麻豆传媒

The treatment landscape for multiple myeloma is evolving rapidly, with novel therapies offering renewed hope for patients with relapsed or refractory disease. At this year's American Society of Hematology (ASH) annual meeting, several studies highlighted innovative approaches that address the unmet needs of heavily pretreated patients, including those resistant to existing therapies. Among these approaches, three therapies stood out for their potential to redefine treatment paradigms and improve outcomes for high-risk patients.

Bispecific Antibodies

Cevostamab, a bispecific antibody targeting FcRH5 and CD3, represents a promising advance in the treatment of heavily pretreated relapsed/refractory multiple myeloma. Presented by Joshua Richter, MD, of the Icahn School of Medicine at Mount Sinai in New York City, this showed the drug's potential as a novel fixed-duration treatment option.

"We're seeing increasing resistance to B-cell maturation antigen (BCMA)- and GPRC5D-targeted agents, which emphasizes the need for new targets," Richter said. "FcRH5, a protein expressed exclusively on B-cell lineage and ubiquitously on multiple myeloma cells, provides a promising alternative for these patients."

The ongoing study enrolled a heavily pretreated patient population, with a median of 7.5 prior lines of therapy. All patients were triple-class refractory, and 86% were penta-refractory, with over half previously exposed to BCMA-targeted therapies.

Despite this challenging cohort, cevostamab demonstrated an overall response rate (ORR) of 44.3%, with responses deepening over time. Patients naive to prior BCMA therapies achieved a higher ORR of 60%, underscoring the potential benefit in earlier treatment lines.

"Responses were durable, with a median duration of response of 10.4 months for partial responders and over 21 months for those achieving VGPR [very good partial response] or better," Richter reported.

Cevostamab's fixed-duration dosing model differentiates it from many other therapies in the relapsed/refractory setting, which are often administered until disease progression or intolerance. Patients received 17 cycles of treatment over approximately 12 months, followed by an observation period.

Remarkably, patients achieving stringent complete response (CR) maintained remission off therapy for extended periods, with some remaining in remission for over 3 years.

"The ability to stop treatment after a fixed duration while maintaining a durable response represents a significant advancement for patient quality of life," Richter noted.

Safety data reinforced cevostamab's potential as a well-tolerated therapy. Cytokine release syndrome (CRS) occurred in 63% of patients but was limited to grades 1 and 2, with no grade 3 or higher events in the triple step-up dosing cohort. Hematologic toxicities were manageable, with grade 3/4 neutropenia occurring in 30% of patients. Infection rates were consistent with other bispecific therapies, with 19% of patients experiencing grade 3 or higher infections, though most infections were grade 1 or 2.

"The safety profile is encouraging, especially compared to other bispecific platforms targeting BCMA," Richter said.

BCL-2 Inhibitors

Lisaftoclax, a novel investigational BCL-2 inhibitor, has also shown promise in treating relapsed/refractory multiple myeloma. Sikander Ailawadhi, MD, of the Mayo Clinic in Jacksonville, Florida, emphasized its potential: "BCL-2 remains an important therapeutic target in myeloma, particularly for patients with limited options. Lisaftoclax provides a unique mechanism of action, combining efficacy with a favorable safety profile."

The ongoing evaluated lisaftoclax in combination with pomalidomide (Pomalyst) and dexamethasone (PD) or daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone. Patients had a median of three prior lines of therapy, with 85% previously exposed to CD38-targeted therapies.

Among the 36 evaluable patients treated with lisaftoclax plus PD, the ORR was 64%, with 31% achieving VGPR or better. In the 1,000-mg cohort, the ORR rose to 89%, with a median progression-free survival of over 11 months. "These results are particularly encouraging in patients previously exposed to CD38-targeted therapies," Ailawadhi explained, highlighting an ORR of 62% in this subgroup, which increased to 87% with the 1,000-mg dose.

Lisaftoclax's safety profile further supports its potential for long-term use. The most common hematologic adverse events were grade 3/4 neutropenia (44%) and anemia (17%), though these were manageable. Non-hematologic toxicities were mostly grade 1 or 2, with only 15% of patients experiencing pneumonia. Importantly, the discontinuation rate due to toxicity was below 5%. "What's noteworthy is that lisaftoclax achieves high-dose safety, something other BCL-2 inhibitors have struggled with," Ailawadhi added.

Ongoing enrollment and dose optimization will confirm lisaftoclax's role in expanding therapeutic options for this disease, he noted.

Trispecific Antibodies

Finally, the introduction of trispecific antibodies marks a new frontier in immunotherapy for relapsed/refractory multiple myeloma, with ISB 2001 leading the charge. simultaneously targets BCMA, CD38, and CD3, enhancing tumor-specific cytotoxicity while minimizing off-target effects.

"ISB 2001's dual high-affinity binding to BCMA and CD38 enhances its ability to combat resistance mechanisms, even in patients with low target expression," explained Hang Quach, MD, MBBS, of St. Vincent's Hospital Melbourne in Australia. "Additionally, its unique anti-CD38 region avoids competition with daratumumab, a commonly used monoclonal antibody in multiple myeloma treatment."

The ongoing, first-in-human phase I trial includes patients with heavily pretreated relapsed/refractory multiple myeloma who had a median of six prior lines of therapy. The results so far are highly promising: the ORR across all cohorts was 75%, with 65% achieving VGPR or better and 20% achieving CR or better. Responses were observed starting at low doses (50 μg/kg) and improved as doses escalated, with patients in dose levels 3-7 showing an ORR of 83%. Responses were durable, with some lasting over 9 months, and deepened over time, with one patient achieving minimal residual disease negativity.

Safety data showed a favorable profile, with no dose-limiting toxicities and minimal neurologic side effects. CRS occurred in 75% of patients but was primarily grade 1 (65%), with only two grade 2 cases reported. "The median time to CRS was just 3 days, lasting a median of 2 days, and most events were limited to the first step-up dose," Quach noted.

Importantly, no cases of immune effector cell-associated neurotoxicity syndrome were observed, and hematologic toxicities such as grade 3/4 neutropenia occurred in only 30% of patients.

ISB 2001 also demonstrated efficacy in difficult-to-treat patient subsets. In those refractory to prior CD38-targeted therapies, the ORR was 86%, and was 100% in patients who progressed on anti-CD38 therapies within the last 6 months. Similarly, patients with prior exposure to BCMA-targeted or T-cell redirection therapies achieved a 75% ORR. Responses were even higher (90% ORR) in patients naive to these therapies, with 30% achieving a CR or better.

"These results suggest that ISB 2001 has significant activity regardless of prior therapies and shows particular promise in patients with high unmet needs," said Quach.

As dose escalation continues, the planned expansion phase will focus on optimizing dosing and evaluating less frequent administration schedules, which could further improve patient convenience and quality of life, he said.

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