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

A proteasome inhibitor (PI) combined with an immune-modulatory dexamethasone has significant activity in replapse and newly diagnosed Multiple Myeloma (MM). Carfilzomib is an effective 2^nd generation PI. We report an update of a Phase 2 trial using Carfilzomib combined with Thalidomide and Dexamethasone in newly diagnosed MM.

This investigator sponsored, dose escalation phase 2 trial was designed to investigate Carfilzomib © combined with Thalidomide (T) and Dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Fifty patients in cohort 1 received 4 cycles of Carfilzomib 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, Thalidomide 200 mg p.o. days 1 through 28 of a 28 day cycle and Dexamethasone 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 (20 patients) the dose of Carfilzomib was escalated from 27 mg/m2 to 36 mg/m2 in the same schedule. In cohort 3 (20 patients) the dose of Carfilzomib increased to 45 mg/m2 in the same schedule. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), followed by consolidation therapy: 4 cycles of Carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), Thalidomide 50 mg days 1-28 of a 28 day cycle and Dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was very good partial response (VGPR) after 4 CTD cycles: secondary endpoints were complete response (CR), stringent CR (sCR), VGPR and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS).

90 patients were included as of 1^st April 2013. We here report the response of cohorts 1+2 (n=70) with a median follow-up of 22 and 7 months respectively. Median age was 58 yrs and ISS stages I/II/III were 27%/40%/27%, respectively. Six (9%) patients had renal failure with serum creatinine > 2 mg/dL. Of 70 patients in cohorts 1 and 2, 8 patients stopped treatment during/after induction and 4 patients after HDM because of refusal (n=2), toxicity (n=4) non-eligibility (n=2) or progression (n=4). 39 patients completed protocol treatment with 19 still on treatment. Overall response rate on protocol treatment was 96%. After induction therapy response was 19% (CR/sCR), 60% (≥ VGPR) and 93% (≥ PR), respectively. The CR/sCR rate increased to 30% after HDM and to 49% after consolidation. CR/sCR rate was not different across ISS staged I/II/III. In addition, response was similar in poor risk FISH (gain 1q or t(4;14) or del17p: 26% of patients) and standard risk FISH (all other). Progression-free survival (PFS) f 70 patients is 74%, overall survival (OS) is 7%. Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 60/60 patients and HDM/ASCT was performed with complete hematologic recovery in 53/53 patients. This regimen was well tolerated. Safety analysis for all 3 cohorts showed non-hematological toxicity CTC Grade 3+4 in < 5%, mainly infections and skin lesions. Other toxicities were Grade 2 ≤ or less than 5% including cardiac symptoms. Purified myeloma plasma cells, obtained in 39 patients at diagnosis were used for gene expression profiling and exome sequencing. The prognostic impact of the EMC-92 gene classifier on outcome with CTd will be presented.

Carfilzomib combined with thalidomide and dexamethasone is a safe and rapidly effective regimen for newly diagnosed MM. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals.

Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.