Lenalidomide With or Without Ixazomib Citrate and Dexamethasone in Treating Patients With Residual Multiple Myeloma After Donor Stem Cell Transplant

Patients who completed induction treatment followed by autologous stem cell transplant as initial therapy for symptomatic myeloma as per IMWG criteria and initiated Revlimid (lenalidomide) maintenance

* Patients must have initiated lenalidomide maintenance at approximately 3 months post autologous stem transplant (preferably 70-90 but not more than 120 days)

* Patients must be receiving lenalidomide 10 mg or 15 mg and be able to tolerate dose escalation to 25 mg daily

* Patients must have received lenalidomide maintenance for 3 months (+1 month window for a maximum of 4 months lenalidomide prior to enrollment)

No evidence of progressive disease on lenalidomide

Any measurable residual disease at the time of screening for the study documented in at least one of the following ways:

* Serum protein electrophoresis (SPEP)/immunofixation studies (IFIX) positive disease

* Freelite only positive disease

* SPEP/IFIX - negative and Freelite- negative but MRD-positive disease is allowed

Evidence of MRD at the time of screening for this study by multi-color flow cytometry (bone marrow procedure at screening required)

Bone marrow specimen will be required at study entry; available deoxyribonucleic acid (DNA) sample will be used for calibration step for MRD evaluation by gene sequencing

Life expectancy of more than 3 months

Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Bilirubin =\<1.5 x upper limit of normal (ULN)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x ULN

Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L

Hemoglobin \>= 8 g/dL

Platelet count \>= 75 x 10\^9/L

Calculated creatinine clearance (by Cockroft-Gault) \>= 50 ml/min or serum creatinine below 2 g/dL

Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Female patients who:

* Are postmenopausal for at least 1 year before the screening visit, OR

* Are surgically sterile, OR

* If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR

* Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)

Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:

* Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR

* Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)

What this study is about