Phase II Study of Carfilzomib-cyclophosphamide-dexamethasone and High-dose Melphalan (HDT) Followed by Randomization Between Observation or Maintenance With Carfilzomib and Dexamethasone in Patients With Relapsed Multiple Myeloma After HDT

The survival in younger myeloma patients improved in the nineties with the introduction of high-dose melphalan with autologous stem cell support (HDT) and despite the emergence of novel therapies HDT remains a keystone in myeloma treatment. However, all patients will eventually experience relapse after HDT performed at diagnosis. Eligible patients with late relapse are considered for salvage HDT. The duration of response after salvage HDT is in most studies reported to be approximately half the length of the response after initial HDT. The choice of induction treatment before HDT might affect the outcome after the induction therapy as well as the outcome after the HDT. In other settings the novel proteasome inhibitor Carfilzomib has showed superiority to the first-in-class proteasome inhibitor bortezomib. In addition, carfilzomib has a favourable profile of side effects. Thus, the aim of this phase 2 study is to evaluate induction therapy with carfilzomib-cyclophosphamide-dexamethasone before salvage HDT. The primary end-point in this part of the study is comparison of time to progression after the initial HDT and time to progression after salvage HDT when four series of carfilzomib-cyclophosphamide-dexamethasone are used as induction therapy. In the study Carfilzomib is also included in the conditioning regimen with administration of Iv carfilzomib 27 mg/sqm on day -2 and -1. The standard conditioning regime consists of Iv melphalan 200 mg/sqm on day -2 and reinfusion of at least 2.0 x 10m CD34+ stem cells/kg body weight on day 0.

The purpose of maintenance therapy in multiple myeloma is to prolong the time to progression of disease. There are limited data on the impact of maintenance therapy after salvage HDT. Another important aim of the study is therefore to evaluate the effect of carfilzomib/dexamethasone given every other week compared to observation without maintenance therapy. This part of the study starts two months after HDT. The randomization is stratified according to relapse 1 - 2 years or > 2 years after HDT, ISS stage and standard versus high-risk cytogenetics. The primary end-point of this part of the study is comparison of time to progression in carfilzomib-dexamethasone maintenance arm and in the observational arm. Patients will continue on maintenance therapy/observation until progression, end of study or fulfil standard criteria for discontinuation of treatment according to the protocol.

The study will include 200 patients with relapse of multiple myeloma more than one year after initial HDT. It is a prerequisite that the patients have at least 2.0 x 10m CD34+ stem cells/kg body weight saved in the freezer. The study is conducted by the Nordic Myeloma Study Group (NMSG) at clinics in Denmark, Sweden, Norway, Finland and Lithuania. The first patient was included in January 2015 and enrolment is expected to continue until December 2017. The study ends when the last included patient has been followed for 9 months after randomization.