MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial

• Patients must have RRMM with measurable disease, as defined by at least one of the following:

‣ Serum monoclonal protein \>= 0.5 g/dL

⁃ Urinary monoclonal protein excretion of \>= 200 mg/24 hours

⁃ Kappa or lambda light chain level \>= 10 mg/dL with an abnormal free light chain ratio

• At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.

‣ For proteasome-sensitive expansion cohort: Patients with MM who relapsed or are refractory to a prior line of therapy not including a proteasome inhibitor

⁃ For proteasome-relapsed/refractory expansion cohort: Patients with MM who have relapsed after prior PI exposure or are PI-refractory, defined as nonresponsive to treatment or progresses within 60 days of last exposure to a PI

• Age \>= 18 years

‣ Because no dosing or adverse event (AE) data are currently available on the use of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) in patients \< 18 years of age, and as this disease is exceptionally uncommon in this age group, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)

• Leukocytes \>= 3,000/mcL

• Absolute neutrophil count \>= 1,000/mcL

• Platelets \>= 75,000/mcL

• Bilirubin =\< institutional upper limit of normal (ULN).

‣ Patients with Gilbert's syndrome may enroll if direct bilirubin =\< 1.5 x ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional ULN

• Creatinine clearance (CrCl) by Cockcroft-Gault \>= 30 mL/min

• Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:

‣ CD 4 count \> 350 cells/mm\^3

⁃ Undetectable viral load

⁃ Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents (e.g. excluding ritonavir)

⁃ No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections

• The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing human fetus are unknown. For this reason and because NAE inhibitory agents are known to be teratogenic, women of child-bearing potential and men must meet the following criteria:

‣ Female patients who are:

• Postmenopausal for at least one year before the screening visit, OR

∙ Surgically sterile, OR

∙ If of childbearing potential, agree to practice 1 highly effective method and 1 additional (barrier) method of contraception, at the same time, from the time of signing the informed consent until 4 months after the last dose of the ixazomib and pevonedistat (female and male condoms should not be used together), or agree to abstain from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence \[e.g,, calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)

⁃ Male patients, even if surgically sterilized, who:

• Agree to practice effective barrier contraception during the entire time enrolled on study through 4 months after completion of ixazomib and pevonedistat administration (female and male condoms should not be used together), OR

∙ Agree to abstain from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)

⁃ Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible