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)

    1. 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
    2. 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.