multiple myeloma
Conditions
Interventions
daratumumab plus nivolumab of daratumumab plus nivolumab plus low dose
cyclophosphamide
daratumumab
nivolumab
refractory MM
relapsed MM
Sponsors
Vrije Universiteit Medisch Centrum
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Age >
Exclusion criteria
Exclusion criteria: 1. Prior therapy with daratumumab or other anti-CD38 therapies 2. Non-secretory myeloma 3. Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom*s macroglobulinemia 4. Subject has known meningeal involvement of multiple myeloma 5. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment. 6. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody 7. Subject has previously received an allogeneic stem cell transplantation (at any time) 8. Inadequate marrow reserve as defined by a platelet count = 1.5 times normal value (except subjects with Gilbert syndrome, who can have total bilirubin = 3 times normal value), unless related to myeloma 12. Creatinine clearance <30 ml/min. 13. Known hypersensitivity to components of the investigational products or severe allergic or anaphylactic reactions to humanized products. 14. Subject has any concurrent severe and/or uncontrolled medical condition that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. 15. Subject is known to be seropositive for HIV or known to have AIDS, or any positive test for hepatitis B or hepatitis C indicating acute or chronic infection. 16. History of active malignancy during the past 3 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer or prostate cancer that is cured, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years. 17. Subjects with active interstitial pneumonitis 18. Subjects with active, known or suspected autoimmune disease or inflammatory disorder. Subjects with vitiligo,type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 19. Subj
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A: Primary objective - To determine which regimen of nivolumab with daratumumab (either with or without low dose cyclophosphamide) merits further evaluation in MM patients with previous exposure to proteasome inhibitor and lenalidomide-resistant disease, based on safety and efficacy data Part B Primary objective - To investigate the efficacy of nivolumab combined with daratumumab with or without low dose cyclophosphamide, as determined by the (s)CR+VGPR+PR rate. | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A: Secondary objective - Evaluate the safety of nivolumab-daratumumab with or without low dose cyclophosphamide in MM patients with previous exposure to proteasome inhibitor and lenalidomide-refractory disease - Evaluate the preliminary efficacy of nivolumab-daratumumab with or without low dose cyclophosphamide in MM patients with previous exposure to proteasome inhibitor and lenalidomide-resistant disease - To evaluate the immunomodulatory effects of nivolumab combined with daratumumab with or without low dose cyclophosphamide in blood and bone marrow by using flow cytometric analysis Part B: Secondary objectives - To evaluate toxicity. - To evaluate progression-free survival - To evaluate overall survival - To evaluate prognostic factors for response and survival, which includes cytogenetic abnormalities by FISH, *2-microgloublin, LDH, and MRD-negativity, as well as analysis of CD38, CIPs (CD46, CD55, and CD59), PD-L1 and PD1 expression - To evaluate the effects of daratumumab plus nivolumab with or without low dose cyclophosphamide on CD38 expression levels, CIPs (CD46, CD55, and CD59), and immune cells (e.g. T cells, NK cells, Tregs, and MDSCs) by using flow cytometric analysis and CYTOF - To analyze the prognostic value of myeloma gene expression profiles - To assess the prognostic value of mutations as determined by sequencing | — |
Countries
The Netherlands
Outcome results
None listed