Carfilzomib Plus Lenalidomide/Dexamethasone After Transplant Extends PFS Over Lenalidomide in MM

Andrej Jakubowiak, MD, PhD

Results from the phase 3 ATLAS trial (NCT02659293) show that extended treatment with carfilzomib (Kyprolis) plus lenalidomide (Revlimid) and dexamethasone (KRd) after autologous stem cell transplant (ASCT) improved progression-free survival (PFS) over standard lenalidomide maintenance in patients with multiple myeloma.¹

Data presented at the 19th International Myeloma Society Annual Meeting showed that after a median follow-up of 33.8 months, the median PFS in the KRd arm was 59.0 months (95% CI, 52.5–not reached) vs 41.1 months (95% CI, 33.4-65.4) with lenalidomide (HR, 0.56; 95% CI, 0.34-0.93; P = .026). This translates to a 44% reduction in the risk of disease progression or death with KRd.

“This is, we believe, the first randomized phase 3 trial which could indicate superior PFS with extended post-transplant KRd therapy compared with standard of care lenalidomide maintenance,” said lead study author Andrej Jakubowiak, MD, PhD, professor of medicine at the Comprehensive Cancer Research Center and director of the Myeloma Program at The University of Chicago Medical Center, in a presentation on the data. “Here, we used a minimal residual disease (MRD)–directed, risk-adapted maintenance which we believe is a potentially more effective alternative to lenalidomide maintenance and may represent a new standard of care.”

Treatment after ASCT for patients with multiple myeloma continues to be an area of active investigation. Previous results have shown that extended treatment with post-ASCT KRd following KRd induction treatment can further improve depth of response linked with prolonged PFS benefit, according to Jakubowiak. These data, along with findings from the phase 2 FORTE trial (NCT02203643), provided the rationale to directly compare post-ASCT KRd with lenalidomide maintenance treatment, he added.

The multicenter, randomized, open-label, phase 3 trial enrolled patients with newly diagnosed multiple myeloma who received any induction therapy for up to 12 months followed by a single ASCT and achievement of at least stable disease within 100 days following transplant.² Patients could not have received more than 2 induction regimens.

Study participants were randomly assigned 1:1 to the KRd or lenalidomide arms. Those in the lenalidomide arm received the agent at 10 mg for cycles 1 to 3 and then 15 mg daily followed by lenalidomide maintenance. Those in the KRd arm received carfilzomib at 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 1 to 4 and on days 1, 2, 15, and 16 for cycles 5 to 8; lenalidomide at 25 mg on days 1 to 21 for cycles 1 to 8; and dexamethasone at 20 mg on days 1, 8, 15, and 22 of cycles 1 to 8 of 28-day cycles.

Those with standard risk disease who achieved MRD negativity per International Myeloma Working Group (IMWG) criteria following cycle 6 de-escalated therapy to lenalidomide alone following cycle 8. The rest of the cohort continued to receive KRd through cycle 36, followed by lenalidomide alone until disease progression.

Patients were stratified based on post-ASCT response (very good partial response rate [VGPR] or better vs <VGPR), cytogenetic risk (standard risk vs high risk), and location of trial site (United States vs Poland).

The primary end point of the trial was PFS, and key secondary end points included MRD at cycles 6 and 12, objective response rate, VGPR rate, complete response (CR) rate, stringent CR rate, and safety.

A total of 180 patients underwent randomization; 93 were allocated to the KRd arm and 87 were allocated to the lenalidomide arm; 92 and 86 patients, respectively, went on to receive treatment and could be evaluated for efficacy.

The median age of patients enrolled to the KRd arm was 57 years (range, 32-70) vs 59 years (range, 34-71) in the lenalidomide arm; 50% vs 41%, respectively, were women. Regarding ECOG performance status, 48% and 37% of patients, respectively, had a status of 1, and 52% vs 63%, respectively had a status of 2.

In the KRd arm, 42% of patients had stage I disease at baseline per the International Staging System (ISS), 41% had stage II disease, and 16% had stage III disease; these rates were 32%, 48%, and 20%, respectively, in the lenalidomide arm. In the KRd and lenalidomide arms, 88% and 92% of patients, respectively, had a VGPR or better at the time of study entry; 23% vs 21% of patients, respectively, had high-risk cytogenetics. The median time from ASCT was 92 days and 94.5 days, respectively.

The most common induction regimen received in the KRd and lenalidomide arms, respectively, was bortezomib (Velcade), thalidomide (Thalomid), dexamethasone (68% vs 60%). In the KRd arm, 11% of patients previously received lenalidomide and 4% had prior carfilzomib; these rates were 13% and 6%, respectively, in the lenalidomide arm. In the KRd and lenalidomide arms, 8% and 6% of patients, respectively, received 2 induction regimens.

Additional data presented during the meeting showed that the hazard ratios for PFS favored extended post-transplant KRd vs lenalidomide maintenance across most subgroups analyzed. The only exception occurred in those with ISS III disease (HR, 1.95; 95% CI, 0.69-5.49).

MRD negativity as per the IMWG definition was achieved in 44% of those in the KRd arm (n = 90) vs 27% of those in the lenalidomide arm (n = 84; P = .019) at cycle 6. By next-generation sequencing, MRD negativity at a sensitivity threshold of 10-5 was achieved in 50% of those in the KRd arm (n = 66) vs 33% of those in the lenalidomide arm (n = 63; P = .055). MRD negativity at a sensitivity threshold of 10-6 was achieved by 33% and 24% of patients, respectively (P = .231).

“Because this was an MRD-directed, risk-adapted study design in which standard-risk patients could be de-escalated, when we focus on MRD evaluations and PFS for standard-risk patients we see [a clear] difference between KRd and lenalidomide,” Jakubowiak said.

MRD negativity by IMWG criteria was achieved by 45% of those in the KRd arm who had standard-risk cytogenetics (n = 69) vs 27% of those in the lenalidomide arm (n = 67; P = .028). The median PFS was not yet reached (95% CI, 54.8–not reached) in the KRd arm vs 65.4 months (95% CI, 33.1-65.4) in the lenalidomide arm (HR, 0.44; 95% CI, 0.24-0.81; P = .01).

“In standard-risk patients who achieved MRD negativity, which is the group of patients who de-escalated on the KRd arm…we see a benefit with KRd vs lenalidomide,” Jakubowiak noted, with a hazard ratio of 0.23 (95% CI, 0.06-0.86; P = .01).

Overall survival data are still immature, “with a limited number of events,” Jakubowiak added. At the data cutoff, 11.2% of patients have died; this includes 9.8% of those in the KRd arm and 12.8% of those in the lenalidomide arm. The median OS in the KRd arm has not yet been reached (95% CI, NR-NR) vs 81.8 months (95% CI, 61.8-NR) in the lenalidomide arm (HR, 0.92; 95% CI, 0.37-2.26; P = .86).

The most common grade 3 or higher hematologic toxicities reported in the KRd and lenalidomide arms, respectively, were neutropenia (47% vs 63%), febrile neutropenia (4% vs 6%), thrombocytopenia (13% vs 7%), lymphopenia (8% vs 2%), and anemia (4% vs 0%).

Adverse effects of special interest in the KRd and lenalidomide arms, respectively, were cardiovascular toxicities (4% vs 6%), infection (17% vs 8%), secondary malignancies (0% vs 1%), and treatment-related deaths (1% vs 0%).

Other toxicities included elevated liver enzymes (7% vs 0%), diarrhea (1% vs 2%), neurological events (1% vs 2%), rash (1% vs 2%), dental toxicities (1% vs 0%), flu-like symptoms (1% vs 1%), hyperglycemia (2% vs 0%), hypokalemia (1% vs 1%), and cataract (1% vs 1%).

_References

_{1. Jakubowiak AJ, Wrobel T, Jamtroziak K, et al. ATLAS: a phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. Presented at: 19th Annual International Myeloma Society Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-010}

_{2. Dytfeld D, Wrobel T, Jamroziak K, et al. ATLAS: a phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. J Clin Oncol. 2022;40(suppl 16):8001. doi: 10.1200/JCO.2022.40.16_suppl.8001}