Trial Analyzes Efficacy of Tailoring MM Treatment to MRD Response

Twice weekly high doses of carfilzomib (56 mg/m²) in combination with lenalidomide and dexamethasone (KRd-56) was tolerable and effective among patients with newly diagnosed multiple myeloma (NDMM), according to research published in the American Journal of Hematology. The findings suggest the treatment method could serve as an induction regimen for NDMM patients.

“NDMM patients who achieve and sustain minimal residual disease (MRD) negative complete response/stringent complete response (CR/sCR) demonstrate clinical benefit with prolonged progression-free survival (PFS) and overall survival,” authors wrote.

The researchers conducted a single-center phase 1/2 clinical trial to investigate if high doses of carfilzomib (either 45 or 56 mg/m²) with lenalidomide and dexamethasone, (KRd-45 and KRd-56, respectively) resulted in improved outcomes among patients and to assess the prevailing doctrine of fixed number of cycles of induction therapy by integrating MRD testing into the clinic.

Phase 1 included a standard 3 + 3 schema design based on dose-limiting toxicities occurring during cycle 1, while phase 1/2 used a Simon’s optimal 2-stage design at the maximum tolerated dose (MTD) to determine the proportion of patients who achieved CR/sCR MRD negativity within 12 cycles, researchers explained.

Each patient underwent 28-day cycles of KRd-45 or KRd-56 and those who achieved CR/sCR underwent MRD testing. Then, the patients who achieved MRD-negative status received 2 additional cycles from conversion time and ceased further protocol therapy. The trial consisted of a maximum of 12 cycles between October 2016 and May 2020.

In phase 1, 3 patients received KRd-45 and 6 received KRd-56. As no dose-limiting toxicity (DLT) events occurred in this phase, researchers continued to investigate the MTD of 56 mg/m² of twice weekly carfilzomib. “An additional 20 patients (8 patients stage 1 and 11 patients stage 2) were enrolled and treated with KRd‐56 in phase II,” authors said. One patient withdrew consent after 1 cycle of therapy. Patients were followed-up with for a median of 36.7 months.

Analyses revealed:

• The most common grade 3/4 hematologic treatment-related adverse event (TRAE) was lymphopenia n = 7(24%)
• The most common grade 3/4 non-hematologic TRAE was electrolyte abnormalities n = 10 (34%)
• 13 serious AEs occurred including 7 infections, and single incidents of atrial fibrillation, non-ST elevation myocardial infarction, thromboembolic, decreased ejection fraction, gastrointestinal perforation, and severe constipation
• Best responses at MTD dose level KRd‐56 were CR/sCR MRD‐negative 48% (95% CI, 0.28-0.69), CR/sCR MRD unconfirmed 4% (95% CI, 0-0.2), very good partial response (VGPR) 40% (95% CI, 0.21-0.61), partial response 8% (95% CI, 0.01-0.26), objective response rate 100% (95% CI, 0.86-1.0), and ≥ VGPR serum response with MRD‐negative bone marrow 60% (95% CI, 0.39-0.79)
• Median number of cycles for patients to achieve CR/sCR MRD‐negative status was 8 (range, 2–12), and the median number of cycles delivered to the CR/sCR MRD‐negative group was 10 (range, 2–12)
• The MRD response‐adapted approach demonstrated 36‐month PFS rates at 73% (95% CI, 55%‐96%) for KRd‐56 and 77% (95% CI, 60%‐97%) for combined dosing cohorts

Toxicity profiles for KRd-45 and KRd-56 were comparable to KRd-36 regimens. However, “The KRd‐56 regimen yielded a CR/sCR MRD‐negative rate of 48% and a ≥VGPR MRD‐negative rate of 60%, meeting primary endpoint and similar to KRd‐36 regimens with and without autologous hematopoietic cell transplantation (AHCT),” researchers noted.

The median number of cycles delivered to patients achieving CR/sCR MRD-negative status (8) was also higher than the usual 4 cycle limit threshold followed by immediate AHCT, highlighting the individualized nature of disease response.

“It is unclear whether obtaining a simple MRD‐negative response after induction therapy is an optimal strategy for decision making in the high‐risk disease setting due to rapidly evolving kinetics,” authors said. “Perhaps MRD surveillance is particularly relevant in high‐risk disease patients and these patients should be considered for intensification regardless of MRD status.”

Future studies ought to be carried out to validate MRD response adopted approaches and sustainability in clinical practice, they concluded.

Reference

Korde N, Mastey D, Tavitian E, et al. Tailored treatment to MRD response: a phase I/II study for newly diagnosed multiple myeloma patients using high dose twice‐weekly carfilzomib (45 and 56 mg/m2) in combination with lenalidomide and dexamethasone. Am J Hematol. Published online March 4, 2021. doi:10.1002/ajh.26150