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.
Multiple myeloma (MM) patients that develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months. This clearly illustrates that new anti-MM agents are needed with different mechanisms of action. Importantly, daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients, also those achieving complete response, will develop progressive disease during daratumumab therapy. Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59. At the time of progression, there is a reduced level of CD38 on the MM cells, whereas CD55 and CD59 levels are increased. This indicates that these factors are also involved in the development of daratumumab-resistant disease. Importantly, 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. The investigators will treat relapsed/refractory MM patients in two stages. The first stage (part A) consists of treatment with daratumumab monotherapy. In case these patients have progressive disease after cycle 1, less than minimal response after cycle 2, or less than partial response after cycle 3 (unless ongoing response) to single agent daratumumab, or in case these patients progress during daratumumab therapy after previous response, then ATRA will be added to daratumumab (part B). The aims of this study are to develop a safe ATRA and daratumumab combination suitable for clinical use and evaluation in subsequent randomized clinical trials. To this end, the maximum tolerated dose (MTD) of ATRA and daratumumab will be determined for patients with relapsed/refractory disease, who were treated with daratumumab but failed to achieve a partial response, or developed progressive disease during daratumumab treatment. This will be followed by a second part in which the investigators will examine the effectivity and toxicity profile of the combination at the MTD.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Phase 1 and 2: daratumumab 16 mg/kg, first 8 infusions are given weekly, then 8 infusions every 3 weeks, then every 4 weeks until progression Phase 1: ATRA 15, 30, or 45 mg/m2/day for 3 days. Phase 2: ATRA will be administered twice daily as an oral formulation at the MTD dose, or if no MTD is reached, at the dose of 45 mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled daratumumab infusion. The last administration of ATRA will be given in the evening of the day that daratumumab was administered (days -2, -1, and 0; day 0 is the day of daratumumab infusion).
VU University Medical Center
Amsterdam, North Holland, Netherlands
MTD
To determine the maximum tolerated dose (MTD) of daratumumab combined with ATRA. MTD is defined during the first treatment cycle (4 weeks).
Time frame: phase 1, during the first treatment cycle (28 days)
overall response rate
To investigate the efficacy of daratumumab combined with ATRA at the RDL, as determined by the overall response rate. This will be determined through study completion.
Time frame: Phase 2, every 28 days, until last treatment received, estimated to be 8 months
RDL
To determine the recommended phase 2 dose level (RDL) of daratumumab combined with ATRA. RDL is defined during the first treatment cycle (4 weeks).
Time frame: phase 1, during the first treatment cycle (28 days)
Incidence of severe adverse events
evaluation of severe adverse events (SAEs) through study completion. The analysis of treatment toxicity will be done primarily by tabulation of the incidence of adverse events CTCAE grade 2 or more by treatment cycle. Data from all subjects who receive any study drug will be included in the safety analyses. In the by-subject analysis, a subject having the same event more than once will be counted only once. Adverse events will be summarized by worst CTCAE grade.
Time frame: Phase 1 and 2, throughout treatment, estimated to be 8 months
Progression-free survival (PFS)
Progression-free survival is defined as time from registration until progression or death, whichever comes first. Actuarial survival curves for PFS will be computed using the Kaplan-Meier method, and 95% confidence interval (CI) will be constructed.
Time frame: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
overall survival (OS)
OS will be determined until study completion
Time frame: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for response
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Time frame: phase 1 and 2, every 28 days, until last treatment received, estimated to be 8 months
prognostic factors for PFS
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Time frame: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for OS
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Time frame: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
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