MUK eight: A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor.

Start date: 1 January 2015
End date: 1 January 2020
Partners and collaborators:
Funder: An NIHR Portfolio Trial developed within the Myeloma UK Early Phase Clinical Trial Network
Primary investigator: Professor Gordon Cook
Co-investigators: Professor Mark Cook, Dr David Meads, Dr Holger Auner, Dr Martin Kaiser, Professor Julia Brown, Dr Sarah Brown, Katrina Walker, Bryony Dawkins

Description

Multiple myeloma is a clonal late B-cell disorder in which malignant plasma cells expand and accumulate in the bone marrow leading to cytopenias, bone resorption, renal impairment and the production of a monoclonal protein. Myeloma represents 1.5% of all malignant diseases, with an incidence of 6.9/100,000 per year accounting for 4,500 new cases each year in the UK (representing 2,600 deaths per year).

Therapeutic options for myeloma have changed for both the young and the elderly patients with the arrival of potent novel agents such as proteasome inhibitors and IMiDs. Multi-agent combination chemotherapies with both conventional (Cyclophosphamide, Corticosteroids, Melphalan) and novel agents (Bortezomib, Lenalidomide, Thalidomide) when employed together, elicit frequent, rapid, and deep responses. Despite these benefits in both OS and PFS, myeloma remains incurable and patients develop resistance to both proteasome inhibitors and IMiDs. A retrospective study has recently demonstrated that patients with relapsed myeloma who were refractory to bortezomib and were relapsed following, refractory to, or ineligible to receive IMiD, had a median overall survival (OS) and event-free survival (EFS) of nine and five months, respectively. Thus, there is a need for novel agents for these patients.

From a clinical and pharmacoeconomic point of view it is believed that the evaluation of ixazomib in combination with cyclophosphamide and dexamethasone (ICD) is a valuable option for patients relapsing after IMIDs and first generation proteasome inhibitors.

Primary objective: To evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improves progression free survival compared to cyclophosphamide and dexamethasone (CD) in patients with relapsed or refractory multiple myeloma (RRMM) who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor.

Secondary objectives:

To determine the safety and toxicity profile of ICD
To estimate the cost-effectiveness of ICD vs. CD using a model based economic evaluation from the NHS perspective
To determine quality of life with ICD
To assess the impact of baseline Charlson index score on outcomes and deliverability of planned treatment

Exploratory Objectives:

To identify possible biomarkers of response to ICD

For the “cross-over” phase of the trial (from CD to ICD after progression on CD):

To estimate second progression-free survival (PFS2)
To determine the safety and toxicity profile of ICD