KRd Improves PFS as Maintenance Therapy in Transplant-Eligible Multiple Myeloma

Maintenance therapy with carfilzomib, lenalidomide, and dexamethasone led to a significant improvement in progression-free survival vs lenalidomide alone in patients with newly diagnosed multiple myeloma who underwent autologous stem cell transplant after induction therapy, according to an unplanned interim analysis of the phase 3 ATLAS trial.

Maintenance therapy with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) led to a significant improvement in progression-free survival (PFS) vs lenalidomide alone in patients with newly diagnosed multiple myeloma who underwent autologous stem cell transplant (ASCT) after induction therapy, according to findings from an unplanned interim analysis of the phase 3 ATLAS trial (NCT02659293). However, treatment with the KRd combination made no difference in overall survival (OS).

At a median follow-up of 33.8 months (interquartile range [IQR], 20.9-42.9), the median PFS was 59.1 months (95% CI, 54.8-not estimable) with KRd vs 41.4 months (95% CI, 33.2-65.4) with lenalidomide alone (HR, 0.51; 95% CI, 0.31-0.86; P = .012). OS was not significantly different between the KRd and lenalidomide arms (HR, 0.83; 95% CI, 0.35-2.00; P = .68). The median OS was not reached (95% CI, not evaluable [NE]-NE) in the experimental arm vs 61.8 months (95% CI, 61.8-NE) for the control.

“In this interim analysis of the ATLAS study, we showed that minimal residual disease [MRD]–directed and risk-adapted treatment with carfilzomib, lenalidomide, and dexamethasone for 8 to 36 cycles might offer a PFS benefit compared with lenalidomide alone as maintenance therapy after ASCT in patients with newly diagnosed multiple myeloma,” the study authors wrote in the publication.

In newly diagnosed, transplant-eligible multiple myeloma, lenalidomide maintenance following induction therapy and ASCT is standard of care. Attempts to improve PFS and OS after transplant with short consolidation therapy or tandem transplant have shown mixed results. However, emerging evidence from two phase 2 trials (NCT01816971; NCT02203643) suggest that KRd may be superior to lenalidomide maintenance alone.

To be eligible for enrollment in this trial, patients at least 18 years of age had to have newly diagnosed multiple myeloma and completed any type of induction followed by single ASCT. Patients had to have stable disease or better and received transplant within 100 days, initiated induction 12 months before enrollment, had an ECOG performance status of 0 or 1, an absolute neutrophil count of at least 1 × 10⁹ cells/L, a platelet count of at least 70 × 10⁹ platelets/L, adequate liver function, and creatinine clearance of at least 50 mL/min or serum creatinine lower than 2 mg/dL.

Patients were randomly assigned to receive KRd or lenalidomide alone as maintenancetherapy. Patients in the KRd arm received between 8 and 36 cycles of 20 mg/m² of intravenous carfilzomib in cycle one on days 1 and 2 then 36 mg/m² on days 1, 2, 8, 9, 15, and 16 in cycles 1 to 4 and 36 mg/m² on days 1, 2, 15, and 16 from cycle 5 up to 36; 25 mg of oral lenalidomide on days 1 to 21; and 20 mg of oral dexamethasone on days 1, 8, 15, and 22 in 28-day cycles.

Patients in the lenalidomide arm received 10 mg of oral lenalidomide for the first 3 cycles and then at the best tolerated dose (≤15 mg for 28 days in 28-day cycles until disease progression or unacceptable toxicity). After 36 cycles, patients in both treatment arms received lenalidomide maintenance.

To minimize the risk of financial and treatment-related toxicity, patients in the KRd arm without detectable MRD after cycle 6 and standard-risk cytogenetics proceeded to lenalidomide maintenance as of cycle nine.

Patients discontinued therapy if they had disease progression, unacceptable toxicity, were noncompliant with the study protocol, withdrew consent, or required alternative therapy.

All patients received prophylactic herpes zoster and venous thromboembolism for the duration of treatment. Other concomitant medications were permitted at the investigator’s discretion.

The primary end point was PFS, and secondary end points included the rate of MRD at 6, 12, 18, 24, and 36 months, correlation of MRD with PFS, duration of MRD, depth of response, improvement in the depth of response at 6 and 12 months, OS, and safety.

The unplanned interim analysis was triggered because 59 (61%) of the anticipated 96 events occurred for the primary analysis. Patients will continue to undergo follow-up until the primary analysis, at which point the last enrolled patient will reach 4 years of follow-up.

From June 10, 2016, to October 21, 2020, investigators assessed 193 patients for eligibility; 180 of whom were randomly assigned to receive KRd (n = 93) or lenalidomide alone (n = 87; intention-to-treat population.

Efficacy was analyzed in the intention-to-treat (ITT) population (n = 180). The safety population included 178 patients.

Baseline characteristics were balanced between the cohorts. The median patient age was 59.0 years (IQR, 49.0-63.0), and 84 (47%) patients were female.

Thirty-five patients in the ITT population of the KRd cohort had standard-risk disease and MRD negativity and were switched to lenalidomide maintenance after cycle 8.

At the data cutoff, 71 (76%; 95% CI, 66%-85%) patients in the KRd arm vs 62 (71%; 95% CI, 61%-80%) in the lenalidomide arm achieved complete response or better. However, investigators observed no significant difference in the depth of response (P = .71). Fifty (54%) patients in the experimental arm experienced improvement in the depth of response after 6 months compared with baseline assessment following ASCT vs 38 (44%) patients in the control arm (P = .18).

The rate of MRD negativity evaluated after cycle 6 was higher in the KRd arm (n = 48/91; 53%) vs in the lenalidomide arm in all evaluable patients (n = 26/84; 31%; P = .0035).

Regarding safety, grade 1/2 adverse effects (AEs) were more common in the KRd arm (n = 86/92; 93%) vs in the lenalidomide arm (n = 71/86; 83%), including higher occurrences of lymphopenia (n = 11; 12% vs n = 6; 7%) and anemia (n = 11; 12% vs n = 1; 1%) and upper respiratory tract infections (n = 51; 55% vs n = 36; 42%), fever (n = 16; 17% vs n = 2; 2%), and diarrhea (n = 27; 29% vs n = 17; 20%).

Grade 3/4 AEs occurred in 70 (76%) patients in the KRd arm vs 63 (73%) in the lenalidomide arm. The most frequent grade 3/4 AEs were neutropenia (n = 44; 48% vs n = 52; 60%), thrombocytopenia (n = 12; 13% vs n = 6; 7%), and lower respiratory tract infections (n = 7; 8% vs n = 1; 1%).

AEs that led to treatment discontinuation occurred in four (4%) patients in the KRd arm and ten (12%) in the lenalidomide arm. Serious AEs occurred in 28 (30%) patients in the KRd arm and 19 (22%) in the lenalidomide arm. Lower respiratory tract infections were the most common serious AE in both cohorts (n = 11; 12% vs n = 3; 3%).

One case of respiratory failure due to severe pneumonia led to death in the KRd arm and three second primary malignancies occurred overall (n = 1, KRd; n = 2, lenalidomide).

Reference

Dytfeld D, Wrobel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;S1470-2045(22)00738-0. doi:10.1016/S1470-2045(22)00738-0

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