Post-transplant KRd a new SoC for MM?

In the ongoing phase III ATLAS study evaluating patients with newly diagnosed multiple myeloma (MM), progression-free survival (PFS) was better with maintenance treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) than lenalidomide (R) alone after autologous stem-cell transplantation (ASCT).

“Post-ASCT treatment for MM remains an area of active investigation,” said study investigator Dr Dominik Dytfeld from Poznan University of Medical Sciences, Poznan, Poland, at EHA 2022.

Given evidence suggesting a potential benefit of extended post-ASCT KRd therapy, [Blood 2020;36:2513-2523; Lancet Oncol 2021;22:1705-1720] Dytfeld and colleagues sought to explore whether post-transplant KRd treatment can improve the outcomes of R maintenance, which is an established standard of care (SoC), in the first-line treatment of patients with MM. [J Clin Oncol 2017;35:3279-3289]

The ATLAS study comprised 180 newly diagnosed MM patients (median age 58 years, 54 percent male) who had two lines of induction regimen at most, had bone marrow transplantation not later than 100 days before study entry, and had no progression at any time. Participants were randomized 1:1 to receive KRd* or daily R 10 mg (cycle[C]1–C3) or 15 mg (from C4 through 36, if tolerated). KRd was terminated after C8 among those who had standard risk (SR) cytogenetics and who achieved MRD** negativity at C6; they were then de-escalated to R alone (n=34). [EHA 2022, abstract S175]

After a median follow-up of 33.8 months, fewer patients on KRd progressed compared with those on R (25 percent vs 44 percent). Median PFS was longer with KRd vs R (59 vs 41 months; hazard ratio [HR], 0.56; p=0.026).

PFS was also much longer with KRd vs R among patients with SR cytogenetics (not reached [NR] vs 65.4 months; HR, 0.44; p=0.01), as well as among patients who had both SR cytogenetics and MRD negativity (HR, 0.23; p=0.01).

IMWG***-defined MRD-negative rates by C6 were higher in the KRd vs the R arm, both in the overall analysis (44 percent vs 27 percent; p=0.027) and among patients with SR cytogenetics (44 percent vs 26 percent; p=0.05).

Overall survival, toxicities

At data cutoff, 20 patients have died (nine in the KRd arm and 11 in the R arm). Median overall survival was NR in the KRd arm and 81.8 months in the R arm (HR, 0.92; p=0.86). This shall be further evaluated, noted Dytfeld, as it is still early even after ~3 years of follow-up.

In general, KRd treatment was well-tolerated, he continued, adding that their findings generally correlated with previous reports. Apart from the slightly higher rate of neutropenia with R vs KRd (59 percent vs 48 percent) and of infections with KRd vs R (15 percent vs 6 percent), adverse event rates were comparable between arms.

“Focusing on the toxicities of interest, there was no difference in cardiovascular (4 percent vs 6 percent) and neurological (1 percent vs 2 percent) toxicities between the KRd and the R arms,” he added.

This is the first randomized phase III trial indicating the superiority of post-transplant extended KRd therapy over R maintenance in terms of PFS, said Dytfeld. “[Moreover,] MRD-directed, risk-adapted KRd maintenance is potentially a more effective alternative to R maintenance. Therefore, MRD/risk-adapted post-ASCT extended KRd treatment may represent a new SoC for [newly diagnosed MM].”