with MM,” they concluded.

Extending Bispecifics Into Lymphoma Care for the Very Elderly

The promise of bispecific antibodies extends beyond multiple myeloma, a study presented at the American Society of Hematology Annual Meeting held in New Orleans in December showed. In diffuse large B-cell lymphoma (DLBCL), treatment options for elderly patients who are ineligible for anthracycline-based chemotherapy have historically been limited, particularly for those aged 75 or 80 years and older with significant comorbidities. With one-third of veterans now over 75, restricting therapies based on age creates serious treatment challenges in the VA.

In a phase II study evaluating a CD3-CD20 bispecific monoclonal antibody in elderly patients with newly diagnosed DLBCL considered ineligible for standard chemoimmunotherapy, investigators reported high and durable response rates with a fixed-duration, largely outpatient regimen. Among 60 evaluable patients, the objective response rate was 73%, with 62% achieving complete responses.⁴

Treatment of DLBCL in this age group “is challenging, and most of them are not eligible for doxorubicin-containing regimens, so epcoritamab may offer an alternative chemo-free option for these patients,” said Umberto Vitolo, MD, in an oral abstract session.

At a median follow-up of 18.1 months, the complete response rate remained 62%, with most patients who completed one year of therapy remaining in remission at the data cutoff. Median overall survival had not yet been reached, and the 1-year overall survival rate was 65%. While cytokine release syndrome was common, the majority of events were low grade and resolved with standard management.

Implications for Veterans and VA Oncology Practice

For veterans, these findings carry particular significance. Many hematologic malignancies treated with bispecific antibodies are presumptive conditions linked to military exposures, and older adults with comorbidities, a group that has historically been underrepresented in clinical trials, are disproportionately represented in the VA population.

Across multiple studies, bispecific antibodies and BiTEs demonstrated consistent efficacy and manageable safety profiles in patients aged 70, 75, and even 80 years and older, including those classified as frail. Rates of cytokine release syndrome and neurotoxicity appear comparable to those seen in younger or fitter patients and are increasingly managed through standardized monitoring, step-up dosing, and supportive care.

For a veteran population that often faces both biologically aggressive disease and limited tolerance for intensive chemotherapy, bispecific antibodies represent a meaningful advance. As experience with these agents grows within VA and academic centers, they are likely to play an expanding role in treating blood cancers where age, exposure history, and comorbidity have long constrained therapeutic options.

In hematologic malignancies that disproportionately affect veterans, bispecific antibodies and BiTEs are beginning to close the gap between clinical trial promise and real-world applicability, bringing durable responses within reach for patients once considered too old or too frail to benefit.

 

1. Pasvolsky O, Dima D, Feng L, Dong W, Richards T, Davis JA, et al. Outcomes of elderly patients with relapsed refractory multiple myeloma (RRMM) treated with teclistamab: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium. Blood Cancer J. 2025 May 9;15(1):92. doi: 10.1038/s41408-025-01297-7. PMID: 40346049; PMCID: PMC12064690.
2. Adegbite B, Tan CR, Shekarkhand T, Firestone RS, Jurgens EM, Miller K, et al. Outcomes in frail patients receiving BCMA-directed bispecific antibodies for relapsed/refractory multiple myeloma. Blood Adv. 2025 Aug 12;9(15):4016-4022. doi: 10.1182/bloodadvances.2025015973. PMID: 40315372; PMCID: PMC12345270.
3. Abdullah N, Rees M, Gupta S, Elhag M, Bansal R, Menser T, et al. Frailty-based Outcomes with Bispecific Antibodies in Older Patients with Multiple Myeloma. Blood. 2024 Nov 5;144(S1):4695. doi: 10.1182/blood-2024-211768.
4. Vitolo U, Duell J, Burgues JMB, et al. Fixed-duration epcoritamab monotherapy induces high response and MRD-negativity rates in elderly patients with newly diagnosed large B-cell lymphoma (LBCL) and comorbidities: Results from EPCORE DLBCL-3. Blood. 2025.146(S1):63. doi:10.1182/blood-2025-63