Short summary

The primary hypothesis of this study is that six cycles of melflufen and dexamethasone re-induction as an adjunct to continued daratumumab in subjects that have become refractory to daratumumab will recapture and potentiate the clinical efficacy of daratumumab by suppressing the daratumumab-refractory myeloma sub-clones.

Rationale

Melflufen is a peptidase-potentiated alkylator. Due to its lipophilicity and peptidase-dependent distribution profile, a strong increase of alkylator is achieved in cancer cells, without a corresponding increase in other cells.

Preliminary data from several phase 2 studies show that melflufen is a safe and effective treatment of relapsed and refractory multiple myeloma. These studies are:

o O-12-M1 (melflufen-dexamethasone)

o HORIZON (melflufen-dexamethasone)

o ANCHOR (daratumumab/bortezomib-melflufen-dexamethasone)

Daratumumab is a first-in-class, human CD38 antibody. Daratumumab monotherapy is approved for the treatment of relapsed and refractory multiple myeloma. Daratumumab in combination with standard anti-myeloma regimens is approved for the treatment of both newly diagnosed and relapsed refractory myeloma.

The mechanisms by which myeloma cells become refractory to daratumumab are poorly understood.

Multiple myeloma is a clonally heterogenic disease driven by sub-clonal evolution. It is possible that daratumumab loses its effect due to the emergence of daratumumab-refractory myeloma sub-clones.

Description of the cohort

Adults with multiple myeloma who after an initial response have become refractory to daratumumab in their last line of therapy

Data and biological material

Blood samples.

Urine samples.

Bone marrow biopsy samples.

Skin biopsy sample.

Quality of life questionnaires.

Collaborating researchers and departments

Oslo Myeloma Center (Fredrik Schjesvold), Rigshospitalet (Peter Brown)