A Multicenter Open Label Phase II Study of Pomalidomide and Cyclophosphamide and Dexamethasone in Relapse/Refractory Multiple Myeloma Patients Who Were First Treated Within the IFM/DFCI 2009 Trial (PCD)

Inclusion Criteria:

1. Patients must have been treated in first line within the IFM/DFCI 2009 trial to betreated within the PCD trial in second line

2. Must be able to understand and voluntarily sign an informed consent form

3. Must be able to adhere to the study visit schedule and other protocol requirements

4. Age: 18-70 years

5. Life expectancy >6 months

6. Patients must have progressive (+/- symptomatic) Myeloma as defined by the IMWGcriteria with increase of ≥25% from lowest response value in any one or more of thefollowing:

• Serum M-component and/or (the absolute increase must be ≥0.5 g/dl)

• Urine M-component and/or (the absolute increase must be ≥200 mg/24h)

• Only in patients without measurable serum and urine M-protein levels: thedifference between involved and uninvolved FLC levels. The absolute increasemust be >10 mg/dl

• Bone marrow plasma cell percentage; the absolute percentage must be ≥10%

• Definite development of new bone lesions or soft tissue plasmacytomas ordefinite increase in the size of existing bone lesions or soft tissueplasmacytomas

• Development of hypercalcaemia (corrected serum calcium >11.5 mg/dl or 2.65mmol/l) that can be attributed solely to the plasma cell proliferativedisorder.

7. Patients must have a clearly detectable and quantifiable monoclonal M-componentvalue:

• IgG (serum M-component >10g/l)

• IgA (serum M-component >5g/l)

• IgD (serum M-component >0.5g/l)

• Light chain (serum M-component >1g/l or Bence Jones >200mg/24h)

• In patients without measurable serum and urine M-protein levels and in theabsence of renal failure: when the absolute serum FreeLightChain (sFLC) is ≥100mg/l and an abnormal sFLC K/λ ratio (<0.26 or>1.65) is found.

8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

9. Adequate bone marrow function, documented within 96 hours prior to treatment withouttransfusion or growth factor support, defined as:

• Absolute neutrophils ≥1000/mm3

• Platelets ≥75000/mm3

• Hemoglobin ≥8.5g/dl

10. Adequate organ function, documented within 96 hours prior to treatment, defined as:

• Serum SGOT/AST or SGPT/ALT <3.0 X Upper Limit of Normal (ULN)

• Serum creatinine clearance (Cockcroft-Gault formula) ≥50 ml/min

• Serum total bilirubin <2.0 mg/dl

11. Wash out period of at least 2 weeks from previous antitumor therapy or anyinvestigational treatment.

12. Able to take antithrombotic medicines such as low molecular weight heparin oraspirin.

13. Subjects affiliated with an appropriate social security system

14. Agree to abstain from donating blood while taking study drug therapy and for atleast 28 days following discontinuation of study drug therapy

15. Agree not to share study medication with another person and to return all unusedstudy drug to the investigator

16. Female subjects of childbearing potential (*) must:

• Understand the potential teratogenic risk to the unborn child

• Understand the need and agree to use, and be able to comply with, two reliableforms of contraception simultaneously or to practice complete abstinence fromheterosexual contact during the following time periods related to this study:

1. for at least 28 days before starting study drug;
2. while participating in the study;
3. dose interruptions; and
4. for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective methodand one additional effective (barrier) method. Females of childbearing potentialmust be referred to a qualified provider of contraceptive methods if needed. Thefollowing are examples of highly effective and additional effective methods ofcontraception:

• Highly effective methods:

• Intrauterine device (IUD)

• Hormonal (birth control pills, injections, implants)

• Tubal ligation

• Partner's vasectomy

• Additional effective methods:

• Male condom

• Diaphragm

• Cervical Cap Because of the increased risk of venous thromboembolism in patients with multiplemyeloma taking pomalidomide and cyclophosphamide and dexamethasone, combined oralcontraceptive pills are not recommended. If a female subject is currently usingcombined oral contraception the patient should switch to another one of the highlyeffective methods listed above. The risk of venous thromboembolism continues for 4-6weeks after discontinuing combined oral contraception. The efficacy of contraceptivesteroids may be reduced during co-treatment with dexamethasone. Implants and levonorgestrel-releasing intrauterine devices are associated with anincreased risk of infection at the time of insertion and irregular vaginal bleeding.Prophylactic antibiotics should be considered particularly in patients withneutropenia. o Agree to have pregnancy testing based on the frequency outlined below. Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml must beperformed for females of childbearing potential, including females of childbearingpotential who commit to complete abstinence:

• Before starting study drug: females of childbearing potential must have twonegative pregnancy tests prior to starting study drug. The first pregnancy testmust be performed within 10-14 days prior to the start of study drug and thesecond pregnancy test must be performed within 24 hours prior to the start ofstudy drug. The patient may not receive study drug until the study doctor hasverified that the results of these pregnancy tests are negative.

• During study participation and for 28 days following study drugdiscontinuation: Females of childbearing potential with regular or no menstrual cycles must agree tohave pregnancy tests weekly for the first 28 days of study participation and thenevery 28 days while on study, at study discontinuation, and at day 28 followingstudy drug discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly for thefirst 28 days and then every 14 days while on study, at study discontinuation, andat days 14 and 28 following study drug discontinuation.

*Criteria for women of childbearing potential: This protocol defines a female ofchildbearing potential as a sexually mature woman who: 1) has not undergone ahysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) forat least 24 consecutive months (ie, has had menses at any time in the preceding 24consecutive months).

17. Male subjects must:

• Practice complete abstinence or agree to use a condom during sexual contactwith a pregnant female or a female of childbearing potential whileparticipating in the study, during dose interruptions and for at least 28 daysfollowing study drug discontinuation, even if he has undergone a successfulvasectomy.

• Agree not to donate semen or sperm during study drug therapy and for at least 28 days following discontinuation of study drug.

Exclusion Criteria:

1. Any other uncontrolled medical condition or comorbidity that might interfere withsubject's participation

2. Primary amyloidosis or myeloma complicated by amyloidosis

3. Pregnant or breast feeding females

4. Use of any other experimental drug or therapy within 2 weeks before study treatmentinitiation (except local radiotherapy and/or corticosteroid until dose ofdexamethasone 160mg)

5. Known positive for HIV or Active infectious hepatitis, type B or C

6. Patients with non-secretory MM

7. Prior history of malignancies within 10 years

8. Evidence of Central Nervous System (CNS) involvement

9. Any >grade 2 toxicity unresolved

10. Peripheral neuropathy >grade 2

11. Known hypersensitivity to thalidomide, lenalidomide, cyclophosphamide ordexamethasone

12. Ongoing active infection, especially ongoing pneumonitis

13. Participant with clinical signs of heart or coronary failure, or evidence of LeftVentricular Ejection Fraction (LVEF) inferior to 40%. Participant with myocardial infarction within 6 months prior to enrolment or haveNew York Heart Association (NYHA) Class III or IV heart failure, and controlledangina, severe uncontrolled ventricular arrhythmias, or electrocardiographicevidence of acute ischemia or active conduction system abnormalities

14. Inability or unwillingness to comply with birth control requirements

15. Unable to take antithrombotic medicines at study entry

16. Unable to take corticotherapy at study entry

17. Scheduled vaccination with a live agent such as yellow fever vaccine

18. Individually deprived of liberty or placed under the authority of a tutor