This phase II trial studies how well daratumumab works in treating transplant-eligible patients with multiple myeloma. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread.

PRIMARY OBJECTIVE:

I. To determine the percentage of patients achieving minimal residual disease (MRD) negativity by multiparameter flow cytometry (MPF) after autologous stem cell transplant (SCT) (at day 100) using pre-SCT daratumumab consolidation.

SECONDARY OBJECTIVES:

I. To determine percentage of patients achieving MRD negativity by MPF after 1 year of daratumumab+lenalidomide-based maintenance therapy.

II. To determine progression-free survival (PFS) for peri-SCT treatment with daratumumab.

III. To determine percentage of MRD negativity by MPF after pre-SCT consolidation with daratumumab.

IV. To determine safety profile of peri-SCT daratumumab with lenalidomide. V. To determine the overall response rate (ORR) of patients receiving peri-SCT daratumumab for MM.

VI. To determine the overall survival (OS) for patients receiving peri-SCT daratumumab for MM.

OUTLINE:

CONSOLIDATION I: Patients receive daratumumab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1-2, and on days 1 and 15 of cycles 3-4. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION II: Beginning 8 weeks after completion of daratumumab cycle 2 or 4, patients undergo autologous stem cell transplant (ASCT).

MAINTENANCE: Within 14 days after completion of day 100 visit post-SCT, patients receive daratumumab IV on day 1 and lenalidomide orally (PO) daily on days 1-21. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who are still maintaining response continue to receive daratumumab IV every 3 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3-6 months for up to 3 years.

Inclusion Criteria:

• Considered transplant eligible

• Pathologically confirmed diagnosis of multiple myeloma who are transplant eligible and have received any prior induction therapy (with or without maintenance)

• Measurable MRD in bone marrow within 28 days prior to registration (MPF method)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 at registration

• Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support, obtained =< 14 days prior to registration

• Platelets >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis < 50% or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%, obtained =< 14 days prior to registration

• Calculated or measured creatinine clearance >= 30 ml/min, obtained =< 14 days prior to registration

• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome, in which case the direct bilirubin must be =< 1.5 X ULN, obtained =< 14 days prior to registration

• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) =< 3 x ULN, obtained =< 14 days prior to registration

• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 X ULN, obtained =< 14 days prior to registration

• Negative urine or serum pregnancy test for women of childbearing potential

  • NOTE: females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program

• Provide informed written consent

• Measurable disease of multiple myeloma at the time specified by one of the following:

  • If no relapse prior to transplant, values obtained at the time of diagnosis
  • If disease relapse prior to transplant and the patient did not have treatment for the relapsed disease prior to transplant, the values obtained at the time of relapse immediately prior to the transplant.
  • If disease relapse prior to transplant and the patient did have treatment for the relapsed disease prior to transplant, the values obtained prior to this therapy, i.e., the time of relapse

Exclusion Criteria:

• Any previous ASCT for multiple myeloma (MM) (NOTE: Patient may have had prior stem cell collection before registration on the study)

• Any prior therapy with daratumumab

• Non-secretory MM or known amyloid light-chain (AL) amyloidosis

• Clinically significant active infection requiring intravenous antibiotics (=< 14 days prior to registration)

• >= grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

• Other prior malignancy

  • Exceptions:

    • Adequately treated basal cell or squamous cell skin cancer
    • Any in situ cancer
    • Adequately treated stage I or II cancer from which the patient is currently in complete remission, or
    • Any other cancer from which the patient has been disease free for at least 3 years

• Concurrent therapy considered investigational

  • NOTE: patients must not be planning to receive any radiation therapy (except localized radiation for palliative care that must be completed prior to starting cycle 1, day 1)

• Pregnant women

• Nursing women (lactating females are eligible provided that they agree not to breast feed while taking lenalidomide)

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Major surgery =< 4 weeks prior to registration

• History of stroke/intracranial hemorrhage =< 6 months prior to registration

• Clinically significant cardiac illness including New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to registration

• Known human immunodeficiency virus positive (HIV+) patients

• Known hepatitis B or hepatitis C infection

• Exhibiting clinical signs of meningeal involvement of multiple myeloma

• Known severe chronic obstructive pulmonary disease or asthma defined as forced expiratory volume (FEV1) in 1 second less than < 60% of expected

3 years