A New Era In Multiple Myeloma Treatment: Advances and Future Directions

Multiple myeloma treatment has undergone a dramatic transformation in recent years, ushering in a new era of therapeutic possibilities. With the emergence of advanced immunotherapies and targeted agents, we have entered a new therapeutic era—particularly for patients with relapsed/refractory disease. Outcomes are improving, deeper remissions are becoming more common, and there is increasing discussion around the possibility of functional cures for select patient populations.

A Look at the Novel Therapeutic Landscape

CAR T-Cell Therapy

CAR T-cell therapy has redefined the prognosis for many patients with heavily pretreated disease. Idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) have demonstrated high response rates and durable remissions in patients with triple- or penta-refractory multiple myeloma. The FDA first approved ide-cel in March 2021 for the treatment of patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, which included an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.1 In February 2022, the FDA approved cilta-cel for the treatment of patients with relapsed/refractory multiple myeloma following 4 or more lines of treatment, including an IMiD, a PI, and an anti-CD38 monoclonal antibody.2 Both CAR T-cell therapies were approved in April 2024, which reflected utilizing ide-cel and cilta-cel in earlier lines of therapy. Ide-cel was specifically approved for the treatment of patients with relapsed/refractory multiple myeloma following 2 or more prior lines of therapy, including an IMiD, a PI, and an anti-CD30 monoclonal antibody.3 In a similar trend, cilta-cel was approved for the treatment of patients with relapsed/refractory multiple myeloma who were previously treated with at least 1 line of therapy, including an IMiD, a PI, and those who were refractory to lenalidomide (Revlimid).4

While logistical challenges— such as T-cell harvesting, manufacturing time, and insurance barriers— remain, the clinical impact of these therapies is undeniable. Toxicity, particularly cytokine release syndrome and neurotoxicity, requires vigilance and experienced management.

Bispecific Antibodies

Bispecific T-cell engagers represent a compelling alternative, offering off-the-shelf access compared with autologous CAR T cells. Agents such as teclistamab (targeting BCMA; Tecvayli), elranatamab (BCMA; Elrexfio), and talquetamab (GPRC5D; Talvey) are demonstrating strong efficacy, even in patients with refractory disease. These therapies are also being tested in earlier lines, with the potential to replace or augment current standard regimens.

Antibody-Drug Conjugates

Belantamab mafodotin (Blenrep), an anti-BCMA antibody-drug conjugate, initially offered a novel option for relapsed/refractory multiple myeloma when it was FDA-approved in August 2020, but was withdrawn from the US market because the phase 3 DREAMM-3 trial (NCT04162210) did not meet its primary end point of progression-free survival.5 However, clinical refinement in dosing and ocular toxicity management may support its return in a revised form. Its unique mechanism could reestablish its place as part of a multimodal strategy.

XPO1 Inhibitors

Selinexor (Xpovio), an oral selective inhibitor of nuclear export (XPO1), has been incorporated into treatment regimens for relapsed/refractory disease, typically in combination with PIs or IMiDs. Although it is not curative, its inclusion has broadened the armamentarium and provided options for patients whose disease is more difficult to treat.

These advancements herald a new era in multiple myeloma treatment, characterized by deeper and more durable remissions. Emerging data indicate higher rates of minimal residual disease negativity, particularly with CAR T-cell therapies and bispecific antibodies. Although still rare, the possibility of functional cures is becoming a reality, with some patients experiencing long-term, treatment-free remission after CAR T-cell therapy. The expanding therapeutic arsenal allows for increasingly personalized treatment pathways, tailoring therapies based on prior treatment exposures, individual mutational profiles, and comorbidities. Furthermore, ongoing clinical trials are evaluating the use of novel therapies in earlier treatment lines, potentially reshaping the role of autologous stem cell transplantation (ASCT) and solidifying this new era of improved outcomes in multiple myeloma.

The pace of discovery in multiple myeloma is accelerating. In the near term, several shifts are anticipated that could further improve patient outcomes, including the following:

• Earlier use of immunotherapies: Clinical trials are exploring CAR T-cell and bispecific therapies earlier in the disease course. If data continue to show high efficacy and manageable toxicity, we may see a paradigm shift toward earlier immunebased interventions.
• Post-transplant immune modulation: Leveraging bispecific antibodies and other immune-targeted therapies in the post-ASCT setting could enhance consolidation and delay relapse.
• Next-generation agents: Improved versions of CAR T cells, including dual-targeting constructs and allogeneic platforms, are on the horizon. Likewise, novel bispecific antibodies with extended half-lives and improved safety profiles are in development.
• Biomarker-guided precision medicine: Genomic and molecular profiling is beginning to guide treatment decisions. As more validated biomarkers emerge, expect a shift toward stratified therapy, especially for high-risk cytogenetics or extramedullary disease.
• Optimized combination regimens: Ongoing studies are refining how novel agents can be best combined with existing standards—such as IMiDs, PIs, and monoclonal antibodies—to increase response depth and duration.
• Enhanced quality of life: A growing focus is being placed on treatment tolerability, minimizing steroid burden, and maximizing time off therapy. Patient-reported outcomes will continue to influence drug development and regulatory decisions.
• Outpatient delivery of complex therapies: Many centers are transitioning select patients to outpatient administration of CAR T-cell and bispecific antibody therapies, improving convenience and resource utilization.

We are witnessing a renaissance in multiple myeloma therapy, marked by unprecedented options and optimism. While a cure remains elusive for most, the trajectory is unmistakably upward, with longer remissions, fewer complications, and a more nuanced approach to each patient’s disease.

As this field continues to evolve, staying abreast of trial data, novel approvals, and real-world outcomes will be critical. The future of multiple myeloma management lies in balancing efficacy with safety, access with personalization, and innovation with equity.

References

1. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 29, 2021. Accessed June 26, 2025. https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-approves-idecabtagenevicleucel- multiple-myeloma
2. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. Updated March 7, 2022. Accessed June 26, 2025. https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-approvesciltacabtagene- autoleucel-relapsed-or-refractory-multiple-myeloma U.S. FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb. April 5, 2024. Accessed June 26, 2025. https://news.bms.com/news/details/2024/ U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for- Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two- Prior-Lines-of-Therapy/default.aspx
3. Carvykti is the first and only BCMA-targeted treatment approved by the U.S. FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 6, 2024. Accessed June 26, 2025. https://www.jnj.com/ media-center/press-releases/carvykti-is-the-first-and-only-bcma-targetedtreatment- approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractorymultiple- myeloma-who-have-received-at-least-one-prior-line-of-therapy
4. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated March 7, 2024. Accessed June 26, 2025. https://www.fda.gov/drugs/resources-information-approveddrugs/ fda-granted-accelerated-approval-belantamab-mafodotinblmf- multiple-myeloma