Lonial Spotlights CAR T-Cell and Off-the-Shelf Treatments in Multiple Myeloma

As chimeric antigen receptor (CAR) T-cell therapies and off-the-shelf options with T-cell engagers continue to revolutionize the treatment paradigm in multiple myeloma, several recent regulatory approvals of T-cell engagers are providing more options for improved personalization. With targets such as BCL2 and FcRH5 having a role in determining therapeutic agents, Sagar Lonial, MD, FACP, detailed recent data on targeted agents, CAR T-cell therapies, and off-the shelf agents that may also shed light on how best to incorporate these agents into a potential new sequencing algorithm.

“Treating a patient [who experiences] late relapse is more complicated now than it was 3 years ago [because] we have more options targeting BCMA, options targeting GPRC5D, and [we are] getting comfortable with either referring patients for CAR T-cell [therapy] earlier or referring for T-cell engager therapy earlier,” Lonial said in an interview with OncologyLive^®. “[These] are things that need to be top of mind unless your practice can sustain giving patients T-cell engagers from the get-go or sustain CAR T cells on their own, depending upon the kind of practice setting you’re in. Those are key parts of improving outcomes for patients with myeloma.”

Ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), the CAR T-cell products holding indications in multiple myeloma,^1,2 have continued to demonstrate encouraging results, but new approvals of off-the-shelf agents and the development of targeted therapies such as sonrotoclax (BGB-11417) are generating excitement, according to Lonial (Figure). Lonial is chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine and is the chief medical officer at the Winship Cancer Institute.

Car T-Cell Therapy Shines Vs Soc

“There were a number of trials that came out in the past 12 to 18 months that are driving current treatment practice. The phase 3 trials comparing CAR T cells with standard therapies in earlier lines of therapy—CARTITUDE-4 [NCT04181827] and KarMMa-3 [NCT03651128]—are important studies that are setting the stage for bringing CAR T-cell therapy earlier in the treatment paradigm,” Lonial said.

The final progression-free survival (PFS) analysis of KarMMa-3, which was conducted with a median follow-up of 30.9 months, revealed that patients with triple-class–exposed relapsed or refractory multiple myeloma experienced deep and durable responses with ide-cel vs standard-of-care (SOC) regimens. Patients achieved an overall response rate (ORR) of 71% (95% CI, 66%-77%) in the ide-cel arm (n = 254) comprised of a 44% (95% CI, 38%-50%) complete response (CR) rate vs a 42% (95% CI, 34%-51%) ORR in the standard regimen arm (n = 132) comprised of a 5% (95% CI, 2%-9%) CR rate. The median duration of response (DOR) was 16.6 months (95% CI, 12.1-19.6) in the ide-cel arm vs 9.7 months (95% CI, 5.5-16.1) in the SOC arm. A significant benefit was observed with the CAR T-cell therapy regarding PFS: The median PFS was 13.8 months in the ide-cel arm vs 4.4 months in the SOC arm (HR, 0.49; 95% CI, 0.38-0.63).³

Additional data from KarMMa-3 presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition revealed that health-related quality-of-life (QOL) improvements occurred sooner with CAR T-cell therapy vs SOC; investigators noted that patients who received the onetime infusion of ide-cel (n = 249) experienced health-related QOL improvements approximately 2 to 3 months following the infusion that were sustained for greater than 2 years.⁴

The CARTITUDE-4 trial also showed that QOL improvements were seen with CAR T-cell therapy compared with standard of care for patients with relapsed or refractory multiple myeloma.⁵ At month 12, 40% of patients receiving cilta-cel (n = 126) achieved a clinical meaningful improvement in global health status score compared with 24% in the SOC arm (n = 125). At a median follow-up of 15.9 months (range, 0.1-27.3), the risk of disease progression or death was significantly lower for those treated with cilta-cel (n = 208) vs SOC (n = 211).⁶ The median PFS was not reached (NR) in the cilta-cel arm vs 11.8 months in the SOC arm (HR, 0.26; 95% CI, 0.18-0.38; P < .001) and 12-month PFS rates were 75.9% (95% CI, 69.4%-81.1%) vs 48.6% (95% CI, 41.5%-55.3%), respectively.

Lonial stressed the importance of timing when administering CAR T-cell therapy, noting that patients are sometimes referred to him following treatment with several lines of therapy, at which point blood counts and renal function are poor, leaving the patient with limited or no treatment options.

“Referral even at the time of first relapse so that you get on the agenda of the CAR T-cell center and receive guidance on what to do next and when to see the patient back [is needed]. Early visits with a CAR T center are going to remain critically important,” Lonial said.

Off-The-Shelf Approaches With T-Cell Engagers

Treatment options for patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy—including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody—include the following agents that hold recent accelerated approvals: elranatamab-bcmm (Elrexfio; August 14, 2023),⁷ teclistamab-cqyv (Tecvayli; October 25, 2022),⁸ and the most recent, talquetamab-tgvs (Talvey; August 9, 2023).⁹

“Seeing the updated data on the T-cell engagers elranatamab and teclistamab was important in the past year [regarding] how to use these agents in an effective way. The other new targeted [agent] we got in the past year was talquetamab,” Lonial said.

In the phase 2 MagnetisMM-3 trial (NCT04649359), patients treated with elranatamab who had received 4 prior lines of therapy but had not received prior BCMA-directed therapy (n = 97) achieved an objective response rate of 57.7% (95% CI, 47.3%-67.7%) comprised of a 25.8% CR or better rate; the median DOR was NR (95% CI, 12.0-not estimable).¹⁰ With teclistamab, patients who were also BCMA naive (n = 110) achieved an ORR of 61.8% (95% CI, 52.1%-70.9%) in the MajesTEC-1 trial (NCT03145181; NCT04557098).⁸

Further, meaningful ORRs were observed in patients treated with talquetamab who had received at least 4 prior lines of therapy and were not exposed to prior T-cell redirection therapy (n = 187).¹¹ In the phase 2 MonumenTAL-1 trial (NCT04634552), those given the agent at 0.4 mg/kg weekly (n = 100) achieved an ORR of 73% (95% CI, 63.2%-81.4%) with a CR rate of 9%. Patients given talquetamab 0.8 mg/kg biweekly (n = 87) achieved an ORR of 73.6% (95% CI, 63.0%-82.4%) with a CR rate of 13%.

“These treatments allow an off-the-shelf approach for management of relapsed and refractory myeloma. CAR T-cell therapies are great, but of the people that you want to give a CAR T-cell therapy to, maybe half of them [receive one], whereas talquetamab, elranatamab, and even teclistamab are off the shelf. There are some challenges with logistics to giving them if you’re in a community practice, but in general, they can be done within a week, which from a patient perspective is a whole lot easier than waiting 6 or 8 weeks and figuring out what to do from a CAR T perspective,” Lonial noted.

Examining Promising Targets

“We’re excited about the next-generation BCL2 inhibitors,” Lonial said. “We saw data at the ASH meeting from compounds [such as] sonrotoclax, [which] appears to be more potent than venetoclax [Venclexta] with a better adverse effect profile. That is a drug and target we’re very interested and excited about.”

The BCL2 inhibitor sonrotoclax is a BH3 mimetic with a short half-life of 4 hours. The agent has demonstrated high selectivity and has greater than 10-fold potency than venetoclax.¹²

Preliminary results from the phase 1b/2 BGB-11417-105 trial (NCT04973605) revealed that sonrotoclax given daily at 80 mg, 160 mg, 320 mg, and 640 mg in 21-day cycles was well tolerated in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with translocation 11;14 who previously received at least 3 prior lines of therapy.¹³ At a median follow-up of 5.5 months (range, 2.4-21.1), patients treated with the 640-mg dose (n = 10), which was selected as the recommended phase 2 dose, achieved an ORR of 70%; responses were partial (30%), very good partial (20%), complete (10%), and stringent complete (10%). The most common any grade treatment-emergent adverse effects at the 640 mg dose level included insomnia (40%) and nausea (40%). Additionally, no dose-limiting toxicities or significant hematologic toxicities occurred at any dose level.

Enrollment is currently ongoing for the sonrotoclax plus dexamethasone expansion cohort as well as the dose-finding sonrotoclax plus dexamethasone and carfilzomib (Kyprolis) arms.¹³

“Another T-cell engager, cevostamab, which targets FcRH5, is a drug that we’re excited about,” Lonial said. Cevostamab is being evaluated in an ongoing phase 1 study (NCT03275103) as monotherapy in patients with relapsed or refractory multiple myeloma.¹⁴ The phase 1/2, multicohort CAMMA 2 study (NCT05535244) is also ongoing and enrolling patients with relapsed or refractory multiple myeloma who previously received BCMA-targeted therapy.¹⁵

Lonial also added that “the new CELMoDs iberdomide [CC-220] and mezigdomide are drugs we’re very excited about. They’re more potentthan lenalidomide [Revlimid] and pomalidomide [Pomalyst] and seem to have a better safety profile as well.”

Additionally, the novel, potent, oral CRBN E3 ligase modulator iberdomide in combination with bortezomib (Velcade) and dexamethasone had more tumoricidal activity and immune-modulatory effects than immunomodulatory agents such as lenalidomide, according to investigators who presented the data at the 20th Annual International Myeloma Society Meeting. Of patients with transplant-ineligible, newly diagnosed multiple myeloma who received iberdomide plus bortezomib and dexamethasone in the phase 1/2 CC-220-MM-001 trial (NCT02773030), the regimen elicited an ORR of 100% in the efficacy-evaluable population (n = 16). Median follow-up was 12.63 months.¹⁶

Determining Treatment Plans

When considering approaches and developing a treatment plan for patients with multiple myeloma, Lonial explained that “we’ve gotten good at giving continuous therapy in myeloma, but we need to get away from the continuous therapy model and get to defined duration of therapy guided by depth of response—things like MRD might be helpful. The question I get from patients is: Can we replace transplants with CAR T cells? I don’t know that we can right now and so transplants need to remain an important part of their treatment approaches. But is there a way to put our best drugs and best targets together so that [we] can combine them and ultimately cure [patients with] the disease and stop treatment?”

When considering therapies and weighing the pros and the cons, the 28th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma (Winter Hematology) serves as a platform for practitioners to connect and dive into treatment scenarios as well as clinical situations. Advances in CAR T-cell therapy and T-cell engagers will be spotlighted along with bispecific agents and antibody-drug conjugates at the conference, which is taking place February 29, 2024, to March 3, 2024, in Miami Beach, Florida.¹⁷

“As a community oncologist, you’re [balancing a lot] with every disease, every treatment, and new FDA approvals. The winter hematology conference lets you hear about that from the hematology perspective [and] have access to faculty outside of their lectures to make connections/contacts [that can be] used as a resource for your patients in the coming year,” Lonial, who is cochairing the conference, said.

References

1. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Updated March 7, 2022. Accessed January 10, 2024. bit.ly/3Heb7jT
2. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Updated March 29, 2021. Accessed January 10, 2024. bit.ly/3Hcyevc
3. Otero PR, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class–exposed (tce) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933
4. Delforge M, Patel KK, Eliason L, et al. Effects of idecabtagene vicleucel (ide-cel) versus standard regimens on health-related quality of life (HRQOL) in patients with relapsed/refractory multiple myeloma (RRMM) who had received 2-4 prior regimens: updated results from the phase 3 KarMMa-3 trial. Blood. 2023;142(suppl 1):96. doi:10.1182/blood-2023-179152
5. Mina R, Mylin AK, Yokoyama H, et al. Patient-reported outcomes in the phase 3 CARTITUDE-4 study of ciltacabtagene autoleucel vs standard of care in patients with lenalidomide-refractory multiple myeloma after 1-3 lines of therapy. Blood. 2023;142(suppl 1):1063. doi:10.1182/blood-2023-178798
6. 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
7. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed January 10, 2024. bit.ly/3tsmz7L
8. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 10, 2024. bit.ly/47LPpih
9. FDA D.I.S.C.O. Burst Edition: FDA approvals of Talvey (talquetamab-tgvs) for relapsed or refractory multiple myeloma, and Elrexfio (elranatamab-bcmm) for relapsed or refractory multiple myeloma. FDA. September 26, 2023. Accessed January 10, 2024. bit.ly/3Sgs6sf
10. Elrexfio. Prescribing information. Pfizer; 2023. Accessed January 10, 2024. bit.ly/48Vs7Z5
11. Talvey. Prescribing information. Janssen Biotech, Inc; 2023. Accessed January 10, 2024. bit.ly/3U1Dgm5
12. Tam CS, Anderson MA, Lasica M, et al. Combination treatment with sonrotoclax (BGB-11417), a second-generation BCL2 inhibitor, and zanubrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is well tolerated and achieves deep responses in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (TN-CLL/SLL): data from an ongoing phase 1/2 study. Blood. 2023;142(suppl 1):327. doi:10.1182/blood-2023-179541
13. Quach H, Sborov D, Kazandjian D, et al. Sonrotoclax (BGB-11417) in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma with t(11;14): safety, efficacy, and determination of recommended phase 2 dose. Blood. 2023;142(suppl 1):1011. doi:10.1182/blood-2023-178735
14. Dose-escalation study of cevostamab in participants with relapsed or refractory multiple myeloma (R/​R MM). ClinicalTrials.gov. Updated December 18, 2023. Accessed January 10, 2024. https://clinicaltrials.gov/study/NCT03275103
15. A study evaluating the efficacy and safety of cevostamab in prior B cell maturation antigen (BCMA)-exposed participants with relapsed/​refractory multiple myeloma (CAMMA 2). ClinicalTrials.gov. Updated January 3, 2024. Accessed January 10, 2024. https://clinicaltrials.gov/study/NCT05535244
16. White D, Lipe B, Mesa MG, et al. Iberdomide, bortezomib, and dexamethasone (IberVd) in transplant-ineligible newly diagnosed multiple myeloma: results from the CC-220-MM-001 trial. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-41.
17. 28th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma Agenda. Accessed January 10, 2024. bit.ly/41T926s