Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

IntroductionA phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplanteligible patients with multiple myeloma (MM).We report the results of 4 dose levels.MethodsIn this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m(2) i.v. on days 1, 2 followed by 27 mg/m(2) on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m(2) in cohort 2, to 20/45 mg/m(2) in cohort 3 and to 20/56 mg/m(2) in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m(2)) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m(2)) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg).The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS).ResultsAll 111 patients with a median follow-up of 55, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively.Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4).Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, >= VGPR in 66% of patients, >= PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%.Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4; 14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%.PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) all patients.Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)).Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m(2)), hypertension (n=2) and chest pain (n=1 at 45mg/m(2)).ConclusionCarfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m(2).[GRAPHICS].