This study is to assess for Measurable Residual Disease (MRD) in multiple myeloma at a deeper level than what is currently available by combining novel imaging and laboratory techniques, determine if patients who are MRD-negative by these multiple modalities can safely and effectively discontinue post-transplant maintenance therapy, and determine if liquid biopsies is a more accurate and/or less invasive sampling technique for multiple myeloma.

The purpose of this research is to determine if patients who are MRD-negative by multiple modalities ("multimodality MRD-negative") can safely and effectively discontinue post-transplant maintenance therapy (single agent lenalidomide, pomalidomide, bortezomib, or ixazomib) after receiving at least one year of maintenance therapy.

Inclusion Criteria:

• Males and females > 18 years of age
• ECOG performance status less than or equal to 2 (Karnofsky > 60%)
• Patients with a diagnosis of multiple myeloma who have undergone initial treatment, with or without autologous stem cell transplant, and currently treated with single-agent maintenance therapy (lenalidomide, pomalidomide, bortezomib, daratumumab, or ixazomib) for a duration of at least 1 year. The 1 year duration can include time spent receiving at least 8 cycles of doublet or triplet induction regimens OR multi-agent post-transplant maintenance prior to conversion to single agent maintenance therapy.
• Patients must have had their most recent bone marrow testing within the last 2 years and negative for MRD by flow cytometry (with a sensitivity of at least 10-5) or by NGS with a sensitivity of at least 10-5.
• Patients must have achieved a CR (CR) by IMWG consensus response criteria. For patients with a persistent low level paraprotein ('M-spike'), mass spectrometry may be used to determine if the paraprotein is significant or not. Results of mass spectrometry may be used to supercede results of serum protein electrophoresis.
• Patients must have a most recent PET/CT within the last 1.5 years without evidence of myeloma disease.
• Must have baseline bone marrow sample that can be used for clonality identification for NGS and mass spectrometry if not already performed.
• Willing and able to undergo a bone marrow biopsy and aspiration.
• Ability to understand and the willingness to sign a written informed consent document.
• Females of childbearing potential (FCBP) must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) if continued on lenalidomide as part of standard of care and 2) for at least 28 days after discontinuation of lenalidomide
• All participants in the US must have already been consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the intervention are eligible for this trial.

Exclusion Criteria:

• Progressive disease as determined per IMWG consensus response criteria.
• Have not met the criteria for CR by IMWG consensus response criteria.
• MRD-positive disease by flow cytometry, NGS (1 in 1,000,000 cells), or PCR.
• Concomitant hematologic malignancy.
• Known or suspected amyloidosis.
• Unwilling to undergo a bone marrow biopsy.
• Unwilling to discontinue maintenance therapy.
• Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.