Multiple myeloma (MM) patients who develop bortezomib and lenalidomide-resistant disease have
a very poor survival of only a median of 9 months, indicating that new agents are urgently
needed. Recent studies have shown that daratumumab as a single agent is effective and well
tolerated in these heavily pretreated MM patients. However, approximately 60% of patients do
not achieve a partial response, and ultimately all patients will develop progressive disease
during daratumumab therapy.
The investigators have demonstrated that levels of the target antigen CD38, and expression
levels of the complement inhibitory proteins CD55 and CD59 determine the susceptibility of
the MM cells towards daratumumab. In addition, MM cells have lower CD38 expression levels and
higher levels of CD55/CD59 at the time of progression. Importantly, all-trans retinoic acid
(ATRA) upregulates CD38 levels and downregulates CD55/CD59 levels on MM cells, both in
daratumumab naïve cells and in cells that are resistant to daratumumab because of previous
exposure to this drug. These alterations in expression explain the strong synergy between
ATRA and daratumumab, both in MM cells derived from daratumumab naïve patients and from
patients with daratumumab-refractory disease.
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in
MM patients.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
VU University Medical Center
Collaborators:
Department of Medical Sciences, University of Torino EMC Rotterdam Erasmus Medical Center UMC Utrecht University of Turin, Italy Vejle Hospital Vejle Hospital and University of Southern Denmark