Dr Jagannath on the Potential Utility of Linvoseltamab in R/R Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses the potential utility of treatment with linvoseltamab in patients with triple-class–exposed, relapsed/refractory multiple myeloma.

in a matching-adjusted indirect comparison study

, linvoseltamab was compared with teclistamab-cqyv (Tecvayli) in patients with this disease, and findings presented at the 2024 ASCO Annual Meeting. Investigators reported that linvoseltamab may provide greater efficacy for patients compared with teclistamab for all outcomes, highlighting its potential as a highly effective treatment option.

The FDA is expected to make a decision regarding the potential approval of linvoseltamab for patients with relapsed/refractory multiple myeloma, Jagannath begins. This agent is a fully human bispecific antibody designed with patient convenience and safety in mind, Jagannath says. The administration regimen is carefully structured to maximize patient outcomes and minimize risks, according to Jagannath. Initially, linvoseltamab is given more frequently, but a unique aspect of this regimen is that after 6 months, patients who achieve a complete response (CR) or very good partial response (VGPR) have their dosing frequency reduced to once a month, Jagannath explains. This reduction in dosing frequency is particularly important as it correlates with a decreased risk of infection, which is a significant concern with many treatments, he reports.

In the first week of dosing, the drug is administered on day 1 and day 8, with only a 24-hour hospitalization required for monitoring, Jagannath continues. This minimal hospitalization requirement during the step-up dosing phase underscores the thoughtful design of the drug’sadministration protocol, which prioritizes patient comfort and safety, he states.

Moreover, after the initial 14 weeks of treatment, the dosing frequency is further reduced to every 2 weeks, he continues. By the 6-month mark, patients who have achieved CR or VGPR move to a maintenance phase where the drug is administered once every 4 weeks. This extended dosing interval is convenient for patients and is associated with a dramatic reduction in infection rates, highlighting the compound’s favorable safety profile as demonstrated in clinical trials, Jagannath explains. Linvoseltamab, therefore, offers a promising combination of efficacy and safety, with a well-considered administration schedule that could greatly benefit patients, he concludes.

Videos

Sundar Jagannath, MBBS, discusses the potential use of linvoseltamab in patients with triple-class–exposed, relapsed/refractory multiple myeloma.

Dr Jagannath on Linvoseltamab vs Teclistamab in Triple-Class–Exposed R/R Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses findings from 

an indirect comparison of linvoseltamab and teclistamab-cqyv (Tecvayli

 in patients with triple-class–exposed, relapsed/refractory multiple myeloma.

Jagannath shared data from the indirect comparison at the 

. Both linvoseltamab and teclistamab are bispecific antibodies targeting CD3 on T cells and BCMA on multiple myeloma cells. Using a matching-adjustedindirect comparison approach, patient-level data from the phase 1/2 LINKER-MM1 trial (NCT03761108) of linvoseltamab in patients with relapsed/refractory multiple myeloma and aggregate data from the phase 1/2 MajesTEC-1 trial (NCT03145181, NCT04557098) of teclistamab in this patient population were analyzed. After matching key prognostic factors, linvoseltamab elicited significantly better efficacy vs teclistamab in terms of complete response (CR) rates, progression-free survival, and time to next therapy.

Linvoseltamab is currently in development to address the needs of patients with triple-class–exposed, relapsed/refractory multiple myeloma who have undergone 3 or more prior lines of therapy, akin to the teclistamab indication, Jagannath begins. To ensure the comparability of patient cohorts in this analysis, a matching process was undertaken based on key prognostic factors identified beforehand, he says. The top 6 significant prognostic factors were identified and evaluated, he says.

Upon evaluating these efficacy outcomes, linvoseltamab was superior to teclistamab across various predetermined parameters, Jagannath explains. Subsequent analyses incorporating all identified prognostic factors reaffirmed linvoseltamab’s favorable performance, particularly in terms of overall response and depth of response, with a notable increase in CR rate, Jagannath reports.

Furthermore, linvoseltamab has a promising safety profile, he states. Specifically, it exhibits lower incidences of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome compared with other drug classes, such as CAR-T cell therapy, he explains. Jagannath concludes by stating that this favorable safety profile further underscores the potential of linvoseltamab as a valuable therapeutic option for the specified patient population.

Sundar Jagannath, MBBS, discusses outcomes with linvoseltamab vs teclistamab in patients with triple-class–exposed, relapsed/refractory multiple myeloma.

Dr Jagannath on Safety Considerations With Ide-Cel in Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses takeaways from the FDA’s Oncologic Drugs Advisory Committee (ODAC) Meeting 

on the safety considerations with idecabtagene vicleucel (ide-cel; Abecma)

 in patients with relapsed/refractory multiple myeloma.

On March 15, 2024, the ODAC voted 8 to 3 that the benefits of ida-cel outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

 of ide-cel in patients with relapsed/refractory multiple myeloma, investigators revealed key findings regarding patient survival and treatment complications, Jagannath begins. Similar to allogeneic transplants, some patients experienced infections or other complications despite responding to the treatment. Although there were initial cases of mortality, over time, survival rates improved significantly as patients achieved deep responses, he reports.

Notably, the study involved patients who had undergone 2 to 4 lines of therapy, making their conditions similar to those of late-line therapy patients, he continues. This similarity was due to the upfront use of treatments such as carfilzomib; however, despite these complexities, the study criteria were met, warranting the April 2024 

 for this indication, Jagannath explains.

A particularly impressive aspect of the study was the patient feedback, according to Jagannath. Many patients expressed that ide-cel was life-changing, describing it as a “one and done” treatment that restored their quality of life, Jagannath states. Patients also reported experiencing deep remission without the need for subsequent maintenance therapies, feeling as they did before their multiple myeloma diagnoses. This profound impact on their lives highlighted the importance of making this treatment option widely available to patients, he emphasizes.

Overall, KarMMA-3 demonstrated the significant benefits of ide-cel, showing it as a viable treatment option that could greatly improve the lives of patients with multiple myeloma, Jagannath concludes.

Sundar Jagannath, MBBS, discusses the FDA’s ODAC Meeting on safety considerations with ide-cel in multiple myeloma.

Dr Jagannath on the ODAC Meeting on the Safety of Cilta-Cel in R/R Multiple Myeloma 

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses takeaways from the FDA’s Oncologic Drugs Advisory Committee (ODAC) Meeting on the safety considerations with ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with relapsed/refractory multiple myeloma.

At the ODAC Meeting, the committee voted 11 to 0 that the benefits of cilta-cel outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory drug, and who are refractory to lenalidomide (Revlimid). Notably, data from the phase 3 CARTITUDE-4 trial (NCT04181827) spurred this conversation.

Jagannath begins by saying that in this trial, several patients who were randomly assigned to the control arm and received physician’s choice of standard-of-care (SOC) treatment experienced early disease progression and/or mortality, which raised questions. Specifically, it was noted that patients in the control arm may have been more likely to discontinue trial participation earlier than those in the cilta-cel arm due to awareness of not receiving the CAR T-cell therapy, leading to increased censoring of data in this group, according to Jagannath. This was attributed to the open-label nature of the study, potentially influencing patient decisions to withdraw from the study, he explains.

Furthermore, some patients who experienced disease progression on the control arm sought alternative treatments, including cilta-cel, which was already prepared for those who were randomly assigned to the CAR T-cell therapy arm, Jagannath emphasizes. Although initial outcomes with cilta-cel may appear concerning, survival rates in those who ultimately received the intended cilta-cel therapy were significantly improved over those in patients who received SOC, aligning with patterns seen with other complex medical interventions, he reports.

The consensus among the ODAC committee members was that the study design adequately demonstrated favorable progression-free survival and overall survival outcomes with cilta-cel vs SOC, Jagannath continues. They acknowledged the statistical end points defined by the study and recognized the impact of early events on trial outcomes. Ultimately, the committee felt confident in concluding that the studied drugs had successfully met their end points, he concludes.

Sundar Jagannath, MBBS, discusses takeaways from the FDA’s ODAC consensus on safety considerations with cilta-cel in relapsed/refractory multiple myeloma.

Dr Jagannath on the Safety of Linvoseltamab in Relapsed/Refractory Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses the safety profile of linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma.

the phase 1/2 LINKER-MM1 trial (NCT03761108) were shared

, including safety considerations for the use of the agent. The safety data shed light on key aspects of BCMA-directed bispecific antibody therapy, Jagannath begins, saying one notable consideration with this class of medications is the risk of cytokine release syndrome. Additionally, the trial revealed that low blood counts, particularly neutropenia and anemia, were common adverse effects that require careful monitoring. The depletion of normal plasma cells poses a risk of infection due to reduced antibody production in response to pathogens, he explains.

Neutropenia and anemia were observed during the study, and 73% of patients experienced infections of any grade, with 34% of patients experiencing grade 3/4 infections, Jagannath reports. The trial involved initial weekly dosing for the first 14 weeks, then biweekly dosing from weeks 16 to 23, followed by monthly dosing at 24 weeks for patients achieving very good partial response (VGPR) or better.

The study’s infection rate analysis demonstrated a well-structured design, he says. Infections were more frequent during the first 6 months of treatment, with any-grade infection rates decreasing over time, he expands. Notably, the rate of grade 3/4 infections, which is a significant concern, decreased between the 0-to-3-month and 6-to-9-month periods, reflecting a trend toward improved infection management and decreased severity with continued treatment, Jagannath emphasizes. The treatment responses observed in the trial, including a median time to partial response or better of 4 weeks (range, 0.5-6.3) and a median time to VGPR or better of 2.6 months (range, 0.7-13.1), contributed to the reduction in infection rates over time. The study’s proactive approach to infection management included allowing patients to receive prophylactic antibiotics, he concludes.

Sundar Jagannath, MBBS, discusses the safety of linvoseltamab in relapsed/refractory multiple myeloma.

Dr Jagannath on the Safety Considerations With CAR T-Cell Therapy Multiple Myeloma 

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses considerations to keep in mind prior to CAR T-cell therapy initiation in the management of multiple myeloma treatment during relapse.

Jagannath begins by stating that key factors to influence therapeutic decisions encompass treatment availability, ongoing clinical trial participation, patient preference, and safety concerns. In early relapse scenarios, an array of effective treatment options can include pomalidomide and investigational agents, he explains, saying that these approaches remain accessible, underscoring that there are other treatment options available in the first-line if CAR T-cell therapy is not available.

Jagannath notes that academic centers afford patients access to evolving clinical trials, fostering continued therapeutic advancement. Patient-centric preferences delineate a spectrum of inclinations, with some favoring CAR T-cell therapy as a last option, seeking alternative approaches, remaining wary of potential adverse effects (AEs) and hospitalization burdens, he explains.

Crucially, the temporal relationship between tumor burden and CAR T-cell administration significantly influences safety outcomes, Jagannath continues. Notably, administering CAR T-cell therapy during a phase of controlled disease burden may relate to a diminished risk of cytokine release syndrome (CRS) and neurotoxicity.

The effectiveness of CAR T-cell therapy in relation to the proportional to tumor burden emphasizes the importance preemptive disease control in relation to mitigating AEs, he expands. Jagannath emphasizes the overarching objective of enhancing patients survival by optimizing CAR T-cell therapy safety and efficacy, particularly in those who can receive the therapy in an earlier line of treatment, leading to an improved life expectancy for all patients with multiple myeloma.

With robust therapeutic options available for both initial and subsequent relapses, judicious timing of CAR T-cell therapy administration represents a strategic avenue to augmenting long-term outcomes in multiple myeloma management, Jagannath concludes.

Sundar Jagannath, MBBS, discusses CAR T-cell therapy considerations prior to initiation in the management of multiple myeloma.



Dr Jagannath on the Patient Population in the LINKER-MM1 Trial in Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor, medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses the patient population 

evaluated in the phase 1/2 LINKER-MM1 trial

 (NCT03761108) of linvoseltamab (REGN5458) in relapsed/refractory multiple myeloma.

The patient characteristics of those enrolled in the LINKER-MM1 trial reveal a cohort that mirrors the demographic diversity and disease severity often encountered in real-world multiple myeloma populations, Jagannath begins. A total of 117 patients received the 200 mg dose of linvoseltamab across the phase 1 and phase 2 portions of the study. Additionally, 17.1% of the patients identified as African American, indicating a patient representation that aligns with the broader United States population, a factor significant for assessing external validity in clinical trials, he reports.

A notable inclusion criterion was the prerequisite for patients to have undergone at least 3 prior lines of therapy, including exposure to an immunomodulatory drug, a proteasome inhibitor, and daratumumab (Darzalex), Jagannath explains, saying that such requirements highlight the advanced disease state of the enrolled population. Moreover, the study design specifically allowed for inclusion of patients who were double refractory in the phase 1 portion and expanded to those who were triple-class refractory in phase 2, he notes.

The severity of disease burden was further evidenced by other clinical characteristics. Many patients had bone marrow infiltration exceeding 50% by plasma cells, indicating extensive myeloma involvement. The median soluble BCMA level, a marker correlating with tumor burden, was notably elevated at 368.0 ng/mL, with a broad range spanning from 18.7 ng/mL to 4430.0 ng/mL across patients, Jagannath expands. This collectively points to a population burdened by high tumor activity, a key consideration for understanding treatment response and outcomes, according to Jagannath.

Incorporation of patients with extramedullary disease, confirmed through independent review committee adjudication, further highlights the comprehensive spectrum of disease manifestations within the study cohort, he continues. The inclusion of diverse patient profiles aligns with the external validity criteria essential for regulatory evaluations, particularly for potential FDA assessments, Jagannath says. The study's ability to reflect the real-world patient population lends credence to the potential generalizability of findings to broader patient populations, Jagannath concludes.

Sundar Jagannath, MBBS, discusses the patient population evaluated in the LINKER-MM1 trial of linvoseltamab in relapsed/refractory multiple myeloma.

Sundar Jagannath, discusses the potential role for linvoseltamab in relapsed/refractory multiple myeloma.

Dr Jagannath on the Potential Role for Linvoseltamab in R/R Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor of medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses the potential role for linvoseltamab (REGN5458) in relapsed/refractory multiple myeloma, as well as the agent's continued investigation in this space.

 of the ongoing, open-label, multicenter, dose-escalation and -expansion phase 1/2 LINKER-MM1 trial (NCT03761108), treatment with 200 mg of linvoseltamab resulted in a 71% independent review committee–assessed objective response rate, which included a 46% rate of complete response (CR) or better. The median follow-up was 11.1 months.

Based on these data, investigators are hoping for the early approval of linvoseltamab in this population, Jagannath confirms. On February 21, 2024, the 

FDA granted priority review to linvoseltamab

 (REGN5458) for the treatment of adult patients with relapsed/refractory multiple myeloma who have progressed after 3 or more prior lines of therapy.

Jagannath emphasizes his confidence in these phase 1/2 findings. When looking at data from phase 3 studies supporting recent approvals of other CAR T-cell products in multiple myeloma, the median progression-free survival was often not reached, whereas the median PFS was approximately 3 months with standard chemotherapy, he states. Accordingly, efficacy outcomes with linvoseltamab are similar to that of other CAR T-cell products, further supporting its approval, he explains.

Equally significant is linvoseltamab's safety profile, Jagannath continues. The regimen's design, necessitating only 2 24-hour hospitalization sessions, aims to minimize treatment-related adverse effects. Importantly, this approach has resulted in a low infection rate of 5% after 6 months, positioning linvoseltamab favorably in terms of safety considerations compared to other intensive CAR T-cell therapies, Jagannath says.

The ongoing phase 3 LINKER-MM3 trial (NCT05730036) will further evaluate the efficacy and safety of linvoseltamab in this patient population, Jagannath adds. These forthcoming phase 3 trial results will be pivotal in confirming linvoseltamab's role in the evolving treatment landscape for this challenging disease setting, he concludes.

Dr Jagannath on the Mechanism of Action of Linvoseltamab in R/R Multiple Myeloma

Sundar Jagannath, MBBS, director, Center of Excellence for Multiple Myeloma, professor of medicine (hematology and medical oncology), The Tisch Cancer Institute, Mount Sinai, discusses the mechanism of action of linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma and how the dosing schedule of this agent reflects its tolerability.

Linvoseltamab is a bispecific antibody that binds to both BCMA and CD3, bringing the patient’s T cells in close proximity to cancer cells and promoting their destruction, Jagannath says. Since 2 BCMA-directed bispecific antibodies are already FDA approved for patients with multiple myeloma, oncologists are already familiar with the efficacy of these agents, Jagannath notes. 

 in October of 2022 for patients with relapsed/refractory multiple myeloma who had received at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. 

 for the same indication in August of 2023. The phase 1/2 LINKER-MM1 trial (NCT03761108) is evaluating linvoseltamab in patients with multiple myeloma who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, or those who had double- or triple-class– refractory disease.

Linvoseltamab is a fully humanized antibody, which distinguishes it from other bispecific antibodies, Jagannath explains. Furthermore, patients only need to be admitted to the hospital for 2 24-hour infusions of linvoseltamab during the weekly step-up dosing phase, since the agent demonstrated a tolerable adverse effect profile in LINKER-MM1, Jagannath emphasizes. During step-up dosing, patients receive 5 mg of linvoseltamab on day 1 and 25 mg of the agent on day 8. Beginning at week 3, when patients receive the agent at 200 mg once a week, they do not need to be admitted to the hospital. Furthermore, instances of cytokine release syndrome associated with linvoseltamab have been manageable, according to Jagannath. Therefore, this agent can be administered mostly in outpatient settings, with minimal hospitalization required, Jagannath says.

Sundar Jagannath, MBBS, discusses the mechanism of action and tolerability of linvoseltamab in patients with relapsed/refractory multiple myeloma.

Sundar Jagannath, MBBS, director of the Center of Excellence for Multiple Myeloma and a professor of medicine (hematology and medical oncology) at The Tisch Cancer Institute, Mount Sinai, discusses the FDA approval of ciltacabtagene autoleucel (cilta-cel; Carvykti) in relapsed/refractory multiple myeloma.

FDA approved cilta-cel for the treatment of adult patients with relapsed/refractory multiple myeloma

 following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The approval was based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which demonstrated an objective response rate of 98% (95% CI, 92.7%-99.7%) with cilta-cel in this patient population. Additionally, the stringent complete response rate was 78% (95% CI, 68.8%-86.1%). The median duration of response was 21.8 months at a median follow-up of 18 months.

Updated findings from the study, which were presented at the 2021 ASH Annual Meeting and Exposition, demonstrated progression-free survival and overall survival rates of 60.5% and 74.0% at a median follow-up of 2 years, respectively. These data exceed historical responses with other novel agents, such as selinexor (Xpovio) and belantamab mafodotin-blmf (Blenrep), rendering the approval a significant breakthrough in multiple myeloma management that brings the field one step closer to cure, Jagannath concludes.

Sundar Jagannath, MBBS, discusses the FDA approval of ciltacabtagene autoleucel in relapsed/refractory multiple myeloma.

Sundar Jagannath, MBBS

Articles