Study on the Anti-tumor Activity, Safety and Pharmacology of IPH2101 in Patients With Smoldering Multiple Myeloma

Multicenter Phase II Study on the Anti-tumor Activity, Safety and Pharmacology of Two Dose Regimens of IPH2101, a Fully Human Monoclonal Anti KIR Antibody, in Patients With Smoldering Multiple Myeloma (KIRMONO)

The purpose of this study is to evaluate the anti-tumor activity, safety and pharmacology of two dose regimens (0.2 and 2 mg/kg)of IPH2101 in patients with Smoldering Multiple Myeloma.

This is a randomized Phase II, open label, multi-centre study, with two independent arms.

Patients receive 6 injections of IPH2101, at the dose of 0.2 mg/kg or 2 mg/kg (according to their randomization) administered over one hour infusion at four weeks intervals.

A patient whose disease achieves at least a minimal response to study treatment at any time during the initial period of 6 cycles can be treated with an additional period of treatment of 6 cycles.

Patients are followed 6 months after treatment completion or until a KIR occupancy level < 30% (i.e if the time required for KIR desaturation was > 6 months), whichever is longer.

Inclusion Criteria:

1. SMM of any risk level according to a definition derived of the International Myeloma Working Group definition ( Br J Haematol 2003; 121: 749) : Serum M protein ≥ 3 g/dl , AND/OR Bone Marrow plasma cells ≥ 10 % with no evidence of end-organ damage (CRAB)

   • (C)Absence of hypercalcemia : Ca < 10.5 mg/dl
   • (R)Absence of renal failure : creatinine < 2mg/dl (177 μmol/l) or calculated creatinine clearance(according to MDRD) > 50 ml/min
   • (A)Absence of anemia : Hb > 11 g/dl
   • (B)Absence of lytic bone lesion on standard skeletal survey (MRI could be used if clinically indicated)

2. Measurable disease defined as a disease with a serum M protein ≥ 1 g/dl

3. No evidence of fatigue, recurrent infections or any clinical suspicion of MM

4. Diagnosis of SMM confirmed on two consecutive assessments (ie fluctuation under 25% of serum protein level) performed with at least a 4 week interval.

5. Age > 18 years or < 75 years

6. ECOG performance status of 0 or 1

7. Male or female patient who accepts and is able to use recognised effective contraception (oral contraceptives, IUCD, barrier method of contraception in conjunction with spermicidal jelly) throughout the study when relevant

8. Informed consent signed by the patient

Exclusion Criteria:

1. Previous treatment having a proven or potential impact on myelomatous cells proliferation or survival (including IMiDs or proteasome inhibitors, conventional chemotherapies within the last 5 years, steroids within the last month prior to enrolment). Previous bisphosphonates started less than 3 months prior to enrolment.

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

3. Clinical laboratory values at screening

   • Platelet < 75 x 10^9 /l
   • ANC < 1.5 x 10^9 /l
   • Bilirubin levels >1.5 ULN ; ALT and AST > 3 ULN (grade 1 NCI)

4. Primary or associated amyloidosis

5. Abnormal cardiac status with any of the following

   1. NYHA stage III or IV congestive heart failure
   2. myocardial infarction within the previous 6 months
   3. symptomatic cardiac arrhythmia requiring treatment or persisting despite appropriate treatment

6. Current active infectious disease or positive serology for HIV, HCV or positive Hbs Antigen

7. History of or current auto-immune disease

8. History of other active malignancy within the past five years (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma).

9. Serious concurrent uncontrolled medical disorder

10. History of allograft or solid organ transplantation

11. Pregnant or lactating women

12. Any condition potentially hampering compliance with the study protocol and follow-up schedule