MC210808 Venetoclax in Combination With Lenalidomide and Dexamethasone (Ven-Rd), Daratumumab and Dexamethasone (Ven-Dd), or Daratumumab-Lenalidomide-Dexamethasone (Ven-DRd) for the Treatment of Multiple Myeloma

Inclusion Criteria:

• Diagnosis of active MM with bone marrow plasma cell fluorescence in situhybridization (FISH) test run under an Investigational Device Exemption (IDE)demonstrating of t(11;14), either from time of diagnosis or confirmed with IDE atMayo Clinic after time of diagnosis, during screening period for study. Note:Samples tested beyond 72 hours from the collection will not be considered adequatefor 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 ofnewly diagnosed MM

• Patient is not being considered for stem cell transplant (group 2, newly diagnosedonly)

• 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 toregistration)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (known Gilbert's syndrome areallowed 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 serumimmunoglobulin 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 ofchildbearing 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 orbreastfeeding, 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-fetaltoxicity and prescribed under a pregnancy prevention/controlled distributionprogram, WOCBP participants will be eligible if they commit to either:

• Abstain continuously from heterosexual sexual intercourse as theirpreferred and usual lifestyle (abstinent on a long term and persistentbasis) and agree to remain abstinent OR

• To use birth control as follows:

• Two methods of reliable birth control (one method that is highlyeffective and one additional effective (barrier) method), beginning 4weeks prior to initiating treatment with lenalidomide, duringtherapy, during dose interruptions and continuing for 4 weeksfollowing discontinuation of lenalidomide treatment

• Male participants are eligible to participate if they agree to the following fromthe time of first dose of study treatment until 28-days after the last dose oflenalidomide, to allow for clearance of any altered sperm:

• Refrain from donating sperm PLUS either:

• Be abstinent from heterosexual intercourse as their preferred and usuallifestyle (abstinent on a long term and persistent basis) and agree toremain abstinent OR

• Must agree to use contraception/barrier as detailed below:

• Agree to use a male condom, even if they have undergone a successfulvasectomy, and female partner to use an additional highly effectivecontraceptive method with a failure rate of < 1% per year as whenhaving 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 ActiveMonitoring Phase of the study)

• Willing to provide research bone marrow aspirate specimen

• Willing to follow the requirements of the Revlimid (Registered Trademark) RiskEvaluation and Mitigation Strategy (REMS) program. Note: Exception from Group 2patients enrolled on Arm A.

Exclusion Criteria:

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

• Adequately treated carcinoma in situ of the uterine cervix

• Adequately treated basal cell carcinoma or localized squamous cell carcinoma ofthe skin

• Asymptomatic prostate cancer with no requirement for therapy

• Previous malignancy surgically resected (or treated with other modalities) withcurative 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 abnormalitythat might confound the results of the trial, interfere with the subject'sparticipation for the full duration of the trial, or is not in the best interest ofthe 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 ≤ 28 days prior toregistration

• Known allergy to any of the study medications, their analogues, or excipients in thevarious formulations of any agent

• Participation in other clinical trials, including those with other investigationalagents not included in this trial, ≤ 30 days prior to registration

• Known gastrointestinal (GI) disease or GI procedure that could interfere with theoral 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 Cribonucleic acid (RNA) test result at screening or within 3 months prior to firstdose of study treatment

• Note: Participants with positive hepatitis C antibody due to prior resolveddisease can be enrolled, only if a confirmatory negative hepatitis C RNA testis obtained

• Note: Hepatitis RNA testing is optional and participants with negativehepatitis C antibody test are not required to also undergo hepatitis C RNAtesting