The following criteria is provided for health care professionals.

Inclusion Criteria:

• Symptomatic multiple myeloma having progressed on 2 prior therapies including proteasome inhibitor (i.e. bortezomib, carfilzomib ixazomib), immunomodulatory drug (i.e., thalidomide, lenalidomide, pomalidomide), and daratumumab or other CD38 targeting monoclonal antibody. Proteasome inhibitor refractory patients are eligible. Subjects must not be candidates for treatment regimens known to provide clinical benefit to be eligible for this study.
• Male or female patients 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Patients must have measurable disease defined by at least 1 of the following 3 measurements:
  • Serum M-protein > 0.5 g/dL
  • Urine M-protein > 200 mg/24 hours
  • Serum free light chain assay: involved free light chain level >10 mg/dL (> 100 mg/L) provided the serum free light chain ratio is abnormal

Exclusion Criteria:

1. Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination during the Screening period.
2. Significant cardiac disease as determined by the investigator including:
   1. Known or suspected cardiac amyloidosis
   2. Congestive heart failure of Class III or IV of the NYHA classification
   3. Uncontrolled angina, hypertension or arrhythmia
   4. Myocardial infarction in the past 6 months
   5. Any uncontrolled or severe cardiovascular disease
   6. QTc > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
3. Known active hepatitis B (defined as most recent serum PCR or hepatitis B surface antigen positive) or active hepatitis C (note, hepatitis C in sustained virologic response defined as negative RNA PCR at least 12 weeks after any therapy is permitted).
4. Any medical conditions that, in the investigator's opinion, would impose excessive risk to the subject, e.g., any uncontrolled disease, such as pulmonary disease, infection, seizure disorder, uncontrolled hyperglycemia.
5. Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent or limit compliance with study requirements.
6. Prior or concurrent malignancy, except for the following:
   1. Adequately treated basal cell or squamous cell skin cancer
   2. Cervical carcinoma in situ
   3. Adequately treated Stage I or II cancer from which the subject is currently in complete remission.
   4. Or any other cancer from which the subject has been disease-free for ≥ 3 years
7. Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.
8. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
9. Males or females of childbearing potential who do not agree to practice 2 effective methods of contraception, at the same time through 90 days after the last dose of study drug j. Females who are pregnant or breastfeeding. k. Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, myeloproliferative syndrome, or primary amyloidosis (with the exception of patients whose amyloidosis has been documented as a complication of MM, who will be evaluated on a case-by-case basis for trial participation).
10. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study drug administration.
11. Parkinson's disease
12. Corrected serum calcium ≥ 14 mg/dl within 2 weeks of enrollment (despite appropriate measure such a short course of steroids, bisphosphonates, hydration, and calcitonin).
13. Absolute neutrophil count < 1000 cells/mm3. No growth factors allowed within 1 week of enrollment.
14. Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours prior to study drug administration.
15. Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours before qualifying laboratory value
16. Serum bilirubin ≥ 1.5 x ULN, patients with Gilbert's syndrome and a total bilirubin of < 3 times ULN are permitted)
17. AST or ALT ≥ 3 x ULN.
18. CrCl < 30 ml/min/1.73m2. Creatinine clearance is estimated by the CKD-EPI formula.
19. Major surgery or radiation therapy within 14 days before study drug administration.
20. Kyphoplasty or vertebroplasty within 1 week of enrollment.
21. Administration of chemotherapy, biological, immunotherapy, or investigational agent (therapeutic or diagnostic) within 3 weeks before enrollment (14 days for non-myelosuppressive therapy). Subjects should be 6 weeks from last dose of nitrosourea, nitrogen mustards or monoclonal antibody, 12 weeks from autologous SCT, and 16 weeks from allogeneic SCT.
22. Corticosteroids use exceeding a cumulative dose of 160 mg of dexamethasone during screening.
23. If prior allogeneic stem cell transplant, history of moderate to severe chronic graft versus host disease (GVHD).
24. Treatment with plasmapheresis within 4 weeks before enrollment.
25. NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of enrollment.
26. Current use of a non-standard dialysis membrane.
27. Systemic treatment with strong inhibitors or inducers of CYP450 system should not be used on study including but not limited to fluvoxamine, enoxacin, ciprofloxacin, clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole, rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, buproprion, fluoxetine, paroxetine, ticlopidine, or St. John's wort within 14 days before the first dose of study treatment. Ixazomib has significant drug-drug interactions with strong CYP3A inducers. No drug-drug interactions with the CYP450 screen have been found with ONC201, but the analysis of these studies is not complete, so during the study use of inhibitors or inducers of CYP450 system is excluded.
28. Failure to have fully recovered (i.e., Grade 1 toxicity or less, with the exception of alopecia) from clinically significant effects of prior chemotherapy regardless of interval since last treatment.
29. Allergies and Adverse Drug Reaction Known hypersensitivity to bortezomib, ixazomib, dexamethasone, ONC201