ATLAS Analysis Supports KRd After ASCT in High-Risk, Newly Diagnosed Myeloma

Treatment with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) following autologous stem cell transplant (ASCT) improved survival compared with lenalidomide alone in patients with newly diagnosed multiple myeloma, according to data from an analysis of the high-risk subset enrolled on the phase 3 ATLAS trial (NCT02659293).¹

At a median follow-up of 5.7 years, findings presented at the 22nd Annual International Myeloma Society Meeting and Exposition demonstrated that patients in the intention-to-treat (ITT) population who received KRd (n =92) experienced a median PFS of 72.8 months compared with 37.3 months for those given lenalidomide alone (n = 88; HR, 0.46; 95% CI, 0.30-0.70; P = .0002). The 4-year PFS rates were 67.5% and 38.0%, respectively.

The median OS was not reached (NR) for patients in the ITT arm given KRd, compared with 82.2 months for those treated with lenalidomide alone (HR, 0.49; 95% CI, 0.26-0.90; P = .023).

In the high-risk population, the median PFS was 59.1 with KRd (n = 22) compared with 29.7 months with lenalidomide alone (n = 18; HR, 0.54; 95% CI, 0.22-1.15; P = .13). A benefit was also seen with KRd among standard-risk patients (HR, 0.43; 95% CI, 0.26-0.69; P < .001).

“Based on these results, we believe that risk-stratified, minimal residual disease [MRD]–directed, post-transplant KRd treatment may be considered one of the options for patients with newly diagnosed myeloma,” lead study author Andrzej Jakubowiak, MD, PhD, professor of medicine and director of the Myeloma Program at University of Chicago Medicine in Illinois, said during the presentation.

What Did the ATLAS Trial Investigate in Multiple Myeloma?

Carfilzomib is currently approved as part of multiple regimens for select patients with multiple myeloma; KRd is specifically approved for the treatment of patients with relapsed/refractory disease who have received 1 to 3 prior lines of therapy.²

The international, multicenter, open-label, ATLAS trial enrolled patients with newly diagnosed multiple myeloma who had undergone ASCT after completing no more than 2 standard-of-care induction regimens.¹ Patients needed to be free from disease progression and were required to be 90 to 120 days removed from transplant. They also needed to have complete induction therapy within 12 months of enrollment.

Patients were randomly assigned 1:1 to receive KRd or lenalidomide alone. In the experimental arm, patients were given carfilzomib at 36 mg/m² on days 1, 2, 8, 9, 15, and 16 of cycles 1 to 4, then days 1, 2, 15, and 16 in cycles 5 to 8; lenalidomide at 25 mg on days 1 to 21 of cycles 1 to 8; and dexamethasone at 20 mg on days 1, 8, 15, and 22 of cycles 1 to 8. In cycles 9 to 36, patients with MRD negativity and standard-risk disease received lenalidomide alone at 15 mg on days 1 to 28 of cycles 9 to 36. Those with MRD-negative, high-risk disease after cycle 8 continued on the same KRd regimen used in cycles 5 to 8.

In the control arm, patients received lenalidomide at 10 mg days 1 to 28 of cycles 1 to 3; escalation to 15 mg per day was permitted in cycle 4, and treatment continued for 36 cycles. After cycle 36, all patients in both arms continued on lenalidomide alone.

PFS served as the trial’s primary end point. Secondary end points included OS, MRD status, and safety.

In the ITT population, the median age at baseline was 57.0 years (range, 32-70) in the KRd arm vs 59.0 years (range, 34-71) in the lenalidomide arm. Notably, a higher proportion of patients in the KRd arm were female (53.3%) compared with the lenalidomide arm (40.9%). Most patients in both groups were from Poland (KRd, 88.0%; lenalidomide, 88.6%) and had standard-risk cytogenetics (76.1%; 79.5%). Disease stage per the International Staging System classification criteria was I (43.5%), II (35.9%), or III (20.6%) in the KRd arm; these respective rates were 30.7%, 54.6%, and 4.8% in the lenalidomide arm.

The median time for ASCT was 95.5 days (range, 78-114) in the KRd arm vs 101 days (range, 81-122) in the control arm. Notably, 19.6% of patients in the experimental arm and 23.9% of patients in the control arm were MRD negative at screening.

Induction therapies given prior to the trial included a bortezomib (Velcade)-containing regimen for most patients (KRd, 91.3%; lenalidomide, 89.8%). Proportions of patients were also previously exposed to lenalidomide (12%; 10.2%) and carfilzomib (4.3%; 5.7%). Most patients received only 1 induction regimen (92.4%; 94.3%).

How Did PFS Vary by Baseline MRD Status?

In the ITT population, KRd was associated with improved PFS vs lenalidomide alone in patients who had MRD-positive disease at baseline (HR, 0.49; 95% CI, 0.31-0.77; P = .001). A similar benefit was observed with the triplet in patients with MRD-negative disease at baseline (HR, 0.30; 95% CI, 0.09-0.92; P = .03).

Notably, 14% of patients with high-risk disease in the KRd arm were MRD negative at baseline, and this rose to 41% at cycle 6. These respective rates were 22% and 33% among high-risk patients in the lenalidomide arm.

What Were the Key Safety Findings?

Any-grade adverse effects (AEs) occurred in 98% of patients in the KRd arm vs 95% of patients in the lenalidomide arm. The rates of grade 3 or higher AEs were 79% and 74%, respectively, and the respective rates of grade 5 AEs were 2.2% and 2.3%. Serious AEs were reported in 32% of patients in the KRd arm compared with 23% of patients in the control arm. AEs led to treatment discontinuation in 6.6% and 10.3% of patients, respectively.

The most common any-grade serious AEs reported in the KRd arm included lung infection (11.0%), upper respiratory tract infection (5.5%), and urinary tract infection (3.3%). The most common any-grade serious AEs in the control arm were lung infection (4.6%) and upper respiratory tract infection (3.4%).

Disclosures: Jakubowiak reported serving as a consultant or on advisory boards for AbbVie, Amgen, BMS, Gracell, GSK, Janssen, Regeneron, and Sanofi.

References

1. Jakubowiak A, Wrobel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: analysis of high-risk subset in phase 3 ATLAS trial. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-51.
2. Kyprolis. Prescribing information. Amgen; 2025. Accessed September 20, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Kyprolis/kyprolis_pi.pdf