A Phase II Trial of Anti-KIR in Smoldering Multiple Myeloma

Background:

- Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4
years.

- Smoldering multiple myeloma (SMM) is a premalignant plasma cell disorder characterized
by monoclonal protein greater than or equal to 3 g/dL or bone marrow plasma cells
greater than or equal to 10 percent in the absence of myeloma-related tissue impairment
with 51 percent progression to MM at 5 years.

- Current recommendations do not endorse treatment of SMM with chemotherapy.

- Transplanted Natural Killer (NK) Cells have anti-myeloma activity.

- Anti-KIR (IPH2101) is a monoclonal antibody that facilitates NK cell mediated killing of
myeloma cells by blocking inhibitory receptors (KIR) on NK cells.

Objectives:

- To assess the response rate of anti-KIR(IPH2101) in patients with SMM

- To evaluate the toxicity of anti-KIR(IPH2101) in patients with SMM

- To evaluate the pharmacokinetic parameters and biological activity of anti-KIR (IPH2101)

Eligibility:

- A confirmed diagnosis of SMM

- Age greater than or equal to 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status in the range of 0-1.

- Without serious co-morbidity that would interfere with receipt of anti-KIR(IPH2101)

Design:

- Single-arm Phase II trial of anti-KIR(IPH2101) for patients with SMM.

- All patients will have initial evaluation and confirmation of diagnosis.

- Patients will receive anti-KIR(IPH2101) (1mg/kg) every other month for 6 cycles.

- Patients will have routine blood work with serum protein electrophoresis (SPEP) and
immunofixation monthly.

- Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of
diagnosis and correlative studies.

- Patients may donate cellular products or tissues as appropriate for research purposes.

- Optimal two-stage phase II design will be employed, initially enrolling 9 patients. If 3
or more have a positive outcome, then a total of 21 patients will be enrolled in this
study.

- INCLUSION CRITERIA:

- Diagnosis of smoldering multiple myeloma (SMM) will be made in accordance with the
clinical diagnostic criteria set forth by the International Myeloma Working Group.
These criteria include:

- Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells
greater than or equal to 10 percent

- Absence of anemia: Hemoglobin greater than or equal to 10 g/dl

- Absence of renal failure: calculated creatinine clearance (according to
modification of diet in renal disease (MDRD)) greater than or equal to 40 ml/min
(or alternatively based on standard creatinine level criteria of 2 mg/dl)

- Absence of hypercalcemia: Calcium less than or equal to 10.5 mg/dl

- Absence of lytic bone lesion (skeletal survey)

- The diagnoses will be confirmed by serum/urine protein electrophoresis, immunofixation
and light-chain assays; as well as immunohistochemical analyses of the bone marrow
biopsy.

- Age greater than or equal to 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

- Male or female patient who accepts and is able to use recognized effective
contraception (oral contraceptives, intrauterine contraceptive device (IUCD), barrier
method of contraception in conjunction with spermicidal jelly) through the study and
for four months following the final dose of study drug when relevant.

- The patient must be competent to sign an informed consent form.

EXCLUSION CRITERIA:

- Patients with a diagnosis of multiple myeloma (MM) or a clinical suspicion of an
ongoing progression into full-blown MM

- Patients without measurable disease defined as serum monoclonal protein (M-protein)
less than 1 g/dL.

- Previous treatment having a proven or potential impact on myeloma cell proliferation
or survival (including conventional chemotherapies, immunomodulatory drugs (IMiDs), or
proteasome inhibitors).

- Use of any investigational agent within the last 3 months.

- Clinical laboratory values at screening:

- Platelet levels less than 75 times 10^9/L

- Absolute neutrophil count (ANC) levels less than 1 times 10^9/L

- Bilirubin levels greater than 1.5 upper limit of normal (ULN) ; alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 3.0 ULN
(grade 1 National Cancer Institute (NCI))

- Primary or associated amyloidosis

- Known abnormal cardiac status with any of the following:

- New York Heart Association (NYHA) stage III or IV congestive heart failure

- Myocardial infarction within the previous 6 months

- Symptomatic and/or treatment-refractory cardiac arrhythmia. Patients with
controlled or asymptomatic arrhythmia are not excluded from this study.

- Current active infectious disease or positive serology for:

- Human Immunodeficiency Virus (HIV)

- Hepatitis C Virus (HCV)

- Hepatitis B Surface Antigen

- Severe type of autoimmune disease defined as:

- One which currently requires or previously required long-term systemic
immunosuppressive or immunomodulatory therapy (including corticosteroids,
administered by systemic route)

- And/or it has a substantial probability to cause an irreversible injury to any
tissue (e.g. Hashimoto thyroiditis).

- And/or it is recent or unstable, or has a substantial risk to progress and cause
severe complications (e.g. Graves disease)

- Enrollment of other non severe types of auto-immunes disease requiring topical
therapy, or non-steroidal inflammatory drugs (NSAIDS) can be considered on a case
by case basis by the Principal Investigator.

- History of a lymphoproliferative malignancy.

- History of other malignancy (apart from basal cell carcinoma of the skin or in situ
cervical carcinoma) except if the patient has been free of symptoms and without active
therapy during at least the previous 5 years.

- Serious concurrent uncontrolled medical disorder.

- History of allograft or solid organ transplantation.

- Any psychological or familial condition potentially interfering with compliance with
the study protocol and follow-up schedule.

- Pregnant or lactating women.