BCMA-Directed Bispecifics and ADCs Broaden Treatment Sequencing Options in R/R Myeloma

The arrival of multiple BCMA-directed modalities, including CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates (ADCs), has given clinicians more options than ever to treat patients with relapsed/refractory multiple myeloma. However, the emergence of these agents has also made treatment sequencing more complex.

"It's a remarkable pace of development that's consistently improving every year," Paul G. Richardson, MD, said during a recent OncLive® Peer Exchange during the 23rd International Myeloma Society (IMS) Annual Meeting. "That leaves us with a lovely challenge: How do we sequence these drugs? The heterogeneity of our patients and the diversity of their needs guides me as much as anything else."

Moderated by Hans C. Lee, MD, the panel, which also included Douglas W. Sborov, MD, MS, and Jing Christine Ye, MD, MSc, examined longer-term efficacy data for BCMA-directed bispecific antibodies and ADCs, how disease characteristics and access to care shape treatment selection, emerging combination and earlier-line strategies, and supportive care approaches that are moving bispecific therapy into the outpatient and community settings.

How do clinicians frame the choice among BCMA-directed modalities?

Richardson noted that the movement of immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies into frontline quadruplet regimens has produced unprecedented progression-free survival (PFS) outcomes in the newly diagnosed setting.

In subsequent lines, when presenting BCMA-directed options to patients, Sborov said he separates them into 2 buckets based on mechanism.

"One of my buckets is immune dependency, and that's really where the bispecifics and the CAR T [therapies] live," he explained. "Whereas with the ADC, … it's really about delivering a [cytotoxic] payload and causing direct cytotoxicity."

Beyond mechanism, administration and toxicity profiles drive the conversation. CAR T-cell therapy is given as a single infusion followed by intensive supportive care, whereas bispecific antibodies and ADCs are administered on an ongoing basis. Sborov noted that clinicians tend to focus on cytokine release syndrome (CRS) and neurotoxicity with CAR T-cell therapy, infections with bispecific antibodies, and ocular toxicities with ADCs.

"These are all really highly effective therapies," Sborov said. "We think that we can use all of these drug classes in each of our patients. So how do we sequence them? It's going to come down to what the patient is most comfortable with."

What do longer-term data reveal about BCMA-directed bispecifics and ADCs?

Lee noted that early enthusiasm for BCMA-directed bispecific antibodies centered on response rates exceeding 60% with an off-the-shelf agent, and that longer follow-up is now clarifying the durability of those responses. In the phase 1/2 LINKER-MM1 trial (NCT03761108), linvoseltamab-gcpt (Lynozyfic) delivered at a 200-mg dose produced an overall response rate (ORR) of 70.9% and a complete response or better rate of 52.1% at a median follow-up of 21.3 months; The median duration of response (DOR) was 29.4 months.¹

"For us, we want to see [the] depth of the response and the duration of the response, and both of them hold true," Ye said, adding that clinicians pay extra attention to outcomes in high-risk subgroups, including patients with high-risk cytogenetics and high disease burden.

Lee added that, in his experience, a response to linvoseltamab "really portends [a] durable response. Patients who respond well typically stay in response, even with de-escalation of the frequency of dosing."

Richardson then highlighted data from the phase 3 DREAMM-7 trial (NCT04246047), in which belantamab mafodotin-blmf (Blenrep) plus bortezomib (Velcade) and dexamethasone (BVd) generated a median PFS of 36.6 months vs 13.4 months with daratumumab (Darzalex), bortezomib, and dexamethasone, along with a significant overall survival (OS) benefit (HR, 0.58; 95% CI, 0.43-0.79; P = .0002).^2,3

"People often don't quite grasp that you've got a median PFS that exceeds 36 months," Richardson said. He emphasized that with appropriate dosing, ocular toxicity has been "mild to moderate, … manageable, [and] reversible,” allowing it to truly be an outpatient therapy.

Richardson also cited recent National Comprehensive Cancer Network guideline updates that expanded the positioning of belantamab mafodotin–based regimens. The FDA approved BVd in October 2025 gor the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 2 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.⁴

Ye then reviewed data from the phase 3 DREAMM-8 trial (NCT04484623), in which belantamab mafodotin plus pomalidomide (Pomalyst) and dexamethasone (BPd) led to a 12-month PFS rate of 71% vs 51% with pomalidomide, bortezomib, and dexamethasone.⁵ She noted that the trial enrolled a largely lenalidomide (Revlimid)-refractory population at first relapse, which "is very applicable to our real-world patient population."

How do disease characteristics and access to care influence treatment selection between BCMA-directed therapies?

Sborov cautioned against treating high-risk myeloma as a single entity, distinguishing among high-risk cytogenetics, extramedullary disease, and functionally high-risk disease in patients who progress shortly after diagnosis.

"High-risk disease is still the troublemaker in myeloma," he said. "With that being said, I think all of our BCMA agents are showing us a signal that we're improving outcomes, even in the high-risk patients." He noted that he would lean toward bispecific-based combinations in patients with extramedullary disease and consider CAR T-cell therapy for patients with functionally high-risk disease.

For patients with rapidly progressing disease, panelists noted the off-the-shelf nature of bispecific antibodies and ADCs can be decisive.

"Whenever you have a patient where there's an access issue, there's an insurance approval issue, [CAR T] manufacturing logistic issues, [or] aggressiveness of the disease, all may push us toward a different choice," Ye said.

Geography also plays a role in selection. Sborov noted that patients in remote areas of Utah may not be willing or able to travel for CAR T-cell therapy. "Patients don't want to necessarily drive 10 hours and stay in Salt Lake City for a month," he said. "Those patients who live far away know that they have an ADC in their back pocket as an effective therapy, [which] is something that goes a long way."

How are combination and earlier-line strategies reshaping sequencing?

"This is myeloma. We never use single agents," Sborov said. "It's trying to identify the ideal dancing partners with each of our new therapies."

Richardson underscored that T-cell exhaustion after BCMA-directed immunotherapy is real and that intervening therapies may help restore immune function before subsequent T-cell–redirecting treatment. He pointed to the August 2026 accelerated approval of iberdomide (Zenbexus) in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro) and dexamethasone,⁶ as well as data from the phase 3 SUCCESSOR-2 trial (NCT05552976), in which mezigdomide (CC-92480) plus carfilzomib (Kyprolis) and dexamethasone produced a median PFS of 18.0 months vs 8.3 months with carfilzomib and dexamethasone alone.⁷

"The CELMoDs will float all boats," Richardson said. "[They] will help all the other drugs we've talked about today."

He added that available evidence suggests belantamab mafodotin is not immune exhausting, giving clinicians flexibility to position it "earlier, later, or in between" T-cell–redirecting therapies. Sborov added that emerging data suggest BCMA expression is preserved at progression after belantamab mafodotin, which could preserve later BCMA-directed CAR T-cell or bispecific options. "Belantamab upfront might be the perfect spot for that drug," he said.

That rationale underpins the phase 3 DREAMM-10 trial (NCT06679101), which is comparing belantamab mafodotin plus lenalidomide and dexamethasone with daratumumab, lenalidomide, and dexamethasone in patients with transplant-ineligible newly diagnosed disease.⁸ Ye noted that the trial uses a lower dose and less frequent dosing schedule of belantamab mafodotin to balance efficacy and ocular toxicity. "When the newly diagnosed myeloma patients [are treated], the myeloma clones are less heterogeneous and the T cells [are] less exhausted," she said.

GPRC5D has also emerged as a validated alternative target. Ye said she uses talquetamab-tgvs (Talvey) after BCMA-directed therapy and as bridging before CAR T-cell therapy, and she highlighted the phase 3 MonumenTAL-3 trial (NCT05455320), in which talquetamab plus daratumumab, with or without pomalidomide, significantly improved PFS vs daratumumab, pomalidomide, and dexamethasone.⁹ "One of the advantages [of GPRC5D] is [a] lower rate of high-grade infections compared with BCMA," she noted.

Richardson also pointed to the phase 3 MajesTEC-9 trial (NCT05572515), in which teclistamab-cqyv (Tecvayli) monotherapy improved PFS (HR, 0.29) and OS (HR, 0.60) vs pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone in patients with 1 to 3 prior lines of therapy.¹⁰ "That hazard ratio is unprecedented in early relapse," he said.

Looking further ahead, Sborov named trispecific antibodies such as ramantamig (JNJ-79635322), which targets BCMA, GPRC5D, and CD3 and is being evaluated in a phase 1 study (NCT05652335), as the development to watch.

"We've seen incredible efficacy results in heavily pretreated patients, [and] we're seeing a drug that's emerging [as] better tolerated, which is pretty incredible," he said.

What supportive care strategies make outpatient delivery feasible?

Lee, who practices in the community setting, highlighted the phase 2 OPTec study (NCT05972135), which evaluated a single dose of prophylactic tocilizumab (Actemra) before outpatient step-up dosing of teclistamab or talquetamab in community practices. Among patients treated with teclistamab, CRS occurred in 8.9%, all of which were grade 1, and no immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in either arm.¹¹

"I truly believe that both bispecifics and ADCs can be given in the community oncology setting, which really then tremendously increases the access [to] these agents," Lee said.

Sborov described a fully outpatient approach at his institution that pairs prophylactic tocilizumab with home temperature checks every 6 to 8 hours and a "pill-in-the-pocket" 12-mg dose of dexamethasone that patients take if they develop a fever. "Usually that's enough to resolve any kind of low-grade CRS that we see," he said.

To mitigate infection risk, Ye described a protocol that includes intravenous immunoglobulin (IVIG) replacement regardless of IgG level, infectious disease screening, antiviral and Pneumocystis jirovecii pneumonia prophylaxis, antimicrobial or antifungal prophylaxis during neutropenia, and vaccination when appropriate. Sborov said every patient receiving a bispecific antibody at his center receives monthly IVIG and that he is de-escalating dosing "more and more and faster and faster," adding that "finite therapy is likely where we're headed."

For belantamab mafodotin, Richardson emphasized that dose and schedule modification is "the cornerstone of ocular management," along with artificial tears, eye hygiene, and addressing preexisting cataracts. He also stressed that the Keratopathy and Visual Acuity (KVA) scale used to grade ocular findings "is an early warning system. It is not [the] CTCAE."

Ultimately, the panel agreed that treatment selection should be a shared decision. "We're so lucky in myeloma now because we have the ability to actually offer [patients] real choices," Richardson said.

"I'm a firm believer that BCMA bispecifics can be given in a community oncology setting as an outpatient with prophylactic [tocilizumab]," Lee concluded. "It is doable. … [This can] really improve access to these classes of drugs for our patients."

Hans C. Lee, MD, is the director of myeloma research at Sarah Cannon Research Institute in Nashville, Tennessee.

Paul G. Richardson, MD, is the RJ Corman Professor of Medicine at Harvard Medical School, as well as the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center of Dana-Farber Cancer Institute in Boston, Massachusetts.

Douglas W. Sborov, MD, MS, is an associate professor in the Division of Hematology and Hematologic Malignancies at the University of Utah School of Medicine and director of the Multiple Myeloma Program at Huntsman Cancer Institute in Salt Lake City.

Jing Christine Ye, MD, MSc, is an associate professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

References

1. Lee HC, Zonder JA, Dhodapkar MV, et al. Linvoseltamab in patients with relapsed/refractory multiple myeloma in the LINKER-MM1 study: longer follow-up and subgroup analyses. Clin Lymphoma Myeloma Leuk. 2026;26(2):e201-e212.e8. doi:10.1016/j.clml.2025.11.004
2. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(5):393-407. doi:10.1056/NEJMoa2405090
3. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial. Lancet Oncol. 2025;26(8):1067-1080. doi:10.1016/S1470-2045(25)00330-4
4. Blenrep/ Prescribing information. GlaxoSmithKline; 2025. Accessed November 5, 2026. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Blenrep/pdf/BLENREP-PI-MG.PDF
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6. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone. FDA. August 13, 2026. Accessed November 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
7. Richardson P, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): results from the phase 3 SUCCESSOR-2 trial. J Clin Oncol. 2026;44(suppl 17):LBA7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506
8. A phase 3, randomized, open-label study of belantamab mafodotin administered in combination with lenalidomide and dexamethasone (BRd) versus daratumumab, lenalidomide, and dexamethasone (DRd) in participants with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (DREAMM-10). ClinicalTrials.gov. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT06679101
9. Mina R, Beksac M, Rodríguez-Otero P, et al. Talquetamab-daratumumab in relapsed or refractory myeloma. N Engl J Med. 2026;395(7):671-683. doi:10.1056/NEJMoa2604657
10. Touzeau C, Mina R, Quach H, et al. Teclistamab in multiple myeloma with one to three previous lines of therapy. N Engl J Med. 2026;395(5):440-453. doi:10.1056/NEJMoa2603870
11. Forsberg P, Andorsky D, Rifkin R, et al. OPTec/OPTal: a phase 2 study to evaluate outpatient (OP), step-up administration of teclistamab (Tec) or talquetamab (Tal) with prophylactic tocilizumab (prophyToci) in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2026 Society of Hematologic Oncology Annual Meeting; September 9-12, 2026; Houston, TX. Abstract MM-1078.