Inclusion Criteria:
* Participants must be at least 18 years of age
* Newly diagnosed multiple myeloma, with monoclonal plasma cells in the bone marrow ≥10% or a biopsy proven plasmacytoma and either CRAB criteria or biomarker of malignancy
a. CRAB criteria, one or more of the following: i. Hypercalcemia: serum calcium (\>1 mg/dL) higher than the upper limit of normal or \>11 mg/dL ii. Renal insufficiency: creatinine clearance \<40 mL/min (calculated per local practice) or serum creatinine \>2 mg/dL iii. Anemia: hemoglobin value \>2 g/dL below the lower limit of normal or hemoglobin \<10 g/dL iv. Bone lesions: one or more lytic lesions on skeletal radiography, CT, or PET CT b. Biomarker of malignancy (one or more of the following): i. Clonal bone marrow plasma cells ≥60% ii. Involved:uninvolved serum free light chain ratio ≥100 iii. \>1 focal lesion on magnetic resonance imaging (MRI)
* Measurable disease as defined by one of the following:
1. Serum monoclonal protein ≥0.5 g/dL. For IgA monoclonal protein, total IgA \>500 mg/dL is allowable.
2. Urine monoclonal protein ≥200 mg/24 hours
3. Involved serum free light chain ≥100 mg/L with abnormal free light chain ratio
* Not considered eligible for high dose melphalan and autologous stem cell transplant per treating investigator or plan for deferred high dose melphalan and autologous stem transplant
* ECOG performance status of 0-2
* ANC ≥1000/μL. G-CSF is not permitted within 14 days of screening.
* Platelet count ≥75,000/µL. Platelet count ≥50,000/µL is permitted if bone marrow is \>50% involved. Platelet transfusion and thrombopoietin receptor agonists are not permitted within 7 days of screening.
* Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria.
* Calculated creatinine clearance of ≥ 30 mL/min, not requiring dialysis, with calculation per local practice.
* Serum bilirubin values \< 1.5 x ULN. Isolated bilirubin x 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. total bilirubin \<3 mg/dL and normal direct bilirubin); and
* Serum aspartate transaminase (ALT) and aspartate transaminase (AST) values \< 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range.
* Must be able to comply with thromboembolism prophylaxis with e.g. acetylsalicylic acid (ASA), apixaban, rivaroxaban, lower molecular weight heparin, or equivalent.
* Females of childbearing potential (FCBP) must:
1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy within 10-14 days, with the second test within 24 hours of starting lenalidomide. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with two reliable forms of contraception as defined by lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program.
* Male subjects must follow the lenalidomide REMS.
* Ability and the willingness to undergo repeat bone marrow biopsy assessments.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Prior or current systemic therapy for any plasma cell disorder. An exception is emergency use of corticosteroids (equivalent to dexamethasone 40 mg daily for four days). After discussion with the principal investigator. one cycle of standard of care myeloma therapy (without anti-CD38 monoclonal antibody) is permissible to allow for stabilization of disease, during screening/prior to enrollment.
* Pregnancy, currently breastfeeding, or planned breastfeeding.
* Participant plans to father a child while enrolled in the study or within 100 days after last dose of study treatment.
* Prior history of malignancies, other than MM, unless the patient has completed definitive treatment and has been free of the disease for ≥3 years. Patients who are free of disease \<3 years may enroll after approval of the PI (e.g. localized breast cancer considered to have very low risk of recurrence). Exceptions include the following (i.e. the following are eligible to participate):
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix
3. Ductal carcinoma in situ of the breast
4. Incidental histologic finding of prostate cancer (T1a or T1b) managed with surveillance
5. Other malignancies of clinically localized disease may be permitted to enroll after discussion with the Sponsor-Investigator
* Patients with plasma cell leukemia at time of screening, POEMS syndrome, or primary AL amyloidosis are excluded from this trial.
* Seropositive for HIV infection.
* Hepatitis B viral load positive.
* Hepatitis C viral load positive.
* Peripheral neuropathy ≥grade 2.
* Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to:
1. Congestive heart failure (New York Heart Association \[NYHA\] Class 3 or 4)
2. Unstable angina
3. Clinically significant, uncontrolled cardiac arrhythmia such a 2nd degree or 3rd degree atrioventricular block
4. Recent (within the preceding 6 months) myocardial infarction or stroke
5. Severe non-ischemic cardiomyopathy.
6. Uncontrolled hypertension
7. Diabetes mellitus with \>2 episodes of ketoacidosis in the preceding 12 months
8. Chronic obstructive pulmonary disease (COPD) requiring \>2 hospitalizations in the preceding 12 months.
9. Acute diffuse infiltrative pulmonary disease.
10. Active bacterial, viral, or fungal infection
11. Stroke, transient ischemic attack, or seizure within six months of starting treatment.
* Patient has any other medical, psychiatric, or social condition that would preclude participation in the study, pose an undue medical hazard, interfere with the conduct of the study, or interfere with interpretation of the study results.
* Major surgery within 4 weeks prior to C1D1. Kyphoplasty or vertebroplasty are not considered major surgery.
* Received an investigational drug (or vaccine) or used an invasive investigational medical device within four weeks before screening or is currently enrolled in an interventional investigational study.
* Live or live-attenuated vaccine within 30 days prior to C1D1.
