Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

This research study is a Phase II clinical trial, which tests the effectiveness of an
investigational drug. Preliminary experience suggests that daratumumab may prevent or
postpone SMM from becoming active multiple myeloma. The purpose of this research study is to
determine if the this drug may improve the rate of prevention of multiple myeloma.

Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune
system. Patients with active multiple myeloma generally require treatment. There are
currently no approved therapies for smoldering multiple myeloma or Monoclonal Gammopathy of
Unknown Significance.

Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of
mechanisms by attaching to the CD38 molecule, which is over-expressed in multiple myeloma
cells. This type of drug is called a monoclonal antibody. The FDA (the U.S. Food and Drug
Administration) has not approved Daratumumab for the participant specific disease but it has
been approved for use in active Multiple Myeloma.

Inclusion Criteria:

- Age ≥ 18 years

- Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described
below:

High-Risk MGUS

Must have <10% plasma cells and <3.0g/dL M-spike and at least 2 of the following 3
criteria:

- Abnormal free light-chain (FLC) ratio (<0.26 or >1.65)

- M-protein concentration (≥1.5 g/dL)

- Non-IgG M protein (including IgA)

Low-Risk Smoldering Multiple Myeloma

Must only present with 1 of the following criterion:

- Monoclonal Protein ≥ 3 g/dL

---≥ 10% Bone Marrow Plasma Cells

- FLC ratio < 0.125 or > 8

-No evidence of CRAB criteria† or new criteria of active MM which including the
following:

- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper
limit of normal or >0.275 mmol/dL)

- Renal insufficiency (attributable to myeloma)

- Anemia (Hb 2 g/dL below the lower limit of normal or <10 g/dL)

- Bone lesions (lytic lesions or generalized osteoporosis with compression
fractures)

- No evidence of the following new criteria for active MM including the following:
Bone marrow plasma cells >60%, Serum involved/uninvolved FLC ratio ≥100, and MRI
with more than one focal lesion

- Participants with CRAB criteria that are attributable to conditions other
than the disease under study may be eligible

- ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)

- The following laboratory values obtained ≤ 21 days prior to registration:

- ANC ≥ 1000/uL

- PLT ≥ 50,000/uL

- Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal
patient is eligible.)

- AST ≤ 3 x institutional upper limit of normal (ULN)

- ALT ≤ 3 x institutional upper limit of normal (ULN)

- Creatinine ≤ 2 mg/dL or Creatinine Clearance ≥ 40 mL/min

- Ability to understand and the willingness to sign an informed consent before
performance of any study-related procedure not part of normal medical care,
with the understanding that consent may be withdrawn by the subject at any
time without prejudice to future medical care.

- Female patients who are postmenopausal for at least 1 year before the
screening visit or are surgically sterile are eligible. Females of
childbearing potential (as defined below) may also be eligible but must have
a negative serum or urine pregnancy test with a sensitivity of at least 25
mIU/mL within 21 days of registration.

- A female of childbearing potential is a sexually mature female who:

- Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral
oophorectomy (the surgical removal of both ovaries)

OR

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

Exclusion Criteria:

- Any prior therapy for symptomatic Multiple Myeloma or smoldering Multiple Myeloma
should also be excluded, including prior use of IMIDs, proteasome inhibitors, or CD138
inhibitors. Prior therapy for smoldering Multiple Myeloma with agents that are not
therapeutically active against MM is not an exclusion criterion.

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational. Prior therapy with bisphosphonates is allowed. Prior
radiation therapy to a solitary plasmacytoma is allowed.

- Concurrent exposure to any commercially available agents known to be active against
SMM and MM.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 2 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Subject has known chronic obstructive pulmonary disease (COPD) with a Forced
Expiratory Volume in 1 second (FEV1) < 50% of predicted normal.

- Note that FEV1 testing is required for patients suspected of having COPD and subjects
must be excluded if FEV1 <50% of predicted normal.

- Subject has known moderate or severe persistent asthma within the past 2 years or
currently has uncontrolled asthma of any classification.

- Subjects who currently have controlled intermittent asthma or controlled mild
persistent asthma are allowed in the study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrollable cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Pregnant or nursing women will be excluded from the study.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Daratumumab.

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are
seropositive because of hepatitis B virus vaccine are eligible. Patients who are
positive for hepatitis B core antibody or hepatitis B surface antigen must have a
negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR
positive will be excluded.

- Major surgery within 4 weeks before enrollment.

- Subject is known or suspected of not being able to comply with the study protocol (eg,
because of alcoholism, drug dependency, or psychological disorder). Subject has any
condition for which, in the opinion of the investigator, participation would not be in
the best interest of the subject (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.

- Vaccination with live attenuated vaccines within 4 weeks of first study agent
administration

- Subject has clinically significant cardiac disease, including significant ischemic
coronary disease, congestive heart failure (New York Heart Association [NYHA] Class
III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6
months before randomization, a history of additional risk factors for torsades de
pointes (eg, electrolyte abnormalities, family history of Long QT Syndrome), or a
family history of sudden cardiac death before age 40.

- Participation in other therapeutic clinical trials, including those with other
investigational agents not included in this trial, within 30 days of the start of this
trial and throughout the duration of this trial