Isatuximab-Based Quadruplet Significantly Boosts PFS in Transplant-Eligible NDMM

Bone biopsy of multiple myeloma cells.

Adding isatuximab-irfc (Sarclisa) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Isa-RVd) as induction, followed by autologous stem cell transplant (ASCT), significantly reduced the risk of disease progression or death vs RVD in patients with transplant-eligible newly diagnosed multiple myeloma, according to data from an analysis of part 1 of the phase 3 GMMG-HD7 trial (NCT03617731) presented at the 2024 ASH Annual Meeting.¹

At a median follow-up of 48 months, Isa-RVd (n = 331) given as induction treatment for 18 weeks without consolidation led to a 30% reduction in the risk of disease progression or death vs RVd (n = 329), irrespective the maintenance therapy received (HR, 0.70; 95% CI, 0.52-0.95; stratified log-rank P = .0184). Moreover, weighted risk set estimator accounting for second randomization confirmed a significant benefit for Isa-RVd vs RVd induction followed by standard-of-care (SOC) lenalidomide maintenance only (stratified weighted log-rank P = .016).

The progression-free survival (PFS) benefit with Isa-RVd vs RVd was observed in most clinically relevant subgroups, except for those with a World Health Organization (WHO) performance status of over grade 1 (HR, 1.09; 95% CI, 0.47-2.52; P = .839), high-risk cytogenetics (HR, 1.09; 95% CI, 0.63-1.91; P = .755), and Revised International Staging System (R-ISS) stage III disease (HR, 1.25; 95% CI, 0.53-2.93; P = .608).

“GMMG-HD7 is the first phase 3 study to show that an 18-week initial quadruplet regimen with isatuximab, without consolidation, allows for significant long-term benefits regardless of subsequent maintenance therapy,” Elias K. Mai, MD, hematologist and myeloma specialist in the Department of Internal Medicine V (Hematology, Oncology and Rheumatology) at Heidelberg University Hospital in Germany, said in a presentation of the data.

In September 2024, the FDA approved Isa-RVd for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for ASCT based on findings from the phase 3 IMROZ trial (NCT03319667).² The agent paired with dexamethasone and pomalidomide (Pomalyst) or carfilzomib (Kyprolis) has been approved for adult patients with relapsed or refractory multiple myeloma in several countries.¹

Exploring GMMG-HD7 Enrollment and Patient Characteristics

Part 1 of GMMG-HD7 enrolled a total of 662 patients with newly diagnosed multiple myeloma who were randomly assigned 1:1 to receive Isa-RVd as induction treatment for three 6-week cycles or RVd. Patients received high-dose melphalan followed by an ASCT. Those who had less than a complete response (CR) or high-risk disease could opt for a tandem transplant. In the second part of the trial, patients were again randomly assigned 1:1 to receive maintenance treatment with isatuximab plus lenalidomide or SOC lenalidomide for up to 3 years or until progressive disease.

The trial’s primary end points included post-induction minimal residual disease (MRD) negativity rates, which have already been reported,³ and PFS from second randomization, which will be shared when the data mature, according to Mai.¹

Key secondary end points include PFS for the whole study, overall survival for the whole study and from second randomization, post-induction CR, CR and MRD negativity after high-dose melphalan and during and after maintenance treatment. A selected secondary end point was PFS after first randomization; these data are what were shared during the meeting, comparing induction treatment with Isa-RVd and RVd.

The baseline characteristics of patients enrolled in part 1 were previously shared and were noted to be well balanced. Across the Isa-RVd and RVd arms, the median age at time of randomization was 58.5 years (range, 26-70) and 62.5% of patients were male. Moreover, patients had a WHO performance status of 0 (48% vs 51%), 1 (41% vs 40%), and over 1 (11% vs 9%) in the Isa-RVd vs RVd arms, respectively. More than half of patients had a heavy chain type of IgG (59% vs 58%); most did not have renal impairment (94% vs 93%), high-risk cytogenetics (77% vs 71%), or elevated lactate dehydrogenase levels (81% vs 87%). R-ISS disease stages were I (23% vs 30%), II (66% vs 56%), or III (8% vs 8%); this was not classified for 2% and 6% of patients, respectively.

Of the 662 patients who underwent randomization, 331 comprised the Isa-RVd arm and 329 comprised the RVd arm as the intention-to-treat (ITT) populations. Of the 331 patients in the Isa-RVd arm, 94% started or continued after induction therapy; a first transplant was given to 92% of patients, 24% underwent second transplant, and a total of 150 patients (87%) were randomized to receive maintenance therapy with lenalidomide plus isatuximab or lenalidomide alone. Of the 329 patients in the RVd arm, 89% started or continued induction treatment; 84% and 30% underwent first or second transplant, respectively, and a total of 131 patients (82%) were randomized to maintenance treatment.

Further Data Regarding MRD and Next Steps for GMMG-HD7

“As previously reported, the addition of isatuximab to RVd in GMMG-HD7 in patients with transplant-eligible newly diagnosed multiple myeloma met the first primary end point of MRD negativity after induction therapy,” Mai said.

Additional data from another presentation given by Mai at the 2024 ASH Annual Meeting were focused on the effects of MRD on PFS in the trial. MRD negativity rates after induction were 50.1% in the Isa-RVd arm and 35.6% in the RVd arm (OR, 1.83; 95% CI, 1.34-2.51; P < .0001).⁴ Isa-RVd also led to a deeper MRD-negative response post-transplant vs RVd in the ITT population, at 66.2% vs 47.7% (OR, 2.13; 95% CI, 1.56-2.92; P < .0001). Furthermore, the CR and MRD negative rates post-transplant were 38.1% vs 25.8% (OR, 1.76; 95% CI, 1.25-2.50; P = .001), respectively, and the very good partial response or better and MRD negative rates post-transplant were 63.4% vs 43.8% (OR, 2.22; 95% CI, 1.63-3.03; P < .0001), respectively. Data also revealed that the continued MRD negative rates were 53.1% in the Isa-RVd arm and 38.0% in the RVd arm (OR, 1.84; 95% CI, 1.28-2.63; P = .0008).⁴

“Isa-RVd is the first regimen to demonstrate a deep and rapid response reflected by a statistically significant MRD-negative benefit at the end of induction and post-transplant in a phase 3 trial, which translated to a PFS benefit vs RVd,” Mai noted.¹

When examining the effect of MRD status at the end of induction on PFS, regardless of treatment arm patients who achieved MRD negativity at the end of induction experienced improved PFS vs those who did not (HR, 0.38; 95% CI, 0.26-0.55; P < .001).⁴

“More patients achieved MRD negativity in the Isa-RVd group, however, at this follow up, PFS from [the] end of induction was similar in the Isa-RVd and RVd groups in patients achieving MRD negativity [HR, 1.12; 95% CI, 0.60-2.11; P = .72], while it was significantly longer in the Isa-RVd vs RVd group in patients with MRD positivity [HR, 0.64; 95% CI, 0.43-0.96; P = .03],” Mai noted in a presentation of the data. “At a median follow-up of 48 months, MRD negativity achieved post induction and/or post-transplant resulted in better PFS outcomes than MRD positivity [did] in both the Isa-RVd and RVd arms while Isa-RVd showed a benefit over RVd in MRD positive patients.”

Follow-up of the study is ongoing and the next readout will be on the primary end point of part 2 of the study, which will be PFS data from the second randomization comparing maintenance therapy with isatuximab plus lenalidomide or lenalidomide monotherapy. This is the “only phase 3 study with second randomization before maintenance incorporating SOC lenalidomide, which allows the effects of isatuximab in induction and maintenance to be isolated and evaluated separately,” Mai concluded.¹

Disclosures: Dr Mai disclosed serving in a consulting or advisory role for Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, Stemline, and Takeda. He has received honoraria from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, Pfizer, Sanofi, Stemline, and Takeda. Research funding was provided by BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, and Takeda. Travel accommodations and expenses were supplied by BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline, and Takeda. He has membership on board of directors or advisory committees from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Onctopeptides, Pfizer, Sanofi, Stemline, and Takeda.

References

1. Goldschmidt H, Bertsch U, Pozek E, et al. Isatuximab, lenalidomide, bortezomib and dexamethasone induction therapy of transplant-eligible patients with newly diagnosed multiple myeloma: final progression-free survival analysis of part 1 of an open-label, multicenter, randomized, phase 3 trial (GMMG-HD7). Blood. 2024;144(suppl 1):769. doi:10.1182/blood-2024-193308

2. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed December 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple

3. Goldschmidt H, Mai EK, Bertsch U, et al. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022;9(11):e810-e821. doi:10.1016/S2352-3026(22)00263-0

4. Mai EK, Salwender H, Hundemer M, et al. Impact of minimal residual disease on progression-free survival in patients with newly diagnosed multiple myeloma treated with isatuximab, lenalidomide, bortezomib and dexamethasone induction therapy in the phase 3 GMMG-HD7 trial. Blood. 2024;144(suppl 1):364. doi:10.1182/blood-2024-194768