Myeloma-Developing Regimens Using Genomics (MyDRUG)

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
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.

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
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
Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
Pregnant or breast-feeding females
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
Concurrent symptomatic amyloidosis or plasma cell leukemia
POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
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).
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
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.