Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)
Overview
- Phase
- Phase 1
- Intervention
- Abemaciclib, dexamethasone, ixazomib, pomalidomide
- Conditions
- Relapsed Refractory Multiple Myeloma
- Sponsor
- Multiple Myeloma Research Consortium
- Enrollment
- 103
- Locations
- 16
- Primary Endpoint
- Overall Response Rate - Actionable Genetic Alteration
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Mutations in genes can lead to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. These arms have treatments specifically directed to the mutated genes. Patients that do not have a greater than 25% mutation to the genes listed can be enrolled to a non-actionable treatment arm.
The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies. (NCT02884102).
Detailed Description
The study will enroll 228 patients enrolled to one of eight treatment arms. The study is open to patients relapsing with relapsed refractory multiple myeloma, who have * received at least one prior but no more than 3 prior therapies * exposed to both a PI and an IMiD * had early relapse after initial treatment. Relapse is defined as the IMWG uniform response criteria (Kumar et al, 2016). Early relapse as defined by at least one of the following: 1. Relapse within 3 years post autologous stem cell transplantation (ASCT) on maintenance, or 18 months if unmaintained 2. Relapse within 18 months of initial non-ASCT based therapy
Investigators
Eligibility Criteria
Inclusion Criteria
- •Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and Mitigation Strategy (REMS®) program
- •Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less than 120 days old
- •Disease free of prior malignancies for ≥ 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or prostate cancer not requiring therapy
- •High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
- •received at least one prior but no more than 3 prior therapies
- •exposed to both a PI and an IMiD
- •had early relapse after initial treatment Early relapse as defined by at least one of the following: (Relapse is defined as the IMWG uniform response)
- •Relapse within 3 years of initiation of induction chemo therapy for post autologous stem cell transplantation (ASCT) followed by maintenance, or 18 months if unmaintained after ASCT
- •Within 18 months of initial non-ASCT based therapy
- •Patients must have progressed after their most recent treatment and require therapy for myeloma
Exclusion Criteria
- •Patients will be ineligible for this study if they meet any one of the following criteria:
- •Aggressive multiple myeloma requiring immediate treatment as defined by:
- •Lactate dehydrogenase (LDH) \> 2 times ULN
- •Presence of symptomatic extramedullary disease or central nervous system involvement
- •Hypercalcemia \>11.5 mg/dl
- •Acute worsening of renal function (CrCl \< 30 ml/min) directly related to myeloma relapse
- •Any neurological emergency related to myeloma
- •Clinical symptoms of hyperviscosity related to monoclonal protein
- •Involved serum free light chain \> 100 mg/dL (1000 mg/L) in the setting of prior diagnosis of cast nephropathy
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days of enrolment
Arms & Interventions
Sub-Protocol A1
Patients with CDK activating alteration receive Abemaciclib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Abemaciclib, dexamethasone, ixazomib, pomalidomide
Sub-Protocol B1
Patients with IDH2 activating mutation receive Enasidenib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Enasidenib, dexamethasone, ixazomib, pomalidomide
Sub-Protocol C1
Patients with the presence of RAF/RAS mutation receive Cobimetinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Cobimetinib, dexamethasone, ixazomib, pomalidomide
Sub-Protocol D1
Patients with presence of FGFR3 activating mutations receive Erdafitinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Erdafitinib, dexamethasone, ixazomib, pomalidomide
Sub-Protocol E1
Patients with t(11;14) translocation will be enrolled in arm E1 and randomized to the venetoclax or the IPd control arm. Patients with relapsed Multiple Myeloma will receive Venetoclax, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long.
Intervention: Venetoclax, dexamethasone, ixazomib, pomalidomide
Sub-Protocol Y1
Patients with Non-Actionable Genetic Abnormality receive Daratumumab in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Daratumumab, dexamethasone, ixazomib, pomalidomide
Sub-Protocol Y2
Patients with Non-Actionable Genetic Abnormality receive Belantamab mafodotin in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Belantamab mafodotin, dexamethasone, ixazomib, pomalidomide
Sub-Protocol Y3
Patients with Non-Actionable Genetic Abnormality receive Selinexor in combination with ixazomib, pomalidomide and dexamethasone (IPd)
Intervention: Selinexor, dexamethasone, ixazomib, pomalidomide
Outcomes
Primary Outcomes
Overall Response Rate - Actionable Genetic Alteration
Time Frame: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years
• To evaluate the overall response rate (ORR) with targeted agents used in combination with backbone regimen ixazomib, pomalidomide and dexamethasone (IPd) in patients with an actionable genetic alteration per the International Myeloma Working Group \[IMWG\] consensus criteria (Kumar et al, 2016)
Overall Response Rate - Non-Actionable Genetic Alteration
Time Frame: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years
• To evaluate the ORR with agents used in combination with backbone (or IPd) regimen in patients with no actionable genetic alteration per IMWG consensus criteria (Kumar et al, 2016).