Inclusion Criteria:

• Newly diagnosed MM with bone marrow plasma cell FISH test demonstrating presence of t(11;14) at the time of diagnostic bone marrow biopsy specimen.
• No more than 1 cycle of any commonly used myeloma regimen for treatment of newly-diagnosed Multiple Myeloma (MM).
• Age ≥ 18 years.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Calculated creatinine clearance (using Cockcroft-Gault equation below)*;
    • ≥ 30 mL/min:
      • Creatinine clearance for males = (140-age)(weight in kg)(72)(serum creatinine inmgdL);
      • Creatinine clearance for females = (140-age)(weight in kg)(0.85)(72)(serum creatinine inmgdL).
    • Absolute neutrophil count (ANC) ≥ 1000/mL (without growth factor support);
    • Un-transfused Platelet count ≥ 75000/mL (≥ 50,000/mL if marrow PC% > 50%);
    • Hemoglobin ≥ 8.0 g/dL (transfusion permitted);
    • Total bilirubin ≤ 1.5 x ULN (known Gilberts syndrome are allowed);
    • ALT and AST ≤ 3 x ULN;
    • Alkaline phosphatase ≤ 750 U/L.
• 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.
• ECOG performance status (PS) 0, 1 or 2).
• Provide written informed consent.
• 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 participants: Female participant is eligible to participate if she is not pregnant or breast feeding, 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 patients: 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® 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 a strong or moderate CYP3A inhibitor or inducer ≤ 7 days  prior to registration.
•  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 GI disease or GI procedure that could interfere with the oral absorption or tolerance of venetoclax including difficulty swallowing.
•  Heart failure > NYHA class II.
•  Presence of positive hepatitis C antibody test result or positive hepatitis C 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 9/20/22. Questions regarding updates should be directed to the study team contact.