Daratumumab in Treating Transplant-Eligible Participants With Multiple Myeloma

PRIMARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVES:

I. To correlate peripheral blood and bone marrow-based MRD testing using next generation
sequencing (NGS). II. To correlate the MRD assessment by MPF with that by NGS at all the time
points pre-specified for blood and bone marrow assessments.

III. To profile the immune repertoire of MM patients while receiving maintenance treatment
with daratumumab+lenalidomide.

IV. Correlate antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent
cell-mediated cytotoxicity (ADCC) with activity of daratumumab.

V. To determine daratumumab-induced immune reconstitution of the host through eradication of
immunosuppressive cellular elements.

VI. To assess pharmacokinetics (PK) of every 3-month dosing of daratumumab.

OUTLINE:

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

CONSOLIDATION II: Beginning 8 weeks after completion of daratumumab course 2, participants
undergo autologous stem cell transplant (ASCT).

MAINTENANCE: Within 14 days after completion of day 100 visit post-SCT, participants receive
daratumumab IV on day 1 and lenalidomide orally (PO) daily on days 1-21. Treatment repeats
every 28 days for up to 12 courses in the absence of disease progression or unacceptable
toxicity. Participants 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, participants are followed up at 30 days and every 3-6
months for up to 3 years.

Inclusion Criteria:

- 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 REMS program

- Provide informed written consent

- Willing to provide bone marrow aspirate and core, and blood samples for correlative
research purposes

- Measurable disease of multiple myeloma at the time of baseline values for disease
assessment 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 ? Bone marrow plasma cells
>= 30%

Exclusion Criteria:

- Any previous ASCT for multiple myeloma (MM)

- 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 polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein, skin changes (POEMS syndrome)

- 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