Add-on carfilzomib yields benefits in transplant-ineligible NDMM patients

The addition of carfilzomib to lenalidomide and dexamethasone (KRd) improved outcomes in individuals with newly diagnosed fit or intermediate-fit multiple myeloma who are transplant ineligible (NTE NDMM) as opposed to Rd only in the phase III EMN20 trial.

“Rd has represented a standard of care for NTE NDMM, but MRD* negativity (MRD-) rate and median progression-free survival (PFS) with Rd were still relatively limited compared with three-drug regimens, especially in high-risk patients,” said Dr Benedetto Bruno from the University of Torino in Italy, at ASH 2023.

“There is really an unmet clinical need to improve PFS and deepen responses in this patient category,” he stressed, hence the need for strategies for improving and maintaining responses for longer periods, especially in fit and intermediate-fit patients for whom the treatment goal is to achieve deep and prolonged response.

Despite the limitations of cross-trial comparisons, the KRd regimen appears to have the capacity to address this need, Bruno noted.

“[In this trial,] the upfront treatment of NTE NDMM patients with weekly KRd regimen led to unexpectedly high rates of MRD-,” said Bruno.

Eighty-two participants (median age 74 years, 22 percent with high cytogenetic risk) were randomized 1:1 to receive oral Rd** with or without IV carfilzomib***. About a quarter of participants were 76–80 years. In terms of frailty status, more than half were deemed fit; none were frail. [ASH 2023, abstract 205]

At 1 year, half of KRd recipients achieved MRD-. By year 2, this jumped to 60 percent; 40 percent of the responses were considered sustained MRD-, which was defined as two consecutive MRD- test results, with the first being achieved after a year of treatment and the second at least 12 months after. None were able to achieve these outcomes in the Rd arm. P values of <0.0001 were achieved across all comparisons.

These findings imply that patients were improving over time with therapy, noted Bruno. “MRD- is strongly associated with a delay in [disease] progression.”

The MRD- translated to better PFS with KRd vs Rd after a median follow-up of 31.4 months (median not reached vs 20.9 months; hazard ratio [HR], 0.28; p=0.0013). The respective 2-year PFS rates with KRd and Rd were 81 percent and 48 percent. PFS continued to favour KRd across all subgroups.

In terms of response rates, ≥VGPR^# was markedly higher with KRd vs Rd (93 percent vs 45 percent; p<0.0001), as were ≥CR^# (52 percent vs 5 percent; p=0.0002) and ≥PR^# (95 percent vs 78 percent; p=0.04).

“The deep responses and long progression-free durations were observed regardless of age or cytogenetic risk. [These] stress the importance of adopting highly effective triplet-based regimens in these subcategories of NDMM patients,” Bruno pointed out.

KRd was associated with higher rates of grade 3–5 adverse events (AEs) than Rd, the most common being neutropenia (22 percent vs 12 percent), thrombocytopenia (10 percent vs 2 percent), and anaemia (7 percent vs 0 percent).

The incidence of cardiovascular (CV) AEs was also higher with KRd vs Rd (12 percent vs 3 percent) which, according to Bruno, was expected. “[Nonetheless,] the toxicities were predictable and manageable. For the CV AEs, CV assessment before and during treatment is essential.”

The efficacy and safety findings generally align with previous reports, but what sets the current trial apart from others is the carfilzomib dosing. [J Clin Oncol 2013;31:abstract 8543; JAMA Oncol 2015;1:746-754; N Engl J Med 2019;380:2104-2105] “We gave carfilzomib once weekly instead of twice, which offered convenience for patients,” , Bruno said. Also, the MRD- by NGS^## was higher than that observed in these trials.

A longer follow-up is warranted to ascertain a strategy for reducing the intensity of therapy in MRD- patients.