The Rapid Evolution of Multiple Myeloma Treatment in Recent Years

Multiple myeloma, once considered a disease with a poor prognosis, has experienced a revolution in treatment over the past decade with the emergence of new approaches, such as CAR T-cell therapy and bispecific T-cell engagers. As other novel therapies progress through the development pipeline, investigators will have to consider a variety of patient-specific factors when selecting and sequencing treatments, but the future of the field is bright.

“In 2025, the outcome for [a patient] who is diagnosed with myeloma is much better than it ever was, particularly because of the advent of new treatments, but also because we have better diagnostic tools,” Rafael Fonseca, MD, director for Innovation and Transformational Relationships, at Mayo Clinic in Phoenix, Arizona, said in an interview with OncLive®. “In the 1990s, it was a disease with a median [overall] survival [OS] of [approximately] 2 years. In 2025, survival should be measured in [terms of] 10 to 15 years, or more. In fact, I very carefully discuss with patients that there is a fraction of patients who, with the current treatments, we will consider as cured, especially as we look into the future.”

Frontline treatment is still very much centered around autologous stem cell transplant (ASCT) for eligible patients, often given in combination with melphalan. First-line therapy for these patients usually follows the induction, transplantation, consolidation, and maintenance treatment blueprint, which has been the standard of care for approximately 20 years.1,2 However, the emergence of combination regimens in recent years for use in transplant-eligible patients has built on this blueprint to further improve outcomes for patients.

Chief among these is the triplet of the proteasome inhibitor (PI) bortezomib (Velcade) plus the immunomodulatory drug (IMiD) lenalidomide (Revlimid), and dexamethasone (VRd), which was examined in combination with ASCT in newly diagnosed patients with multiple myeloma in the phase 3 IFM/DFCI2009 study (NCT01191060).2 Data from the trial showed that VRd plus ASCT (n = 350) led to a median progression-free survival (PFS) of 50 months vs 36 months for VRd alone (n = 350), conferring a reduction in the risk of progression or death of 35%.

Another major development was the introduction of quadruplet therapy in the frontline setting with the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex) to VRd and ASCT. Data from the phase 2 GRIFFIN study (NCT02874742) showed that patients who received daratumumab plus VRd (n = 99) achieved a stringent complete response rate after ASCT consolidation of 42.4% vs 32.0% in the VRd arm (n = 97; OR, 1.57; 95% CI, 0.87-2.82; 1-sided P = .068), meeting the primary end point of the study.3 In the confirmatory phase 3 PERSEUS study (NCT03710603), transplant-eligible patients who received daratumumab plus VRd experienced a 58% reduction in the risk of death or disease progression compared with VRd alone (HR, 0.42; 95% CI, 0.30-0.59; P < .001).4

“[Some of] the most practice-changing studies of the last 10 years are PERSEUS and GRIFFIN,” Rahul Banerjee, MD, FACP, said in an interview with OncLive. “These studies led the field to quadruplets earlier than expected. There was this concern that giving daratumumab early would rob patients of options later and GRIFFIN helped to just shatter that notion and [indicated] we should give our best drugs at the beginning, especially for conventional treatment. The paradigm has changed from triplets for everybody to quadruplets for transplant-eligible [patients]. Patients who are diagnosed with myeloma in the US today absolutely should be receiving a CD38 [agent] as part of their regimen, whether they are going to transplant or not.”

Banerjee is an assistant professor in the Clinical Research Division at Fred Hutch Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington, both in Seattle. He is also a member of the International Myeloma Working Group.

“There was a time when the categorization of patients into the various risk categories potentially would be critical as we dictate the next line of therapies,” Fonseca added. “But, as the treatments get better, we’re starting to see the lesser importance of risk classification and more importance on just selecting the right treatment [for an individual patient]. Risk stratification remains important, but it has a lesser weight.”

CAR T and Other Cellular Therapies Lead the Way in the 2020s

The first CAR T-cell agent approved for the treatment of patients with multiple myeloma was idecabtagene vicleucel (Abecma; ide-cel), marking a significant shift towards personalized therapy and better outcomes for patients. In March 2021, the agent earned an indication in adult patients with relapsed/refractory disease following at least 4 prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody.5 In April 2024, the indication of ide-cel was expanded to include patients with relapsed/refractory disease after 2 or more prior lines of therapy, including a PI, IMiD, and anti-CD38 monoclonal antibody.6

The latest approval of ide-cel was supported by findings from the phase 3 KarMMa-3 study (NCT03651128).7 Patients who received ide-cel (n = 254) experienced a median PFS of 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) among patients who received 1 of 5 standard treatment regimens (n = 132; HR, 0.49; 95% CI, 0.38-0.65; P < .001). Notably, KarMMa-3 was the only clinical trial to evaluate a CAR T-cell agent in a patient population with entirely triple-class exposed relapsed/refractory multiple myeloma.6

In February 2022, the FDA approved another CAR T-cell therapy, ciltacabtagene autoleucel (Carvykti; cilta-cel) for the treatment of adult patients with relapsed or refractory multiple myeloma after at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.8 Then, in April 2024, the FDA expanded the indication for cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a PI and an IMiD, and who are refractory to lenalidomide.9

The expanded approval of cilta-cel was supported by findings from the phase 3 CARTITUDE-4 study (NCT04181827).10 At a median follow-up of 15.9 months (range, 0.1-27.3), patients who received cilta-cel (n = 208) experienced a median PFS that was not reached compared with 11.8 months (95% CI, 9.7-13.8) among those who received standard-of-care therapies (n = 211; HR, 0.26; 95% CI, 0.18-0.38; P < .001). The 12-month PFS rates were 75.9% (95% CI, 69.4%-81.1%) vs 48.6% (95% CI, 41.5%-55.3%), respectively.

Due to the impressive outcomes that have been seen with CAR T-cell therapies in relapsed/refractory multiple myeloma, there is a desire within the space from investigators to see these agents move into earlier lines of therapy. However, limiting factors such as the cost of the treatments, the need to often receive the therapy in a large academic medical center, and safety concerns with adverse effects (AEs) such as cytokine release syndrome, have slowed this progress.

“Second-line CAR T-cell therapy is here to stay, which [somewhat mirrors] what we do in lymphoma,” Banerjee said. “At first relapse, generally CAR T is considered, especially if it’s within a year of frontline induction, and it makes sense to do something similar in myeloma. The difference between lymphoma and myeloma is that CAR T in myeloma is not perfect; we are not necessarily offering a cure [and] most patients, if they live long enough, will relapse. There is also [the risk of] severe AEs [such as] delayed motor neurotoxicities and second primary malignancies.”

Beyond CAR T-cell agents, teclistamab-cqyv (Tecvayli) became the first BCMA-directed CD3 T-cell engager to earn an FDA approval in multiple myeloma when it received its indication in 2022 for adult patients with relapsed/refractory disease who have received at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.11 The approval was supported by findings from the phase 1/2 MajesTEC-1 study (NCT03145181; NCT04557098), which showed that patients who received teclistamab (n = 110) achieved an overall response rate (ORR) of 61.8% (95% CI, 52.1%-70.9%). At a median follow-up of 7.4 months, the estimated 6- and 9-month duration of response (DOR) rates were 90.6% (95% CI, 80.3%-95.7%) and 66.5% (95% CI, 38.8%-83.9%), respectively.

Another CD3 T-cell engager, talquetamab-tgvs (Talvey), which targets GPRC5D, was approved by the FDA in August 2023 in adult patients with multiple myeloma following at least 4 lines of prior therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.12 In the supporting phase 1 MonumenTAL-1 trial (NCT03399799; NCT4634552), patients who received talquetamab at a weekly dose of 0.4 mg/kg (n = 100) achieved an ORR of 73% (95% CI, 63.2%-81.4%) and those treated with 0.8 mg/kg biweekly (n = 87) had an ORR of 73.6% (95% CI, 63%-82.4%).

“Bispecific antibodies have changed how we think about the treatment of myeloma, and they have many features that make them attractive,” Fonseca said. “Many more patients can be treated with T-cell therapies because of bispecifics vs CAR T because [CAR T] is a bit more niche. Patients with significant comorbidities can do very well with bispecifics. The notion of combination therapy [in the future], based on the concepts of attrition and duration of benefit, are very exciting.”

Outside of bispecific antibodies, isatuximab-irfc (Sarclisa) when combined with standard-of-care VRd became the first anti-CD38 therapy to show a significant reduction in the risk of disease progression or death vs VRd alone for patients with newly diagnosed multiple myeloma not eligible for transplant.13 The regimen was approved in September 2024 for the treatment of adult patients with newly diagnosed disease who are not eligible for ASCT. The approval was supported by findings from the phase 3 IMROZ trial (NCT03319667), which showed that, at a median follow-up of 59.7 months (IQR, 56.0-63.2), patients who received the isatuximab-containing combination (n = 265) experienced a 40% reduction in the risk of progression or death compared with those treated with VRd only (n = 181; HR, 0.60; 98.5% CI, 0.41-0.88; P < .001).14 The 60-month PFS rates were 63.2% vs 45.2%, respectively, and a PFS benefit was observed across most prespecified subgroups.

In Version 1.2025 of the NCCN Clinical Practice Guidelines in Oncology for multiple myeloma, isatuximab plus VRd was added as a category 1 preferred option for patients who are not candidates for transplant and another recommended regimen as primary therapy for transplant candidates.15 Other notable updates to the guidelines included the category 1 recommendations of carfilzomib (Kyprolis) plus lenalidomide and dexamethasone as well as pomalidomide (Pomalyst) with bortezomib and dexamethasone for patients who are refractory to anti-CD38 therapy. VRd, both with and without daratumumab, were also moved to the preferred and other recommended regimens sections, respectively, for primary therapy for transplant candidates as category 1 recommendations.

In light of all the newly available options, in January 2025, the International Myeloma Working Group released their updated committee recommendation on sequencing immunotherapy for multiple myeloma treatment.16 The recommendation aimed to provide clarity on the impact of T-cell redirecting therapies on tumor biology, immune microenvironment, and guidance on optimal sequencing as more patients become exposed to this class of agents. After reviewing historical evidence and clinical trial data, the 30-member panel provided 9 recommendations on optimal immunotherapy sequencing.

1. There are no concerns with using T-cell redirecting therapy in patients who have received a PI, IMiD, monoclonal antibody, corticosteroid, or any combination of these classes in the most recent line of therapy.
2. Avoid collection of mononuclear cells for CAR T-cell manufacturing if feasible for patients receiving a T-cell engager. Aim for a 4-week minimum washout between the last dose of T-cell engager therapy and apheresis.
3. Avoid high-dose alkylators and bendamustine in patients who are likely to receive CAR T and/or a T-cell engager as next therapy.
4. Bridging therapy after CAR T apheresis should be strongly considered in patients with a high disease burden or risk of morbidity during the CAR T manufacturing period.
5. BCMA-directed T-cell redirecting therapy should be pursued first vs BCMA-targeted ADCs in patients who are reasonable candidates for both due to the higher activity of T-cell redirecting therapy and its lower efficacy after treatment with ADCs.
6. In patients who are reasonable candidates for both BCMA-directed CAR T-cell therapy and T-cell engagers, it is recommended to pursue CAR T-cell therapy. As data with T-cell engager combinations and sequential therapy with various antigen targets evolves, this will need to be revisited.
7. T-cell engagers should be used in patients with rapidly progressing disease who are unlikely to transit through apheresis and bridging due to faster access.
8. BCMA-targeted and GPRC5D-targeted immunotherapy is safe and active in patients who have received previous BCMA-targeted CAR T-cell therapy.
9. Therapy with different mechanisms of action or immunotherapy targeting a different antigen for patients progressing on or shortly after receiving BCMA-targeting T-cell engagers is recommended due to limited data on BCMA-targeted therapy of a different modality following disease progression on a BCMA-targeted T-cell engager.

Optimism Abounds as Investigators Look Towards the Future

There are several agents in the development pipeline that have shown promise in multiple myeloma, headlined by belantamab mafodotin-blmf (Blenrep). The BCMA-targeted ADC was previously approved by the FDA in August 2020 as monotherapy in adult patients with relapsed/refractory multiple myeloma who had received at least 4 prior treatments, including a PI, an IMiD, and an anti-CD38 antibody.17 But, in March 2023, the FDA withdrew the biologics license for the agent after data from the confirmatory phase 3 DREAMM-3 trial (NCT04162210) failed to meet its primary end point of PFS.

However, there is hope amongst investigators that belantamab mafodotin will rejoin the multiple myeloma treatment armamentarium. In November 2024, the FDA accepted the biologics license application (BLA) for belantamab mafodotin plus bortezomib and dexamethasone (Vd) and in combination with pomalidomide and dexamethasone (Pd) for the treatment of patients with multiple myeloma who had received at least 1 prior line of therapy.18 The BLA is supported by findings from the phase 3 DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials, both of which met their primary end point of PFS.

Updated findings from DREAMM-7 showed that patients who received belantamab mafodotin with Vd (n = 243) achieved a significant OS benefit vs DVd (n = 251; HR, 0.58; 95% CI, 0.43-0.79; P = .00023).19 At a median follow-up of 21.8 months (range, < 0.1 to 39.2), data from DREAMM-8 showed that patients treated with belantamab mafodotin plus Pd (n = 155) achieved a 48% reduction in the risk of progression or death vs Pd plus bortezomib (n = 147; HR, 0.52; 95% CI, 0.37-0.73; P < .001).20 The FDA Prescription Drug User Fee Act action date for the BLA is set for July 23, 2025.18

“The biggest unanswered question, which is not yet relevant but probably will be in approximately a year, will be [the place of] belantamab mafodotin,” Banerjee said. “[These were] some of the biggest trials of 2024 that have not yet been reflected with an FDA approval. The [data] are very impressive, and I believe belantamab mafodotin will be back on the market. It’s important to note that [CAR T-eligible] patients and [patients eligible for] BCMA bispecific antibodies are 2 very different populations; there is no sequencing involved. If a patient can get BCMA-directed CAR T-cell therapy, they should, and if they cannot get a BCMA CAR T but can get a BCMA-directed bispecific [antibody], they should get the bispecific. If they cannot get either because of age, frailty, lack of a caregiver, etc., that is a scenario where belantamab mafodotin would be a great drug for them.”

Other up-and-coming agents in the multiple myeloma space include investigational BCMA-directed CAR T-cell therapies, bispecific antibodies, and ADCs.21 These agent classes are also being explored with targets of GPRC5D, FcRH5, and CD38. Additionally, novel approaches in the field such as cereblon-E3 ligase modulating agents, anti-SLAMF7 monoclonal antibodies, and CAR and non-CAR natural killer cells are showing promise.

“I’m excited for anitocabtagene autoleucel [anito-cel] in the [phase 3] iMMagine-3 study [NCT06413498],” Banerjee said. “In the [phase 2] iMMagine-1 study [NCT05396885], there have been no cases of delayed neurotoxicity yet, which is interesting. [Anito-cel] has not been randomized against cilta-cel yet, but if there is a future without this small but real risk of delayed neurotoxicity, that would be wonderful. I’m also looking forward to [additional data] from the [phase 1b/2] RedirecTT-1 study [NCT04586426] of teclistamab plus talquetamab. All my relapses in my personal practice within 6 months of cilta-cel have been in patients with visceral extramedullary disease. In these patients, the teclistamab/talquetamab combination seems to do quite well. It may be that for those patients, you need continued pressure and T-cell redirection for months, if not up to 2 years, so that combination will be very interesting [going forward].”

References

1. Marashi M, Al Farsi K, Al Hateeti H, et al. Frontline management of multiple myeloma patients: optimizing treatment for patients in the Gulf region. Clin Hematol Int. 2025;7(1):14-28. doi:10.46989/001c.128113
2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750
3. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/​blood.2020005288
4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
5. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2021. Accessed February 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma
6. 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 February 24, 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
7. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614
8. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. Updated March 7, 2022. Accessed February 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
9. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed February 24, 2025. https://www.jnj.com/media-center/press-releases/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
10. 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
11. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
12. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. Updated August 10, 2023. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma
13. Sarclisa approved in the US as the first anti-CD38 therapy in combination with standard-of-care treatment for adult patients with newly diagnosed multiple myeloma not eligible for transplant. News release. Sanofi. September 20, 2024. Accessed February 24, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-20-22-36-34-2949916
14. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712
15. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2025. Accessed February 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
16. Costa LJ, Banerjee R, Mian H, et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. Published online January 7, 2025. doi:10.1038/s41375-024-02482-6
17. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated March 7, 2024. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma
18. Blenrep combinations accepted for review by the US FDA for the treatment of relapsed/refractory multiple myeloma. News release. GSK. November 25, 2024. Accessed February 25, 2025. https://www.gsk.com/en-gb/media/press-releases/blenrep-combinations-accepted-for-review-by-the-us-fda-for-the-treatment-of-relapsedrefractory-multiple-myeloma/
19. Belantamab mafodotin shows significant overall survival benefit, reducing the risk of death by 42% in multiple myeloma at or after first relapse. News release. GSK. December 9, 2024. Accessed February 25, 2025. https://us.gsk.com/en-us/media/press-releases/belantamab-mafodotin-shows-significant-overall-survival-benefit-reducing-the-risk-of-death-by-42-in-multiple-myeloma-at-or-after-first-relapse/
20. Dimopoulos MA, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med. 2024;391(5):408-421. doi:10.1056/NEJMoa2403407
21. Lin CHT, Tariq MJ, Ullah F, et al. Current novel targeted therapeutic strategies in multiple myeloma. Int J Mol Sci. 2024;25(11):6192. doi:10.3390/ijms25116192