Multiple Myeloma Awareness Month: Modern Treatment and Unmet Needs

March is multiple myeloma (MM) awareness month, and many clinicians are pushing for novel treatment options to accelerate the journey toward a cure. Blood Cancers Today spoke with Brandon Blue, MD, an assistant member and clinical instructor in the Department of Malignant Hematology at Moffitt Cancer Center, on best practices in MM, novel agents and combinations, and how the myeloma treatment paradigm can potentially change in 3 to 5 years.

Best Practices in Myeloma

CAR T-Cell Therapy

According to Dr. Blue, the biggest advance in MM is chimeric antigen receptor T-cell therapy (CAR-T). “That’s the wave of the future because it works really well and improves patient quality of life, which is always something we strive for,” he said.

Dr. Blue highlighted the CARTITUDE-4 trial, which evaluated ciltacabtagene autoleucel (cilta-cel), an FDA-approved B-cell maturation antigen (BCMA)–directed CAR-T therapy, versus standard of care (SOC) for patients with lenalidomide-refractory MM after 1 to 3 lines of therapy. Cilta-cel resulted in a significantly lower risk of disease progression or death than SOC (hazard ratio [HR], 0.26; 95% CI, 0.18-0.38; P<0.001).¹

At a median follow-up of 15.9 months, the median progression-free survival (PFS) was not reached in the cilta-cel group and was 11.8 months in the SOC group. In addition, more patients in the cilta-cel group achieved a complete response or better compared with those in the SOC group (73.1% vs 21.8%, respectively) for a risk ratio of 2.9  (95% CI, 2.3-3.7; P<0.001).¹ As for safety, grade 3 or 4 adverse events occurred in 96.6% of patients in the cilta-cel group and 94.2% of those  in the SOC group.¹

A second interim analysis of CARTITUDE-4 presented at the 66th American Society of Hematology Annual Meeting & Exposition showed that cilta-cel also led to higher rates of measurable residual disease negativity compared with SOC (57% vs 12%, respectively; P<0.0001).²

Immunomodulatory Agents Plus CAR-T

The addition of immunomodulatory agents to CAR-T is also being evaluated in MM, Dr. Blue noted. A single-center, retrospective study published in the Journal of Translational Medicine found that pomalidomide, a third-generation immunomodulatory agent, improved the antitumor efficacy of BCMA CAR-T therapy for patients with relapsed or refractory MM in the third-line or later setting.³

Of 16 enrolled patients, 8 received pomalidomide before CAR-T and 8 did not. Two patients who received pomalidomide were lost to follow-up. Three months after CAR-T, all 6 remaining patients (100%) who received pomalidomide achieved a very good partial response or better compared with 5 of 8 patients (62.5%) who did not receive pomalidomide.³ The median time to progression was 13 months in the pomalidomide arm compared with 5.85 months in the control arm (P=0.0166). The overall survival (OS) was not reached in the pomalidomide arm compared with 10.7 months in the control arm (P=0.0068).³

“Myeloma is not curable,” Dr. Blue said. “We know the disease is going to come back. However, we’re trying to combine things with CAR-T to see if we can improve the duration of CAR-T. I think that’s getting us closer and closer to finding the cure for myeloma because there’s no 1 single medication that’s going to be the answer for a cure.”

Bispecific T-cell Engagers

Dr. Blue also highlighted bispecific T-cell engagers (BiTEs) for the treatment of MM. In a real-world database study, both BCMA-targeted BiTEs and non–BCMA-targeted BiTEs in monotherapy and in combination with daratumumab demonstrated longer PFS compared with SOC (19.2 vs 5.4 months, respectively; HR, 0.50; 95% CI, 0.33-0.78; P<0.01). However, the OS was not significantly different.⁴

More than half of patients (52%) in the BiTE cohort experienced cytokine release syndrome, and infections were more common in the BiTE cohort than in the SOC cohort (81% vs 49%; P<0.01).⁴

“CAR-T, while amazing, isn’t for everyone,” Dr. Blue said. “It’s good to know that we also have options for people where CAR-T might not be the right choice.”

A Shifting Treatment Paradigm

Looking forward, Dr. Blue believes the biggest change to look for in the next 3 to 5 years is having novel therapies, such as CAR-T or bispecific antibodies, available for patients at the beginning of their myeloma journey.

“Right now, they’re typically approved for people who have relapsed disease,” he explained. “But, I think it would be exciting if someone has newly diagnosed MM, gets a CAR-T or bispecific, and still maintains a very high quality of life. That would be a big win for patients.”

For Dr. Blue, the biggest unmet need for patients with myeloma is perfecting novel combinations and sequencing therapies. “If someone gets several years of disease control from CAR-T, can they potentially get another one?” he posed. “We don’t know what that looks like or what order should they go in. The good thing is that we have so many options, but we don’t know the right order, and the order may be different depending on the type of myeloma. We have all these tools, but how do we play with them in the right way to get the best result?”

References

1. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
2. Popat R, Oriol A, Cavo M, et al. Ciltacabtagene autoleucel (cilta-cel) vs standard of care (SoC) in patients with lenalidomide (len)-refractory multiple myeloma (MM) after 1-3 lines of therapy: minimal residual disease (MRD) negativity in the phase 3 CARTITUDE-4 trial. Abstract #1032. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.
3. Yan Y, Tu Y, Cheng Q, et al. BCMA CAR-T therapy combined with pomalidomide is a safe and effective treatment for relapsed/refractory multiple myeloma. J Transl Med. 2024;22(1):1087. doi:10.1186/s12967-024-05772-w
4. Choi S, Byun JM, Park SS, et al. Efficacy and safety of bispecific T-cell engagers in relapsed/refractory multiple myeloma: a real-world data-based case-controlled study. Transplant Cell Ther. 2025;31(2):74.e1-74.e11. doi:10.1016/j.jtct.2024.11.010