MRD Response-Driven Phase I/II Study for Newly Diagnosed Multiple Myeloma Patients Using Higher Doses of Twice-Weekly Carfilzomib (45 and 56 mg/m2) in Combination with Lenalidomide and Dexamethasone

Introduction

Newly diagnosed multiple myeloma (NDMM) patients achieving and maintaining minimal residual disease (MRD) negativity demonstrate clinical benefit with prolonged progression-free survival and overall survival. The IMWG recently updated response criteria to include MRD guidelines. However, there is no data demonstrating the benefit of integrating MRD testing into a response adapted treatment approach. Based on available data showing MRD negativity with standard dose KRD (36 mg/m2) approximating 40%, we designed the first MRD response-adapted (maybe better?) treatment study for NDMM. In this phase I/II study evaluating higher doses of twice-weekly carfilzomib (car) (45 and 56 mg/m2) in combination with lenalidomide (len) and dexamethasone (dex), the number of treatment cycles is determined based on MRD status, instead of the traditional treatment paradigm of same fixed number of treatment cycles.

Methods

Eligible NDMM patients were given escalating doses of car (45 and 56 mg/m2), len, and dex in a single arm, phase I standard 3+3 schema design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment consisted of 28-day cycles with car 20/45 mg/m2 or 20/56 mg/m2 - days 1,2, 8, 9 15 and 16; len 25 mg - days 1-21; and dex 40 mg weekly cycles 1-4, 20 mg after cycle 4. Patients achieving MRD negative status (serum, urine, and bone marrow with multi-parametric flow cytometry) after any cycle received 2 additional cycles prior to discontinuation of therapy. Patients with less than an MRD negative response after any cycle continued therapy until treatment completion (max 12 cycles), POD or unacceptable toxicity. The primary endpoint of the phase II study is to determine the MRD negative rate at the MTD dose, using a Simon's optimal two-stage design. In this abstract, we present results of phase I and the first stage of phase II.

Results

Seventeen patients meeting eligibility criteria were enrolled onto study (10 male, 7 female, median age 64 years, range 43-71) between October 2016 and May 2017. Baseline characteristics included 12(70%) ISS-I, 4(23%) ISS-II, and 1(6%) ISS-III; 3(18%) patients had high risk FISH - t(4,14), t(14,16), or p53 deletion. There were no DLTs meeting protocol criteria at the first dose level cohort (0/3 patients; 20/45 mg/m2) and second dose level cohort (0/6 patients; 20/56 mg/m2). The MTD chosen was 20/56 mg/m2, and an additional 8 patients were enrolled at the MTD dose. For both dose levels, grade > 3 adverse events were 5/17(29%) lymphopenia; 3/17(18%) metabolic; 3/17 (18%) infection; 3/17(18%) skin; 2/17 (12%) constitutional; 2/17(12%) cardiovascular; 1/17(6%) GI-related, and 1/17 (6%) thromboembolism. Among the 17 patients, two patients came off study: one due to personal preference (during C2), and one due to MI with EF decrease (during C2). Two patients underwent dose reductions of carfilzomib (1- constipation, 1 - liver function test elevation) with subsequent improved tolerability. With a median of 4 cycles delivered (range 1-7), best responses for both dosing cohorts were 1(6%) sCR/CR MRD negative, 1 (6%) sCR/CR MRD positive, 11 (65%) VGPR, and 4(23%) PR. An additional three VGPR patients underwent mid-treatment bone marrow assessments and were found to have no morphologic or immunophenotypic evidence of disease in the marrow.

Conclusion

In this phase I/II correlative study, the results from Stage 1 show that higher doses of twice weekly car (56 mg/m2) in combination with len and dex, resulted in rapid and deep responses, and the safety profile was similar to KRD standard dose (car 36 mg/m2). Stage 2 will open shortly and the study will be fully enrolled and presented at the ASH 2017 meeting. The results of this response-driven treatment study for NDMM patients, if shown to be as effective as expected, may challenge the traditional treatment paradigm consisting of predetermined fixed number of treatment cycles. This approach may represent a new paradigm shift in delivering upfront therapy in NDMM.