Myeloma-Developing Regimens Using Genomics (MyDRUG)

Prior treatment

• Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
• Concurrent symptomatic amyloidosis or plasma cell leukemia
• Residual side effects to previous therapy \> Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
• Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD)
• Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the investigational drug, whichever is longer
• Prior anticancer therapy within 14 days of initiation of protocol therapy (Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
• Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).

Other illness

• Infection requiring systemic antibiotic therapy or other serious infection within 14 days of enrolment
• Known hypersensitivity or development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar drug. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of the agents
• Serious medical or psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance, interfere in the completion of treatment per protocol, or follow-up evaluation
• Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV) infection
• POEMS syndrome \[plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes\]
• Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months

Lab values

• 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

Other

• Patients will be ineligible for this study if they meet any one of the following criteria:
• Pregnant or breast-feeding females
• Other co-morbidity, which would interfere with patient's ability to participate in trial or that confounds the ability to interpret data from the study
  • Sub-Protocol Exclusion Criteria:
  • Refer to each respective Sub Protocol for additional exclusion 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
• Females of reproductive potential must have a negative pregnancy test at baseline, be non-lactating, and willing to adhere to scheduled pregnancy testing
• Females of reproductive potential and males must practice and acceptable method of birth control
• Laboratory values obtained ≤ 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1000/ul
  • Hemoglobin (Hgb) ≥ 8 g/dl
  • Platelet (PLT) ≥ 75,000/ul
  • Total bilirubin \<1.5 x upper limit of normal (ULN) or if total bilirubin is \>1.5 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
  • Aspartate aminotransferase (AST) \<3 x ULN
  • Creatinine Clearance ≥ 30 mL/min
  • Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:
• Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
• ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
• Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda FLC ratio
• Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
  • Ability to take aspirin, warfarin, or low molecular weight heparin
  • Sub-Protocol Inclusion Criteria:
  • Refer to each respective Sub Protocol for additional inclusion criteria.