IFM2012-03

Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy.

Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m². The safety profile appeared otherwise good for this frail population.

We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile.

Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min.

Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m² on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m² weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance.

Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2.

Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts.

As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56.

The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin.

Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m² of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m² of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time.