Testing the Use of Combination Therapy in Adult Patients With Newly Diagnosed Multiple Myeloma, the EQUATE Trial

Inclusion Criteria:

• STEP 0 - Patient must have an Eastern Cooperative Oncology Group (ECOG) performancestatus (PS) of 0-2 (PS 3 allowed if secondary to pain)

• STEP 0 - Patient must have newly diagnosed multiple myeloma (MM) by InternationalMyeloma Working Group (IMWG) criteria

• STEP 0 - Patient must agree to register to the mandatory REVLIMID Risk Evaluationand Mitigation Strategy (RevREMS) program and be willing and able to comply with therequirements of RevREMS

• STEP 0 - Patient must be able to undergo diagnostic bone marrow aspirate followingpreregistration.

• NOTE: Bone marrow aspirate specimen must be submitted to AdaptiveBiotechnologies for clonoSEQ Assay

• NOTE: Adaptive Biotechnologies will release results to the diagnostic Portalfrom the Clonality (ID) test within fourteen (14) days of receipt andreconciliation of fresh bone marrow specimen to the submitting institution

• STEP 1 - Patient must meet all eligibility criteria in STEP 0 with exception ofallergy requirement

• STEP 1 - Institution must have received the Clonality (ID) test results fromAdaptive Biotechnologies and dominant sequences were identified

• STEP 1 - Patient must have standard risk MM as defined by the Revised InternationalStaging System (RISS) stage I or II

• NOTE: R-ISS stage is based on serum beta2 microglobulin, albumin and lactatedehydrogenase (LDH) levels along with presence of chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization (iFISH). Presenceof del(17p), t(4;14), and/or t(14;16) is considered high risk and absence ofthese, including any other findings, are standard risk

• R-ISS stage

• Stage I: ISS stage I [beta2 macroglobulin < 3.5 mg/L, albumin > 3.5 g/dL]AND standard-risk CA AND normal LDH

• Stage II: Not R-ISS stage I or III

• Stage III: ISS stage III [beta2 macroglobulin > 5.5 mg/L] AND high-risk CAOR high LDH (> upper limit of normal) [patients with stage III areineligible]

• STEP 1 - Patient must have measurable or evaluable disease as defined by having oneor more of the following, obtained within 28 days prior to registration:

• >= 1 g/dL monoclonal protein (M-protein) on serum protein electrophoresis

• >= 200 mg/24 hours of monoclonal protein on a 24-hour urine proteinelectrophoresis

• Involved free light chain >= 10 mg/dL or >= 100 mg/L AND abnormal serumimmunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)

• Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

• STEP 1 - Patients must have a serum protein electrophoresis (SPEP), urine proteinelectrophoresis (UPEP), and serum free light chain (FLC) assay performed within 28days prior to registration. In addition, a bone marrow biopsy and/or aspirate isrequired within 28 days if bone marrow is being followed for response

• NOTE: UPEP (on a 24-hour collection) is required, no substitute method isacceptable. Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr. Please note that if both serum and urine M-components arepresent, both must be followed in order to evaluate response

• NOTE: The serum free light chain test is required to be done if the patientdoes not have measurable disease in the serum or urine. Measurable disease inthe serum is defined as having a serum M-spike >= 1 g/dL. Measurable disease inthe urine is defined as having a urine M-spike >= 200 mg/24 hr

• STEP 1 - Calculated creatinine clearance > 30 mL/min (obtained =< 14 days prior toStep 1 registration)

• STEP 1 - Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior toStep 1 registration)

• STEP 1 - Untransfused platelet count >= 75,000/mm^3 (obtained =< 14 days prior toStep 1 registration)

• STEP 1 - Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to Step 1 registration)

• STEP 1 - Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (obtained =< 14 days prior to Step 1 registration)

• STEP 1 - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 xULN (obtained =< 14 days prior to Step 1 registration)

• STEP 1 - Patient must have received no more than one cycle (28 days or less) ofprior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalentdose of prednisone) for treatment of symptomatic myeloma. Patient must not have beenexposed to daratumumab for treatment of symptomatic myeloma. Prior radiation therapyto symptomatic lesions is allowed provided there are no residual toxicity related toradiation and blood counts meet the study requirements. Radiation treatment must becompleted at least 14 days prior to Step 1 registration

• STEP 1 - Human immunodeficiency virus (HIV)-infected patients on effectiveanti-retroviral therapy with undetectable viral load within 6 months ofrandomization are eligible for this trial

• STEP 1 - For patients with evidence of chronic hepatitis B virus (HBV) infection,the HBV viral load must be undetectable on suppressive therapy, if indicated

• STEP 1 - Patients with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently on treatment,they are eligible if they have an undetectable HCV viral load

• STEP 1 - Patients with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial

• STEP 1 - Patients with known history or current symptoms of cardiac disease, orhistory of treatment with cardiotoxic agents, should have a clinical risk assessmentof cardiac function using the New York Heart Association Functional Classification.To be eligible for this trial, patients should be class 2B or better. Patients mustnot have evidence of current uncontrolled cardiovascular conditions, includinghypertension, cardiac arrhythmias, congestive heart failure, unstable angina, ormyocardial infarction within 6 months prior to Step 1 registration

• STEP 1 - Patient may have a history of current or previous deep vein thrombosis (DVT) or pulmonary embolism (PE) but must be willing to take some form ofanti-coagulation as prophylaxis if they are not currently on full-doseanticoagulation

• STEP 1 - Patients with a history of chronic obstructive pulmonary disease (COPD)must have FEV1 testing done within 28 days prior to Step 1 registration and theforced expiratory volume in 1 second (FEV1) must be > 50% of predicted normal

• STEP 2 - Institution must have received Tracking (MRD) test results from AdaptiveBiotechnologies

• STEP 2 - Patient must have completed the Step 1 Induction phase of this protocolwithout experiencing progression

• STEP 2 - Patient must be registered to Step 2 within 8 weeks of completing Step 1Induction Treatment, counting from last day of completion of last cycle

• STEP 2 - Patient must have an ECOG performance status (PS) of 0-2 (PS 3 allowed ifsecondary to pain)

• STEP 2 - Any adverse event(s) related to Step 1 Induction Treatment must haveresolved to grade 2 or less

• STEP 2 - Hemoglobin >= 8 g/dL (obtained within 14 days prior to Step 2randomization)

• STEP 2 - Platelet count >= 50,000/mm^3 (obtained within 14 days prior to Step 2randomization)

• STEP 2 - Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained within 14 days priorto Step 2 randomization)

• STEP 2 - Calculated creatinine clearance >= 30 mL/min (obtained within 14 days priorto Step 2 randomization)

• STEP 2 - Total bilirubin =< 1.5 x ULN (Institutional upper limit of normal) (obtained within 14 days prior to Step 2 randomization)

• STEP 2 - ALT and AST < 3 x ULN (obtained within 14 days prior to Step 2randomization)

Exclusion Criteria:

• STEP 0 - Patient must not have any known allergies, hypersensitivity, or intoleranceto corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or knownsensitivity to mammalian-derived products

• STEP 1 - Women must not be pregnant or breast-feeding due to the potential harm andteratogenic effects to an unborn fetus and possible risk for adverse events innursing infants with the treatment regimens being used. All females of childbearingpotential must have a blood test or urine study with a sensitivity of at least 25mIU/mL within 10-14 days prior to Step 1 registration to rule out pregnancy andagain within 24 hours prior to the first dose of lenalidomide. Females ofchildbearing potential must also agree to ongoing pregnancy testing while onprotocol treatment. A female of childbearing potential is defined as any woman,regardless of sexual orientation or whether they have undergone tubal ligation, whomeets the following criteria:

• Has achieved menarche at some point,

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal (amenorrhea following cancer therapy doesnot rule out childbearing potential) for at least 24 consecutive months (i.e.,has had menses at any time in the preceding 24 consecutive months)

• STEP 1 - Women of childbearing potential must not expect to conceive children byusing accepted and effective method(s) of contraception (for this protocol definedas the use of TWO acceptable methods of birth control, one highly effective methodand one additional effective method AT THE SAME TIME for 1) at least 28 days beforestarting protocol treatment; 2) while participating in the study; 3) during doseinterruptions; and 4) for at least 3 months days after the last dose of protocoltreatment) OR by practicing true abstinence from sexual intercourse for the durationof their participation in the study (periodic abstinence [e.g., calendar, ovulation,symptothermal, post-ovulation methods] and withdrawal are not acceptable methods ofcontraception). Men must not expect to father children by practicing true abstinencefrom sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulationmethods] and withdrawal are not acceptable methods of contraception) OR use a latexcondom during sexual contact with a female of child bearing potential whileparticipating in the study and for at least 3 months after the last dose of protocoltreatment even if they have had a successful vasectomy. Men must also agree toabstain from donating sperm while on study treatment and for 3 months after the lastdose of protocol treatment even if they have had a successful vasectomy. Both womenand men must both agree to abstain from donating blood during study participationand for at least 28 days after the last dose of protocol treatment

• STEP 1 - Patient must not have peripheral neuropathy >= grade 2 on clinicalexamination or grade 1 with pain at time of Step 1 registration

• STEP 1 - Patient must not have any serious medical or psychiatric illness thatcould, in the investigator's opinion, potentially interfere with the completion oftreatment according to this protocol

• STEP 1 - Patient must not have moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification

• NOTE: Patients who currently have controlled intermittent asthma or controlledmild persistent asthma are allowed to register

• STEP 1 - Patient must not receive any other concurrent chemotherapy, or anyancillary therapy considered investigational while on this protocol

• NOTE: Bisphosphonates are considered to be supportive care rather than therapy,and are thus allowed while on protocol treatment

• STEP 2 - Patient must not have received any non-protocol therapy outside of theassigned Step 1 Induction treatment including stem cell transplant

• STEP 2 - Women must not be pregnant or breast-feeding due to the potential harm andteratogenic effects to an unborn fetus and possible risk for adverse events innursing infants with the treatment regimens being used. All females of childbearingpotential must have a blood test or urine study with a sensitivity of at least 25mIU/mL within 10-14 days prior to Step 2 randomization to rule out pregnancy andagain within 24 hours prior to the first dose of lenalidomide. Females ofchildbearing potential must also agree to ongoing pregnancy testing while onprotocol treatment. A female of childbearing potential is defined as any woman,regardless of sexual orientation or whether they have undergone tubal ligation, whomeets the following criteria:

• Has achieved menarche at some point,

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal (amenorrhea following cancer therapy doesnot rule out childbearing potential) for at least 24 consecutive months (i.e.,has had menses at any time in the preceding 24 consecutive months).

• STEP 2 - Women of childbearing potential must not expect to conceive children byusing accepted and effective method(s) of contraception (for this protocol definedas the use of TWO acceptable methods of birth control, one highly effective methodand one additional effective method AT THE SAME TIME for 1) at least 28 days beforestarting protocol treatment; 2) while participating in the study; 3) during doseinterruptions; and 4) for at least 3 months days after the last dose of protocoltreatment) OR by practicing true abstinence from sexual intercourse for the durationof their participation in the study (periodic abstinence [e.g., calendar, ovulation,symptothermal, post-ovulation methods] and withdrawal are not acceptable methods ofcontraception).

Men must not expect to father children by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) OR use a latex condom during sexual contact with a female of child bearing potential while participating in the study and for at least 3 months after the last dose of protocol treatment even if they have had a successful vasectomy. Men must also agree to abstain from donating sperm while on study treatment and for 3 months after the last dose of protocol treatment even if they have had a successful vasectomy. Both women and men must both agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment