Dose Escalation Phase 2 Trial of Carfilzomib Combined with Thalidomide and Low-Dose Dexamethason in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. a Trial of the European Myeloma Network

Background: Carfilzomib has significant activity in newly diagnosed Multiple Myeloma (MM). We present an update of a Phase 2 trial of dose-escalated Carfilzomib combined with Thalidomide and Dexamethasone (CTd).

Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to evaluate the clinical efficacy of standard dose Carfilzomib (C) (20/27 mg/m2) combined with Thalidomide (T) and Dexamethasone (D) (CTd) as induction therapy followed by high-dose Melphalan and autologous stem cell transplantation (ASCT), followed by consolidation therapy with CTd in transplant eligible patients with newly diagnosed symptomatic MM,. The second objective was to establish the maximum tolerated dose of Carfilzomib in this combination. Fifty patients were included in the first part who received 4 cycles of C at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, T 200 mg p.o. days 1 through 28 of a 28 day cycle and D 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In the second part 3 cohorts of 20 patients each were treated with escalated dose of C at 20/36 mg/m2,20/45 mg/m2 and 20/56mg/m2, respectively with T and D at the same dose. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and ASCT, followed by consolidation therapy consisting of 4 cycles CTd with C 27 mg/m2 (part1, n=50) or 36 mg/m2 or 45 mg/m2 or 56 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, respectively, combined with T 50 mg days 1-28 of a 28 day cycle and D 20 mg days 1, 8, 15, 22 of a 28 day cycle. Thrombosis prophylaxis was prescribed. The primary endpoint was very good partial response (VGPR) after 4 CTd cycles: secondary endpoints were complete response (CR), stringent CR (sCR) and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS).

Results: 111 patients were included as of 1^st July 2014. We here report the response of all cohorts with a median follow-up of 34, 19, 12 and 6 months, respectively. Median age was 58 yr and ISS stages II and III were 40% and 27%, respectively. The CTd regimen was well tolerated. Fifteen patients discontinued treatment because of non-eligibility (n=3), refusal (n=2), toxicity (n=7) or progression (n=3). Safety analysis was available for all treatments in cohorts 27mg/m2 through 45mg/m2 and for induction cycles in cohort 56mg/m2. Non-hematological SAEs for the two lower dose levels were infections (n=8), polyneuropathy gr 2 (n=5), cardiac (n=3) and tumor lysis syndrome (n=2) (ASH 2013). Non-hematological SAEs for dose level 45mg/m2 (n=22) included thrombosis (n=1), reversible gastrointestinal event (n=2) and infections (n=5). At dose level 56mg/m2 SAEs were thrombosis (n=2), infections (n=3), reversible cardiac event (n=1). In 111 patients 4 cardiac events were observed (2 grade 2, 2 grade 3) 3 of which resolved completely. Two patients discontinued therapy because of thrombosis (n=1) and pneumonia (n=1). Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 85/85 patients and HDM/ASCT was performed with complete hematologic recovery in 77/78 patients. The primary endpoint ≥VGPR and CR was achieved in 94% and 56% (27mg/m2), 75% and 65% (36mg/m2), 91% and 55% (45mg/m2), 75% and 20% (56mg/m2, induction only). Of 25 CRs in dose levels 36mg/m2 and 45mg/m2, 9 (36%) were stringent CR with no clonal plasma cells in bone marrow and negative serum-free lite. VGPR + CR increased from 63% after induction to 73% after HDM/ASCT and 86% after consolidation, respectively. For CR these figures were 18%, 34% and 58%, respectively. Overall response and CR were not significantly different between dose cohorts. Responses did not differ between poor risk (gain 1q or t(4;14) or del17p) and standard risk FISH. At a median follow-up of 21 months for dose levels 27mg/m2, 36mg/m2 and 45mg/m2 ,78% of patients are alive without progression or relapse. PFS at 18 months is 88 %. Three patients died of myeloma. There were 2 second primary malignancies. Analyses for revised ISS and molecular subgroups will be presented.

Conclusion: C combined with T and D is a safe and effective regimen for newly diagnosed MM. Dosing of Carfilzomib up to 56mg/m2 was well tolerated. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals, an Amgen subsidiary.