Isatuximab in Treating Patients With High Risk Smoldering Plasma Cell Myeloma

PRIMARY OBJECTIVES:

I. To determine the rate of response according to the International Myeloma Working Group
Criteria.

SECONDARY OBJECTIVES:

I. To determine progression free survival (PFS) at 2 years. II. To determine overall survival
(OS). III. To determine duration of response (DOR). IV. To determine the clinical benefit
rate (CBR). V. To evaluate safety of single agent treatment in this population. VI. To
evaluate the immunogenicity of isatuximab.

OUTLINE:

Patients receive isatuximab intravenously (IV) over 5 hours on day 1 of course 1, and over 3
hours thereafter on days 8, 15, and 22 of course 1, on days 1 and 15 of courses 2-6, and on
day 1 of subsequent courses. Treatment repeats every 28 days for up to 30 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Inclusion Criteria:

- Patients must have histologically confirmed smoldering multiple myeloma (SMM) based on
the following criteria; both criteria must be met: (a) serum monoclonal protein (IgG
or IgA) >= 3 g/dL or urinary monoclonal protein >= 500 mg per 24 hours and/or clonal
bone marrow plasma cells 10-60% (b) absence of myeloma defining events or amyloidosis

- Additionally, patients must meet criteria for high risk of progression to multiple
myeloma by PETHEMA CRITERIA (patients must have at least 2 risk factors present)

- >= 95% abnormal plasma cells/total plasma cells in bone marrow compartment (this
is measured as a percentage of the total abnormal versus normal plasma cells in
the bone marrow compartment using standard flow cytometry of the bone marrow
aspirate; having >= 95% abnormal plasma cells/total plasma cells constitutes a
risk factor for progression to multiple myeloma by PETHEMA criteria)

- Immunoparesis (this term refers to the patient having low uninvolved
immunoglobulins in peripheral blood, for example if a patient has IgA smoldering
multiple myeloma, then either having a low IgM and/or low IgG will qualify as a
risk factor for progression to multiple myeloma)

- 2 of 2 risk factors: high risk for progression at a rate of 72% at 5 years

- Creatinine clearance (CrCl) >= 40 ml/min; CrCl will be calculated using the
modification of diet in renal disease (MDRD) equation

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L

- Hemoglobin more or equal than 2 grams/dL below the institutional level of normal

- Platelet count >= 90 x 10^9/L

- Platelet and blood transfusions are allowed on protocol; growth factors, including
granulocyte colony stimulating factors and erythropoietin are allowed

- Bilirubin < 1.5 x the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN

- Females of childbearing potential and male subjects with female partners of
childbearing potential must agree to avoid pregnancy by using an adequate method of
contraception (2 barrier method or 1 barrier method with a spermicide or intrauterine
device for 2 weeks prior to screening, during and 12 weeks after the last dose of
trial medication; adequate methods of contraception are provided as examples; other
acceptable and effective methods of birth control are also permitted (e.g.,
abstinence)

- Men must agree to not donate sperm while on the study and for at least 3 months after
the last dose of study drug(s); women of child bearing potential must have a negative
serum pregnancy test result within 7 days prior to the first administration of
isatuximab and at the end of treatment visit; a negative urine pregnancy test is
required prior to each subsequent isatuximab dose administration

- Subjects must be able to give informed consent

Exclusion Criteria:

- Evidence of myeloma defining events or biomarkers of malignancy due to underlying
plasma cell proliferative disorder meeting at least ONE of the following:

- Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper
limit of normal or > 2.75 mmol/L (> 11 mg/dL)

- Renal insufficiency: creatinine clearance < 50 ml/min or serum creatinine > 2
mg/dL

- Anemia: hemoglobin value < 10 g/dL or 2 g/dL < normal reference

- Bone lesions: one or more osteolytic lesions on skeletal radiography,
computerized tomography (CT) or 2-deoxy-2[F-18] fluoro-D-glucose positron
emission tomography CT (PET-CT)

- Clonal bone marrow plasma cell percentage >= 60%

- Involved: uninvolved serum free light chain ratio >= 100 measured by freelite
assay

- > 1 focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion
must be 5 mm or more in size)

- Bisphosphonates are permitted, including pamidronate, zoledronic acid, alendronate,
ibandronate, risedronate.

- Treatment with corticosteroids is not permitted, unless the patient is on a stable
chronic dose of inhaled steroids to treat respiratory diseases or on stable chronic
steroid replacement therapy for endocrinology disorders.

- Radiotherapy is not permitted.

- Prior or concurrent treatment for smoldering multiple myeloma with chemotherapy agents
approved for the treatment of multiple myeloma or CD38 drugs is not permitted.

- Plasma cell leukemia

- Pregnant or lactating females; breastfeeding should be discontinued if the mother is
treated with isatuximab; these potential risks may also apply to other agents used in
this study.

- Active hepatitis B or C infection

- Known human immunodeficiency virus (HIV) infection

- Intolerance to infused protein products, sucrose, histidine or polysorbate 80

- Concurrent treatment with other anti-cancer therapy is not permitted

- Has significant cardiovascular disease with New York Heart Association (NYHA) class
III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or
myocardial infarction within 3 months prior to enrollment, or unstable angina, or
unstable arrhythmia as determined by history and physical examination

- Uncontrolled intercurrent illness including but not limited to active infection or
psychiatric illness/social situations that would compromise compliance with study
requirements

- Contraindication to any concomitant medication, including pre-medications or hydration
given prior to therapy

- Major surgery within 1 month prior to enrollment

- Patients with pre-existing uncontrolled pulmonary disease will be excluded;
uncontrolled refers to patients having had at least one hospitalization due to
pulmonary disease (for example, asthma, chronic obstructive pulmonary disease) within
the 6 months prior to enrollment in the study; patients with previous history of
pneumonitis will be excluded