Data From 2023 ASH Annual Meeting Provide Positive Updates in Multiple Myeloma

Krina K. Patel, MD, MSc

Multiple myeloma has an estimated global incidence of 7.1 per 100,000 individuals, making it the second most common hematologic malignancy worldwide. Although significant treatment advances have occurred, especially in recent years, multidrug resistance at an early stage and relapse are common. This is due in part to the combination regimens that are often administered, underscoring the need for the continued development of more effective therapeutics.¹

During a recent OncLive Peer Exchange®, a panel of expert oncologists in multiple myeloma highlighted updated findings from clinical trials primarily presented during the 65th American Society of Hematology Annual Meeting & Exposition (2023 ASH Annual Meeting), which took place in December 2023 in San Diego, California. They discussed recent updates from studies evaluating agents for the treatment of patients with newly diagnosed multiple myeloma and examined the role of chimeric antigen receptor (CAR) T-cell therapies and bispecifics in relapsed/refractory disease.

Recent Updates in the Treatment of Newly Diagnosed Multiple Myeloma

The panelists opened their conversation by discussing treatment options for patients with newly diagnosed disease who are eligible for stem cell transplant. Induction therapy with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide maintenance therapy is considered a standard of care for this patient population.²

During the 2023 ASH Annual Meeting, investigators presented findings from the phase 3 Perseus trial (NCT03710603), which randomly assigned patients with newly diagnosed multiple myeloma aged 18 to 70 years who were eligible for high-dose therapy and ASCT 1:1 to receive VRd followed by ASCT induction and ASCT consolidation with lenalidomide maintenance therapy with (n = 355) or without subcutaneous daratumumab (Darzalex; n = 354). Patients who were treated with daratumumab also received maintenance therapy with the agent. The primary end point was progression-free survival (PFS). Key secondary end points included overall complete response or better (≥ CR) rate, overall minimal residual disease (MRD) negativity rate, and overall survival (OS).²

At a median follow-up of 47.5 months, the median PFS in was not reached (NR) in the daratumumab or the control arm; the estimated 48-month PFS rates were 84.3% vs 67.7%, respectively (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). Notably, PFS was improved with the addition of daratumumab across clinically relevant subgroups, such as patients with International Staging System stage III disease and those with high cytogenetic risk. The greater than or equal to CR rate in the investigational and control arms was 87.9% vs 70.1%, respectively (P < .0001), and the MRD negativity rate was 75.2% vs 47.5%, respectively (P < .0001). OS data were immature.²

Study authors from the Perseus trial wrote in the conclusion of their presentation at the 2023 ASH Annual Meeting that their data, together with findings from the phase 2 GRIFFIN trial (NCT02874742), which evaluated the same combination in the same patient population but delivered daratumumab intravenously, support daratumumab plus VRd followed by maintenance with daratumumab and lenalidomide as a new standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. They also noted that the safety profile of the regimen was consistent with the known profile of subcutaneous daratumumab as well as that of VRd.²

During the 2023 ASH Annual Meeting, investigators also presented findings from the phase 3 IsKia trial (NCT04483739), which compared carfilzomib (Kyprolis), lenalidomide, and dexamethasone with or without the addition of the anti-CD38 monoclonal antibody isatuximab-irfc (Sarclisa) before ASCT induction and post ASCT consolidation therapy. The study randomly assigned patients with newly diagnosed multiple myeloma younger than 70 years 1:1 to the isatuximab (n = 151) or control arm (n = 151). The primary end point was the MRD negativity rate after consolidation; secondary end points included the MRD negativity rate after induction and PFS.³

At the data cutoff on May 22, 2023, the MRD negativity rate in the investigational and control arms after consolidation at the 10^-5 cutoff by next-generation sequencing (NGS) was 77% vs 67%, respectively (OR, 1.67; P = .049); the respective rates at an NGS cutoff of 10^-6 were 67% vs 48% (OR, 2.29; P < .001). The MRD negativity rates after induction were 45% vs 26%, respectively (OR, 2.34; P < .001), at the 10^-5 cutoff and 27% vs 14%, respectively (OR, 2.36; P = .004), at the 10^-6 cutoff.³

“There are a lot of different options for our patients with both standard- and high-risk disease,” Krina K. Patel, MD, MSc, said. “We have enough data to say quadruplets beat out triplets. So for patients [with] standard-risk or high-risk [disease] who are fit and transplant eligible, most of us will say we try to do the quadruplets.”

Role of CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

There are currently 2 FDA-approved CAR T-cell agents for the treatment of patients with relapsed/ refractory multiple myeloma: idecabtagene vicleucel (Abecma; ide-cel) and ciltacabtagene autoleucel (Carvykti; cilta-cel). In March 2021, ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma when it received an indication for the treatment of adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy. In February 2022, the FDA approved cilta-cel for the treatment of adult patients with multiple myeloma after 4 or more prior lines of therapy.^4,5

During the 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023), which took place in June in Chicago, Illinois, investigators presented the final results from the phase 1b/2 CARTITUDE-1 study (NCT03548207), which supported the February 2022 FDA approval of cilta-cel. CARTITUDE-1 enrolled patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy or had disease double refractory to a proteasome inhibitor and an immunomodulatory drug. The primary end points were objective response rate (ORR) and safety; secondary end points included PFS, OS, and MRD negativity.⁶

At a median follow-up of 33.4 months (range, 1.5-45.2), patients who received cilta-cel (n = 97) achieved a median duration of response (DOR) of 33.9 months (95% CI, 25.2-not estimable [NE]) and a median PFS of 34.9 months (95% CI, 25.2-NE); the median OS was NR. Among patients evaluable for MRD (n = 49), 26 achieved MRD negativity for at least 1 year. Previous findings conducted with a median follow-up of 27.7 months showed that the ORR was 98%, with a stringent CR (sCR) rate of 83%.⁶ Study authors noted that patients treated with cilta-cel achieved a longer median PFS than any previously reported therapy in heavily pretreated patients with relapsed/refractory multiple myeloma.⁶

Beyond the FDA-approved indications for CAR T-cell agents, there has been interest in moving these therapeutics into earlier lines of therapy. During 2023 ASH Annual Meeting, investigators presented findings from the phase 2 CARTITUDE-2 (NCT04133636) and the phase 3 CARTITUDE-4 (NCT04181827) trials, both of which evaluated cilta-cel in patients with relapsed/refractory multiple myeloma. CARTITUDE-2 enrolled patients after 1 to 3 prior lines of therapy (cohort A; n = 20) and those with early relapse following frontline treatment (cohort B; n =19). CARTITUDE-4 enrolled patients with lenalidomide-refractory disease after 1 to 3 prior lines of treatment.^7,8

At the April 2023 data cutoff, all 17 MRD- evaluable patients in cohort A of CARTITUDE-2 achieved the MRD negativity threshold of 10^-5 as well as 14 of 15 MRD-evaluable patients in cohort B. The ORRs in the full populations of cohort A and B were 95% (95% CI, 75.1%-99.9%) and 100% (95% CI, 82.4%-100%), respectively (Table).⁷ The median PFS was NR in either cohort, and the 24-month PFS rates were 75% (95% CI, 50.0%-88.7%) and 73.3% (95% CI, 47.2%-87.9%), respectively. The 24-month OS rates were 75% (95% CI, 50%-88.7%) and 84.2% (95% CI, 58.7%-94.6%), respectively.⁷

“We heard a little bit at ASH this [past] year about functional patients [with] high-risk [disease] who didn’t achieve a VGPR [very good partial response] or better after their transplant, and we’re looking at where we can use cilta-cel in that regard,” Caitlin Costello, MD, said. “Some of those patients even had lenalidomide maintenance after cilta-cel. We are starting to explore that a bit for our patients [with] higher-risk [disease]. I’d like to see a thoughtful approach to using it in [patients with] early-risk [disease] and not just across the board, since we can’t even get it for the people we know it works for right now.” Findings from CARTITUDE-4, which had a shorter median follow-up of 16 months compared with approximately 29 months in CARTITUDE-2, revealed that cilta-cel significantly improved PFS compared with standard-of-care pomalidomide (Pomalyst), bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone (HR, 0.26; P < .0001). Additionally, the ORR was 99.4%, including a CR/sCR rate of 86.4%, among 176 patients who received cilta-cel as study treatment. Eighty-eight percent of MRD-evaluable patients (n = 144) achieved MRD negativity at any time, and 77% achieved both MRD negativity and at least a CR.⁸

CARTITUDE-4 study authors concluded that “in the context of longer-term data from cohort A of the CARTITUDE-2 study in a similar patient population, these results support the potential for prolonged disease control and the benefit of ciltacel for patients with multiple myeloma as early as after first relapse.”⁸

“The challenge [with CARTITUDE-4] is that most of the patients [did] not [have] daratumumab-refractory [disease],” Amrita Krishnan, MD, commented. “They have not yet plateaued on that curve, and we are seeing that you can still get a great curve in fifth relapse for those patients. I would be very reluctant to use [ciltacel] at first relapse; second or third relapse is where I see it fitting in right now.”

Expanding on the design of the phase 2 KarMMa trial (NCT03361748), which supported the 2021 FDA approval of ide-cel in multiple myeloma and evaluated the agent in patients with relapsed/refractory disease following treatment with at least 3 regimens, the phase 3 KarMMa-3 trial (NCT03651128) compared the CAR T-cell agent with standard regimens in patients with triple class–exposed relapsed/ refractory multiple myeloma. Patients needed to have received at least 2 to 4 prior regimens and have disease refractory to the latest one. The primary end point was PFS; secondary end points included ORR and OS.⁹

Updated findings from KarMMa-3 showed that at the data cutoff of April 28, 2023, with 30.9 months (range, 12.7-47.8) of median follow-up, patients in the ide-cel arm (n = 254) and the standard regimens arm (n = 132) achieved a median PFS of 13.8 months (95% CI, 11.8-16.1) vs 4.4 months (95% CI, 3.4-5.8), respectively (HR, 0.49; 95% CI, 0.38-0.63; P < .0001). Moreover, treatment with ide-cel improved the ORR (71.3% vs 42.4%, respectively), CR rate (43.7% vs 5.3%), and median DOR (16.6 months vs 9.7 months).

Role of Bispecifics in Relapsed/Refractory Multiple Myeloma

The panelists concluded their discussion by outlining the role of bispecifics in the relapsed/ refractory treatment paradigm. “There are several BCMA [B-cell maturation antigen]-directed bispecifics that have been in clinical development, but two are currently FDA approved: teclistamab-cqyv [Tecvayli] and elranatamab [Elrexfio]. More recently, we’ve had longer follow-up data that show that even though the ORRs are about the same, the depth of response has been reported as getting better. There is an update on elranatamab specifically, which is a little interesting. They’re reporting a durability of response that appears to be at least numerically better than teclistamab,” Saad Z. Usmani, MD, MBA, FACP, said.

During ASCO 2023, investigators presented updated findings from the pivotal phase 1/2 MajesTEC-1 study (NCT03145181; NCT04557098) evaluating teclistamab in patients with relapsed/ refractory multiple myeloma who received at least 3 prior lines of treatment. Previous findings from the study led to the agent becoming the first FDA-approved off-the-shelf BCMA × CD3 bispecific antibody for the treatment of patients with relapsed/refractory disease.¹⁰

At the data cutoff on December 9, 2022, with a median follow-up of 22 months, the median DOR was 24 months (95% CI, 16.2-NE) and 43% of patients who received teclistamab at the recommended phase 2 dose (n = 165) achieved at least a CR. Notably, the median DOR among patients who achieved greater than or equal to CR was NR (95% CI, 24-NE). The median OS in the overall population was 21.9 months (95% CI, 16-NE), and the median PFS was 12.5 months (95% CI, 8.8-17.2).¹⁰

During the 2023 ASH Annual Meeting, study authors shared findings from the phase 2 MagnetisMM-3 study (NCT04649359), which evaluated monotherapy with the BCMA-targeted bispecific antibody elranatamab in patients with relapsed/refractory multiple myeloma. Eligible patients needed to have been previously treated with 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. The primary end point was ORR.¹¹

At the data cutoff on April 16, 2023, with a median follow-up of 15.9 months, patients who received elranatamab (n = 123) achieved a confirmed ORR of 61% (95% CI, 51.8%-69.6%), including a greater than or equal to CR rate of 35.8%. Among patients with a greater than or equal to CR evaluable for MRD (n = 29), the MRD negativity rate was 89.7%. In the overall population, the median DOR, PFS, and OS were NR.¹¹

“The populations in MajesTEC-1 and MagnetisMM-3 were a little different. You have to take those nuances into consideration,” Usmani added. “It will be important to see what that follow-up looks like, especially for the high-risk subgroups, because there is probably going to be some uniformity in what we would expect from those patients. We also have data from other novel BCMA bispecifics that were a little behind in clinical development.”

Another trial presented during the meeting, the phase 1b MonumenTAL-2 trial (NCT05050097), evaluated a combination regimen consisting of the T-cell redirecting bispecific antibody talquetamab-tgvs (Talvey) and pomalidomide. The single-arm study enrolled patients with relapsed/refractory multiple myeloma who received at least 2 prior lines of therapy.¹²

Initial efficacy data revealed that patients who received the combination via a weekly dosing schedule (n = 16) achieved an ORR of 86.7% with a greater than or equal to CR rate of 60%. Patients who received the regimen in a twiceweekly dosing schedule (n = 19) achieved an ORR of 83.3% with a greater than or equal to CR rate of 44.4%. The median DOR and PFS were NR in either cohort; the 6-month PFS rates were 93.3% and 88.9%, respectively. Study authors concluded that “the promising efficacy and manageable safety profile of this combination further support talquetamab as a versatile combination partner and warrant further evaluation of this regimen.”¹²

“Bispecifics are very good,” Rafat Abonour, MD, said. “I believe we are going to see patients [experiencing relapse] after BCMA-directed CAR T-cell agents and we are going to see patients [experiencing relapse] after BCMA-directed bispecifics. In my practice, BCMA-[directed bispecifics] are used first because we have the longest experience with them. I will choose talquetamab later after that.”

References

1. Fazio M, Del Fabro V, Parrinello NL, et al. Multiple myeloma in 2023 ways: from trials to real life. Curr Oncol. 2023;30(11):9710-9733. doi:10.3390/curroncol30110705
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplantation (ASCT): primary results of the Perseus trial. Blood. 2023;142(suppl 2):LBA-1. doi:10.1182/blood-2023-191911
3. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib- lenalidomide-dexamethasone vs carfilzomib-lenalidomide- dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/blood-2023-177546
4. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Accessed January 22, 2024. https://www. fda.gov/drugs/resources-information-approved-drugs/fda- approves-idecabtagene-vicleucel-multiple-myeloma
5. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed January 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene- autoleucel-relapsed-or-refractory-multiple-myeloma
6. Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8009. doi:10.1200/ JCO.2023.41.16_suppl.8009
7. Hillengass J, Cohen AD, Agha ME, et al. The phase 2 CARTITUDE-2 trial: updated efficacy and safety of ciltacabtagene autoleucel in patients with multiple myeloma and 1-3 prior lines of therapy (cohort A) and with early relapse after first line treatment (cohort B). Blood. 2023;142(suppl 1):1021. doi:10.1182/blood-2023-178882
8. Sidiqi MH, Corradini P, Purtill D, et al. Efficacy and safety in patients with lenalidomide-refractory multiple myeloma after 1-3 prior lines who received a single infusion of ciltacabtagene autoleucel as study treatment in the phase 3 CARTITUDE-4 trial. Blood. 2023;142(suppl 1):4866. doi:10.1182/blood-2023-178778
9. 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
10. van de Donk NWCJ, Moreau P, Garfall AL, et al. Long-term follow-up from MajesTEC-1 of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16):8011. doi:10.1200/ JCO.2023.41.16_suppl.8011
11. Tomasson M, Iida S, Niesvizky R, et al. Long-term efficacy and safety of elranatamab monotherapy in the phase 2 Magnetismm-3 trial in relapsed or refractory multiple myeloma (RRMM). Blood. 2023;142(suppl 1):3385. doi:10.1182/blood-2023-182130
12. Matous J, Biran N, Perrot A, et al. Talquetamab + pomalidomide in patients with relapsed/refractory multiple myeloma: safety and preliminary efficacy results from the phase 1b MonumenTAL-2 study. Blood. 2023;142(suppl 1):1014. doi:10.1182/ blood-2023-187706