Inclusion Criteria:

* Diagnosis of active MM with bone marrow plasma cell fluorescence in situ hybridization (FISH) test demonstrating presence of t(11;14) at the time of diagnostic bone marrow biopsy specimen at Mayo Clinic. NOTE: Testing for t(11;14) will be performed using specific FISH test under an Investigational Device Exemption (IDE). Samples tested beyond 72 hours from the collection will not be considered adequate for trial enrollment
* Group 1 - At least once prior line of therapy which did not include venetoclax
* Group 2 - No more than 1 cycle of any commonly used myeloma regimen for treatment of newly diagnosed MM
* Patient is not being considered for stem cell transplant (group 2, newly diagnosed only)
* Age ≥ 18 years
* Calculated creatinine clearance (using Cockcroft-Gault equation) ≥ 30 mL/min (obtained ≤ 14 days prior to registration)
* Absolute neutrophil count (ANC) ≥ 1000/uL (without growth factor support) (obtained ≤ 14 days prior to registration)
* Un-transfused Platelet count ≥ 75000/uL (≥ 50,000/uL if marrow plasma cells \[PC\]% \> 50%) (obtained ≤ 14 days prior to registration)
* Hemoglobin ≥ 8.0 g/dL (transfusion permitted) (obtained ≤ 14 days prior to registration)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (known Gilbert's syndrome are allowed provided bilirubin ≤ 2.5 mg/dL) (obtained ≤ 14 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (obtained ≤ 14 days prior to registration)
* Alkaline phosphatase ≤ 750 U/L (obtained ≤ 14 days prior to registration)
* Measurable disease of multiple myeloma as defined by at least ONE of the following:

* Serum monoclonal protein ≥ 1.0 g/dL
* ≥ 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
* Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Provide written informed consent
* Ability to complete questionnaire(s) by themselves or with assistance
* Negative serum pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only
* Willing to follow strict birth control measures as suggested by the study
* Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

* Is not a woman of childbearing potential (WOCBP) OR
* Due to lenalidomide being a thalidomide analogue with risk for embryo-fetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, WOCBP participants will be eligible if they commit to either:

* Abstain continuously from heterosexual sexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
* To use birth control as follows:

* Two methods of reliable birth control (one method that is highly effective and one additional effective (barrier) method), beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment
* Male participants are eligible to participate if they agree to the following from the time of first dose of study treatment until 28-days after the last dose of lenalidomide, to allow for clearance of any altered sperm:

* Refrain from donating sperm PLUS either:

* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
* Must agree to use contraception/barrier as detailed below:

* Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of \< 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)
* Life expectancy ≥ 12 weeks
* Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
* Willing to provide research bone marrow aspirate specimen
* Willing to follow the requirements of the Revlimid (Registered Trademark) Risk Evaluation and Mitigation Strategy (REMS) program

Exclusion Criteria:

* History of any active malignancy within the past 2 years prior to screening, with the exception of:

* Adequately treated carcinoma in situ of the uterine cervix
* Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
* Asymptomatic prostate cancer with no requirement for therapy
* Previous malignancy surgically resected (or treated with other modalities) with curative intent
* Other concurrent chemotherapy or any ancillary therapy considered investigational

* NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
* Major surgery ≤ 14 days prior to study registration
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
* Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Administration of strong/moderate CYP3A inhibitors or inducers ≤ 14 days OR 5 half-lives prior to registration, whichever is longer
* Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
* Participation in other clinical trials, including those with other investigational agents not included in this trial, ≤ 30 days prior to registration
* Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of venetoclax including difficulty swallowing
* Heart failure \> New York Heart Association (NYHA) class II
* Presence of positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment

* Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained
* Note: Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/20/2024. Questions regarding updates should be directed to the study team contact.