Next generation treatments for multiple myeloma
The treatment landscape for multiple myeloma is rapidly evolving, with new treatments providing 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 unmet needs of patients undergoing intensive treatment, including those resistant to current treatments. Among these approaches, three treatments have stood out for their potential to redefine treatment paradigms and improve outcomes for high-risk patients.
Bispecific antibodies
Sifostumab, a bispecific antibody targeting FcRH5 and CD3, represents a promising advance in the treatment of previously treated relapsed/refractory multiple myeloma. Presented by Joshua Richter, MD, of the Icahn School of Medicine at Mount Sinai in New York City, this The first stage: I study Demonstrated the potential of the drug as a new duration-limited treatment option.
“We are seeing increasing resistance to B-cell maturation antigen (BCMA)- and GPRC5D-targeted agents, underscoring the need for new targets,” Richter said. “FcRH5, a protein expressed exclusively in B cell lineages 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 treatment. All patients were triple-refractory, and 86% were quintuple-refractory, with more than half having previous exposure to BCMA-targeted therapies.
Despite this challenging combination, cefostamab demonstrated an overall response rate (ORR) of 44.3%, with responses deepening over time. Patients who were refractory to previous BCMA treatments had a 60% higher OR, confirming the potential benefit in previous lines of treatment.
“Responses were durable, with a median duration of response of 10.4 months for partial responders and more than 21 months for those who achieved VGPR.” [very good partial response] Or better,” Richter reported.
The fixed-duration dosing model of cefostumab distinguishes it from many other therapies in the relapse/refractory setting, which are often given until disease progression or intolerance. Patients received 17 courses of treatment over approximately 12 months, followed by an observation period.
Strikingly, patients who achieved a strict complete response (CR) maintained remission from treatment for long periods, with some remaining in remission for more than 3 years.
“The ability to stop treatment after a specified period while maintaining a durable response represents a major advance in the patient’s quality of life,” Richter noted.
Safety data have strengthened the potential of cefostumab as a well-tolerated treatment. 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-dose group. Hematological toxicity was manageable, with grade 3/4 neutropenia occurring in 30% of patients. Infection rates were consistent with other dual treatments, with 19% of patients experiencing grade 3 or higher infections, although 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 new investigational BCL-2 inhibitor, has also shown promise in the treatment of relapsed/refractory multiple myeloma. Sikander Aylawadi, MD, of the Mayo Clinic in Jacksonville, Florida, emphasized its potential: “BCL-2 remains an important therapeutic target in myeloma, especially for patients who have limited options. Lisaftoclax offers a unique mechanism of action, which combines effective and positive impact.
The current one Phase I/II trial lisaftoclax has been evaluated 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% having prior exposure to CD38-targeted therapies.
Among 36 evaluable patients treated with lisaftoclax plus PD, the ORR was 64%, with 31% achieving VGPR or better. In the 1,000 mg group, the incidence of disease rose to 89%, with a median progression-free survival of more than 11 months. “These results are particularly encouraging in patients previously exposed to CD38-targeted therapies,” Elwadi explained, highlighting the probability of response rate of 62% in this subgroup, which rose to 87% with the 1,000 mg dose.
The safety profile of Lisaftoclax also supports its long-term use. The most common hematological adverse events were grade 3/4 neutropenia (44%) and anemia (17%), although these were manageable. Non-hematological toxicities were mostly grade 1 or 2, with only 15% of patients developing pneumonia. Importantly, the discontinuation rate due to toxicity was less than 5%. “What is noteworthy is that lisavoclax achieves safety at high doses, something that other BCL-2 inhibitors have struggled with,” Aylawade added.
He pointed out that continued registration and dose optimization will confirm the role of lisavoclax in expanding treatment options for this disease.
Trispecific antibodies
Finally, the introduction of trispecific antibodies represents a new frontier in immunotherapy for relapsed/refractory multiple myeloma, with ISB 2001 leading the charge. This T cell engagement It simultaneously targets BCMA, CD38, and CD3, enhancing tumor-specific cytotoxicity while minimizing off-target effects.
“The high-affinity dual binding of ISB 2001 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 in Melbourne, Australia. . “In addition, the unique anti-CD38 region avoids competition with daratumumab, a monoclonal antibody commonly used in the treatment of multiple myeloma.”
The ongoing phase 1 human trial includes patients with previously relapsed/refractory multiple myeloma who have had a median of six prior lines of treatment. The results to date are very promising: the ORR in all groups was 75%, with 65% achieving VGPR or better and 20% achieving CR or better. Responses were observed starting at low doses (50 mcg/kg) and improved as doses were escalated, with patients at dose levels 3-7 showing a CPR of 83%. Responses were durable, with some lasting more than 9 months, and deepened over time, with one patient achieving minimal residual disease negativity.
Safety data showed a positive profile, with no dose-limiting toxicities and minimal neurological 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 reach CRS was only 3 days, the median lasted 2 days, and most events were limited to the first ascending dose,” Quach noted.
Importantly, no cases of immune cell-associated neurotoxicity syndrome were observed, and hematological toxicities such as grade 3/4 neutropenia occurred in only 30% of patients.
ISB 2001 has also proven effective in difficult-to-treat patient subgroups. In those refractory to previous CD38-targeted therapies, the ORR was 86%, and was 100% in patients who progressed on anti-CD38 therapies within the past 6 months. Likewise, patients previously exposed to BCMA-targeted therapies or T-cell redirection therapies achieved an ORR of 75%. Responses were higher (90% ORR) in patients naive to these treatments, with 30% achieving a CR or better.
“These results indicate that ISB 2001 has significant activity regardless of previous treatments and shows particular promise in patients with high unmet needs,” Quash said.
As dose escalation continues, the planned expansion phase will focus on optimizing dosing and evaluating less frequent administration schedules, which may improve patient comfort and quality of life.
Disclosures
Richter reports financial relationships with Janssen, Bristol-Myers Squibb, Sanofi, Adaptive Biotechnologies, Karyopharm, Genentech, AbbVie, Regeneron, Takeda, and Pfizer.
Ailawadhi has established financial relationships with Ascentage, Bristol Myers Squibb, Xencor, Regeneron, AbbVie, Johnson & Johnson, Celectar, Amgen, BeiGene, Takeda, GSK, Sanofi, Janssen, and Pharmacyclics.
Quach has established financial relationships with Johnson & Johnson, Roche, Pfizer, Sanofi, Bristol-Myers Squibb, Karyopharm, GSK, and AbbVie.