Quadruplet Regimens Stand Strong in Newly Diagnosed Multiple Myeloma

The treatment landscape of newly diagnosed multiple myeloma has seen significant gains in 2024, headlined by the July 2024 FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd).1 Additional compelling data have also been reported from studies examining other combination regimens in the frontline setting, and multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated strong activity among patients with relapsed/refractory disease, leading to the expansion of their indications in this patient population by the FDA in 2024.

“I am most excited about [the fact that] we have the diagnostics, the monitoring tools, and the treatments, and we are going to be able to use them in combination,” Thomas Martin, MD, said. “Start with a quadruplet and [also consider] immunotherapies, CARs, and bispecific [antibodies], and then stop treatment. That would be our definition of cure.”

During the 2024 International Myeloma Society (IMS) Annual Meeting, OncologyLive filmed a Peer Exchange onsite in Rio de Janeiro, Brazil, to obtain commentary from leading myeloma experts regarding impactful data updates that were presented during and around the meeting. The panelists discussed updated findings from clinical trials in newly diagnosed multiple myeloma, including the phase 3 PERSEUS (NCT03710603), CASSIOPEIA (NCT02541383), and IsKia (NCT04483739) studies. They also highlighted data from the phase 3 KarMMa-3 (NCT03651128) and CARTITUDE-4 (NCT04181827) studies, which are examining CAR T-cell therapies in relapsed/refractory multiple myeloma.

Quadruplets Hold Center Stage In Newly Diagnosed Multiple Myeloma

The PERSEUS study enrolled patients with transplantation-eligible, newly diagnosed multiple myeloma and randomly assigned them 1:1 to receive induction therapy with D-VRd followed by consolidation D-VRd and daratumumab and lenalidomide maintenance or induction and consolidation with VRd (bortezomib, lenalidomide, and dexamethasone) followed by lenalidomide maintenance therapy.2 The primary end point was progression- free survival (PFS); complete response (CR) or better, minimal residual disease (MRD)–negative status with a CR or better, and overall survival (OS) represented key secondary end points. Data from PERSEUS supported the July 2024 FDA approval of D-VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).1

At a median follow-up of 47.5 months (range, 0-54.4), data from the primary analysis of PERSEUS, which were published in the New England Journal of Medicine, demonstrated that patients who received D-VRd (n = 355) experienced a significant PFS benefit compared with those who received VRd alone (n = 354; HR, 0.42; 95% CI, 0.30-0.59; P < .001).2 The estimated 48-month PFS rates were 84.3% (95% CI, 79.5%-88.1%) in the D-VRd group and 67.7% (95% CI, 62.2%-72.6%), respectively. The CR or better rates were 87.9% and 70.1%, respectively (P < .001) and the MRD negativity rates at a threshold of 10–5 were 75.2% and 47.5%, respectively (P < .001).

“PERSEUS confirmed what everyone suspected after the [phase 2] GRIFFIN [NCT02874742] data came out [which was] the combination of daratumumab with bortezomib, dexamethasone, [and lenalidomide] has been a game changer for newly diagnosed myeloma,” Natalie Callander, MD, said. “The results [in terms of] response rate and 4-year PFS [rate] for PERSEUS have been amazing, really nothing else has come close.”

During the 2024 IMS Annual Meeting, investigators presented additional data from a cytogenetic risk analysis of PERSEUS.3 The median PFS favored the D-VRd arm vs the VRd arm across all cytogenetic risk subgroups, with the most pronounced improvements being reported in the isolated amp(1q21) (HR, 0.11; 95% CI, 0.01-0.87; P = .0115), revised standard risk (HR, 0.29; 95% CI, 0.15-0.56; P = .0001), and standard risk (HR, 0.35; 95% CI, 0.22-0.56; P < .0001) subgroups. Moreover, MRD negativity and sustained MRD negativity rates at thresholds of both 10–5 and 10–6 favored D-VRd over VRd across all cytogenetic risk subgroups.

CASSIOPEIA is evaluating another daratumumab-containing quadruplet in patients with transplant-eligible, newly diagnosed multiple myeloma.4 During the consolidation phase of the study, patients were randomly assigned 1:1 to receive daratumumab with bortezomib, thalidomide (Thalomid), and dexamethasone (D-VTd) or bortezomib, thalidomide and dexamethasone (VTd). Patients with a partial response or better following the completion of the consolidation phase were eligible for the maintenance phase and underwent a second random assignment prior to this portion to receive daratumumab maintenance or observation only. The primary end point for the maintenance phase was PFS from second randomization; secondary end points included MRD negativity rate, CR or better rate, and OS.

At a median follow-up of 80.1 months, findings from CASSIOPEIA presented during the 2024 IMS Annual Meeting showed that the median PFS among patients who received D-VTd followed by daratumumab (n = 229) was not yet reached (NR) vs 72.1 months in the D-VTd followed by observation group (n = 229; HR, 0.76; 95% CI, 0.58-1.00; P = .0480).5 In the VTd arm, patients who received daratumumab maintenance (n = 213) achieved a median PFS of NR compared with 32.7 months among those who received observation (n = 215; HR, 0.34; 95% CI, 0.26-0.44; P < .0001). The overall MRD negativity rates were 77.3% and 70.7% in the D-VTd arm with daratumumab maintenance or observation, respectively. These respective rates were 70.9% and 51.2% in the VTd arm.

“When you use the quadruplet, those are the patients who do the best,” Noopur Raje, MD, said. “We are seeing a deepening of MRD over time in patients who are continuing the consolidation as well as maintenance. CASSIOPEIA taught me that, because of the second randomization, as long as patients got daratumumab or an anti-CD38 monoclonal antibody, they did quite well and their PFS improved considerably, suggesting that as long as [patients] get daratumumab in their treatment algorithm, they’re going to do well, but the patients who did the best were the ones who were able to continue daratumumab from the start.”

“One of the controversies that still exists is do you use daratumumab just for induction, just for maintenance, or for both? My practice has been to use it before and after because [if I believe a patient is] going to relapse 8 or 9 years later, we’re not going to use daratumumab [at that point]. We’re going to have something new,” Martin added.

In the phase 2 GMMG-CONCEPT study (NCT03104842), the quadruplet of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide, and dexamethasone (Isa-KRd) was evaluated in patients with transplant-eligible and transplant-ineligible, newly diagnosed, high-risk multiple myeloma.6 The primary end point was MRD negativity rate after consolidation and PFS represented the key secondary end point.

Four-year follow-up data presented during the 2024 IMS Annual Meeting demonstrated that transplant eligible patients (n = 127) achieved MRD negativity at any time point at a rate of 83.5%; patients sustained MRD negativity for more than 6 and 12 months at rates of 73.7% and 66.9%, respectively. Transplant-ineligible patients (n = 26) were MRD negative at any time point at a rate of 69.7% and achieved MRD negativity for over 6 and 12 months at rates of 57.7% and 50.0%, respectively. At a median follow-up of 54 months (range, 0-77.7), the 4-year PFS rate in the transplant-eligible group was 59.4% (95% CI, 51.7%-68.9%). In the transplant- ineligible group, at a median follow-up of 51 months (range, 0-67.7), the 4-year PFS rate was 54.3% (95% CI, 37.6%-78.3%).

Isa-KRd is also being examined in IsKia, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma.7 Eligible patients were randomly assigned 1:1 to receive Isa-KRd induction and consolidation or KRd induction and consolidation. The primary end point was the rate of MRD negativity by next-generation sequencing following consolidation. MRD negativity after induction and PFS represented key secondary end points.

During the 2023 American Society of Hematology Annual Meeting, investigators presented initial data from IsKia which showed that patients in the Isa-KRd arm (n = 151) achieved an MRD negativity rate of 77% at a threshold of 10–5 compared with 67% in the KRd arm (n = 151; OR, 1.67; P = .049). At a threshold of 10–6, the MRD negativity rates were 67% and 48%, respectively (OR, 2.29; P < .001). The MRD negativity rates at a threshold of 10–5 post ASCT were 64% and 49%, respectively (OR, 1.93; P = .006)

“Looking at the PFS curves [in GMMGCONCEPT and IsKia], you see in the high-risk [subgroup] you can achieve MRD negativity, but you do see some relapses over time and there isn’t a plateau,” Martin said. “You really have to keep the pressure on. In other words, you can’t stop consolidation- or maintenance-based therapy. [These patients] need to have continuous maintenance.”

The panelists concluded their discussion of frontline data updates in multiple myeloma by highlighting updated findings from CEPHEUS, which examined D-VRd vs VRd in patients with newly diagnosed multiple myeloma who are ineligible for ASCT or for whom transplant is deferred.8 Patients were randomly assigned 1:1 to receive D-VRd followed by maintenance with daratumumab, lenalidomide, and dexamethasone, or VRd with lenalidomide and dexamethasone maintenance. The primary end point was MRD negativity rate; key secondary end points included PFS, sustained MRD negativity, CR or better rate, and OS.

During the 2024 IMS Annual Meeting, initial data from CEPHEUS were presented and showed that patients who received D-VRd (n = 197) achieved an MRD negativity rate of 60.9% at a 10–5 threshold compared with 39.4% in the VRd arm (n = 198; OR, 2.37; 95% CI, 1.58-3.55; P < .0001). Patients sustained MRD negativity for at least 12 months at rates of 48.7% and 26.3%, respectively (OR, 2.63; 95% CI, 1.73-4.00; P < .0001). The respective CR or better rates were 81.2% and 61.6% (OR, 2.73; 95% CI, 1.71-4.34; P < .0001).

In September 2024, data from CEPHEUS supported the submission of a supplemental biologics license application to the FDA seeking the approval of D-VRd for the treatment of adult patients with newly diagnosed multiple myeloma for whom ASCT is deferred or those who are ineligible for ASCT.9

“In this older patient population, the toxicity is not trivial, and the adverse effects [in terms of] infections in CEPHEUS were on the higher side,” Raje said. “In the real world, we don’t use the bortezomib twice a week except when [a patient] has high-burden and high-risk disease. I believe we can attenuate that toxicity but it’s something that we need to think about.”

“Most patients can tolerate the quadruplet at least to start off with, and if they are poorly tolerated, you can always decrease either the dose or the frequency. But most patients, even those that would be qualified as transplant ineligible, can still tolerate quadruplets, as we’re seeing with all this transplant-ineligible data. I look forward to the day where we stop using transplant eligibility as the first fork in the road in newly diagnosed patients,” Adriana Rossi, MD, added.

CAR T-Cell Agents Offer Options for Patients With Relapsed/Refractory Disease

There are currently 2 FDA-approved CAR T-cell agents for the treatment of patients with relapsed/ refractory multiple myeloma: idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti). Ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma in March 2021, earning an indication for the treatment of patients following at least 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.10 In February 2022, the FDA approved cilta-cel for the same patient population.11

In April 2024, the FDA expanded the approval of ide-cel in multiple myeloma to include patients with relapsed/refractory disease following at least 2 prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.12 The regulatory decision was supported by findings from KarMMa-3, which examined ide-cel vs standard regimens in patients with triple-class exposed relapsed/refractory multiple myeloma who received 2 to 4 prior regimens. The primary end point was PFS.

Updated findings from KarMMa-3 published in Blood demonstrated that patients who received ide-cel (n = 254) achieved a median PFS of 13.8 months compared with 4.4 months among those treated with standard regimens (n = 132; HR, 0.49; 95% CI, 0.38-0.63); the 18-month PFS rates were 41% and 19%, respectively.13 The median OS was 41.4 months (95% CI, 30.9-NR) vs 37.9 months (95% CI, 23.4-NR), respectively (HR, 1.01; 95% CI, 0.73-1.40). The ORR in the ide-cel arm was 71% (95% CI, 66%-77%), with a 44% stringent CR (sCR)/CR rate, compared with 42% (95% CI, 34%-51%), with a 6% sCR/CR rate, in the standard regimens arm.

Following its initial FDA approval, cilta-cel was examined vs standard-of-care (SOC) regimens in patients with relapsed/refractory multiple myeloma following 1 to 3 prior lines of treatment, including a proteasome inhibitor and an immunomodulatory agent, in CARTITUDE-4.14 The primary end point was PFS; secondary end points included CR or better rate, ORR, MRD negativity, and OS. Updated findings from the study were presented during the 2024 IMS Annual Meeting.

“Long-term toxicities are something we need to think about [with CAR T-cell agents],” Raje said. “As we move these therapies earlier, we have to have that discussion with our patients. The good news is we haven’t seen anything new, and when a patient needs a CAR T-cell [therapy] I would not withhold it, even with the secondary cancer risk.”

At a median follow-up of 33.6 months (range, 0.1-45.0), patients who received cilta-cel (n = 208) experienced a significant OS benefit vs those in the SOC arm (n = 211; HR, 0.55; 95% CI, 0.39-0.79; P = .0009); study authors noted that cilta-cel was the first CAR T-cell agent to demonstrate an OS benefit in multiple myeloma. The 30-month OS rates were 76.4% and 63.8%, respectively. Cilta-cel also conferred a significant PFS benefit over SOC regimens (HR, 0.29; 95% CI, 0.22-0.39; P < .0001), with 30-month PFS rates of 59.4% and 25.7%, respectively.

“One of the things that we learned from CARTITUDE-4 is the importance of controlling disease prior to CAR T infusion,” Ajai Chari, MD, noted. “There’s an International Myeloma Working Group sequencing paper [in which] we’re proposing the term onboarding, which is what you do before you get to collection and then bridging would be what you do after collection.”

Data from CARTITUDE-4 led to the April 2024 FDA approval of 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 proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.15 The expanded indication made cilta-cel the only B-cell maturation antigen– directed therapy approved by the FDA in multiple myeloma as early as first relapse.

“The very exciting news is we have these 2 [FDA]-approved CAR T products, ide-cel and cilta-cel, and this year we’ve had them both move up in the treatment paradigm,” Rossi said. “Instead of [them] being [available] in multiple- relapse [disease after] 4 prior lines, we have cilta-cel in [patients who received a] prior proteasome inhibitor and immunomodulatory agent [who are] refractory to lenalidomide and ide-cel for patients who’ve had 2 lines of therapy, including a proteasome inhibitor, immunomodulatory agent, and a CD38–[directed antibody]. [These are] slightly different indications, but [they’re helping us] work toward that plateau envy if we can get these effective therapies done earlier.”

References

1. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed November 11, 2024. bit.ly/40HnRul
2. 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
3. Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA SC)/bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance in transplanteligible (TE) newly diagnosed myeloma (NDMM): PERSEUS cytogenetic risk analysis. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-48.
4. Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014. doi:10.1016/S1470-2045(24)00282-1
5. Corre J, Vincent L, Moreau, et al. Daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) and DARA maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM): CASSIOPEIA minimal residual disease (MRD) update. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-47.
6. Leypoldt L, Besemer B, Hanel M, et al. Isa-KRd in high-risk newly diagnosed multiple myeloma – 4-year-follow-up from the GMMG-CONCEPT trial. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-53.
7. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomiblenalidomide- dexamethasone vs carfilzomib-lenalidomidedexamethasone as pre-transplant induction and posttransplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/ blood-2023-177546
8. Usmani SZ, Facon T, Hungria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-63.
9. Johnson & Johnson files for U.S. FDA approval of Darzalex Faspro-based quadruplet regimen for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 30, 2024. Accessed October 10, 2024. bit.ly/40NF99n
10. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 29, 2021. Accessed November 11, 2024. bit.ly/3YMPcbS
11. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. March 7, 2022. Accessed November 11, 2024. bit.ly/3Heb7jT
12. 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 November 11, 2024. bit.ly/3UykBhC
13. Ailawadhi S, Arnulf B, Patel KK, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. Published online August 28, 2024. doi:10.1182/blood.2024024582
14. Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 21st International Myeloma Society Annual Meeting; September 25- 28, 2024; Rio De Janeiro, Brazil. Abstract OA-65.
15. 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 6, 2024. Accessed November 11, 2024. bit.ly/44aJDXa