Quadruplets and Fast CARs: “Breathtaking” New Data for Frontline MM Treatment

Session cochair Sonja Zweegman, MD, PhD, promised the audience at the European Hematology Association (EHA) 2024 Congress that they would hear “breathtaking new results” on frontline treatment of multiple myeloma (MM), and the presenters did not disappoint, delivering exciting data from trials spanning phase 1 to phase 3 that explored new strategies to treat newly diagnosed MM.

With findings like these, hematologists can begin to replace the question marks in their treatment strategies for frontline MM with actionable knowledge. | Image Credit: © David Litman - stock.adobe.com

First up was Juan Du, MD, PhD, professor and chief physician in Changzheng Hospital in Shanghai, China, who discussed GC012F, a chimeric antigen receptor T-cell (CAR T) therapy also called FasTCAR-T because of its short manufacturing time of just 1 day. This novel manufacturing process also improves T-cell fitness, with a higher concentration of young phenotype T cells, which endow them with “greater potential for in vivo expansion and improved function,” Du said. She presented data from a phase 1 study of GC012F in 22 patients with transplant-eligible, newly diagnosed, high-risk MM (NCT04935580).¹

In terms of the primary end point of safety, all events of cytokine release syndrome were grade 1 or 2 and resolved within 4 days, and there were no events of immune effector cell–associated neurotoxicity syndrome or neurotoxicity. The secondary end points of efficacy were also encouraging, with all patients achieving an overall response and all achieving minimal residual disease (MRD) negativity at a sensitivity of 10^–6. The median duration of response and progression-free survival (PFS) were not reached after a median follow-up of 22 months, so Du and colleagues will continue their analysis to see whether this “amazing response rate” persists.

Next was Pieter Sonneveld, MD, PhD, professor at Erasmus Medical Center in Rotterdam, the Netherlands, to present data from the phase 3 PERSEUS trial (NCT03710603) of daratumumab (D) plus bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible patients with newly diagnosed MM.² The primary analysis had already shown a 58% reduction in risk of progression or death over 4 years in patients who received D-VRd vs VRd alone, but his talk today featured insights on the deepening responses and MRD negativity during maintenance therapy.

Specifically, MRD negativity rates at 10^–6 increased by 30% during maintenance therapy that included daratumumab, and rates of sustained MRD negativity were 2.5-fold higher for D-VRd followed by daratumumab and lenalidomide vs VRd followed by lenalidomide. Sonneveld expects the PFS curves to diverge even further with longer follow-up, but in the meantime these data are encouraging, especially in showing the increased likelihood of conversion to MRD negativity with the use of daratumumab and lenalidomide in the maintenance phase for those who were MRD positive at the end of the consolidation phase. When an audience member asked about the role of novel immunotherapies and CAR T therapies considering such impressive results with daratumumab, Sonneveld replied that he welcomes them, particularly as an option for those who are still MRD positive.

Marc Raab, MD, professor at Heidelberg University Hospital in Germany, presented data on another quadruplet regimen, this time isatuximab plus VRd in the phase 3 GMMG-HD7 trial (NCT03617731) of patients with transplant-eligible newly diagnosed MM.³ Incorporating this anti-CD38 monoclonal antibody into the triplet achieved the primary end point of MRD negativity in prior data; this presentation focused on the secondary end points of complete response (CR) and MRD negativity after the intensification period with high-dose therapy and autologous stem cell transplantation.

These new data confirmed superiority of isatuximab plus VRd vs VRd alone, with MRD negativity rates of 72% vs 56%, as well as a higher rate of conversions to MRD negativity after intensification, and the addition of isatuximab had no significant impact on the safety profile. Raab noted that the trial is ongoing and investigators hope to answer questions around the use of isatuximab in the maintenance setting following a second randomization.

Next up to present quadruplet data from a different angle was Xavier Leleu, MD, PhD, professor at Hôpital La Miletrie in France. He delivered results from the phase 3 BENEFIT IFM-2020-05 trial (NCT04751877) on the value of adding weekly bortezomib (V) to isatuximab plus Rd (Isa-Rd) for patients with transplant-ineligible newly diagnosed MM. The Isa-VRd arm met the primary end point, achieving a 53% MRD negativity rate at 10^–5 at 18 months vs 26% for Isa-Rd alone (OR, 3.16). That MRD benefit was consistent even in difficult-to-treat patient subgroups with negative prognostic factors. Safety was also “excellent,” which Leleu noted as especially important in transplant-ineligible patients, who may be more frail; 91.6% of participants were able to receive the regimen as planned per protocol.

This improved efficacy and safety profile supports the incorporation of bortezomib into the standard of care for these patients, Leleu said. Full results are now published in Nature Medicine.⁴

Finally, Philippe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France, took the podium to deliver updated data from the phase 3 CASSIOPEIA trial (NCT02541383) in transplant-eligible patients with newly diagnosed MM, which previously demonstrated superior PFS with daratumumab plus bortezomib/thalidomide/dexamethasone (VTd) vs VTd alone. These long-term outcomes, at a median follow-up of 80.1 months from first randomization, show that the addition of daratumumab to VTd in the induction/consolidation phase was associated with a median PFS about 2.5 years longer than with only VTd, as well as reducing the risk of death by 45%.

Daratumumab was also valuable in the maintenance phase, as it reduced the risk of progression or death by 51% vs observation. The patients who received daratumumab plus VTd at first and daratumumab maintenance had the most pronounced PFS benefit.

“When we first reported these study results, we had a question mark regarding the impact of daratumumab in maintenance, and we were wondering if it was important to receive dara for those patients who are treated upfront with daratumumab during induction. This slide is clearly showing that [daratumumab] is also important to improve on the PFS during maintenance,” Moreau said. Full results were published in the Lancet Oncology simultaneous with the presentation.⁵

With findings like these, hematologists can begin to replace the question marks in their treatment strategies for frontline MM with actionable knowledge on the most efficacious regimens.

References

1. Du J, Qiang W, Lu J, et al. A phase I open-label single-arm study of dual targeting BCMA and CD19 FasTCAR-T (GC012F) as first-line therapy for transplant-eligible newly diagnosed high-risk multiple myeloma. Presented at: EHA 2024 Congress; June 15, 2024; Madrid, Spain. Accessed June 15, 2024. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.eha/temp/eha24_abstract_bodies/S200.pdf

2. Sonneveld P, Moreau P, Dimopoulos MA, et al. Daratumumab + bortezomib/lenalidomide/dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma: analysis of minimal residual disease in the PERSEUS trial. Presented at: EHA 2024 Congress; June 15, 2024; Madrid, Spain. Accessed June 15, 2024. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.eha/temp/eha24_abstract_bodies/S201.pdf

3. Raab MS, Mai EK, Bertsch U, et al. Isatuximab, lenalidomide, bortezomib and dexamethasone for newly-diagnosed, transplant-eligible multiple myeloma: post transplantation interim analysis of the randomized phase III GMMG-HD7 trial. Presented at: EHA 2024 Congress; June 15, 2024; Madrid, Spain. Accessed June 15, 2024. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.eha/temp/eha24_abstract_bodies/S202.pdf

4. Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. Published online June 3, 2024. doi:10.1038/s41591-024-03050-2

5. 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. Published online June 15, 2024. doi:10.1016/S1470-2045(24)00282-1