Cyclophosphamide With Biochemical Progression During Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma (MM)

Inclusion Criteria:

• Patient with relapse/refractory multiple myeloma who experienced biochemicalprogression, without CRAB, during treatment with Rd. CRAB means the presence of organdamage, multiple myeloma related (renal impairment and/or anemia and/or new bonelesions and/or hypercalcemia). It is sufficient one of the previous signs for definingthe presence of CRAB. Biochemical progression means: positivization of serum/urineimmunofixation for patients who reached a complete remission with Rd treatment or atleast 25% increment of monoclonal component in serum/urine for patients who reached atleast a stable disease (SD).

• Patient exposed to previous therapy included Lenalidomide, Thalidomide, Bortezomiband/or autologous stem cell transplantation (ASCT) and in treatment with Rd.

• Patient is, in the investigator(s) opinion, willing and able to comply with theprotocol requirements.

• Patient has given voluntary written informed consent before performance of anystudy-related procedure not part of normal medical care, with the understanding thatconsent may be withdrawn by the patient at any time without prejudice to their futuremedical care.

• Female patient is either post-menopausal or surgically sterilized or, if atchildbearing potential, must: understand that the study medication could have anexpected teratogenic risk.

• Agree to use, and be able to comply with, effective contraception withoutinterruption, 4 weeks before starting study drug, throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy,even if she has amenorrhea. This applies unless the subject commits to absolute andcontinued abstinence confirmed on a monthly basis. The following are effective methodsof contraception*:

• Implant**

• Levonorgestrel-releasing intrauterine system (IUS)**

• Medroxyprogesterone acetate depot

• Tubal sterilisation

• Sexual intercourse with a vasectomised male partner only; vasectomy must beconfirmed by two negative semen analyses

• Ovulation inhibitory progesterone-only pills (i.e., desogestrel)

• Combined oral contraceptive pills are not recommended. If a subject was using combinedoral contraception, she must switch to one of the methods above. The increased risk ofvenous thromboembolism (VTE) continues for 4 to 6 weeks after stopping combined oralcontraception.

• **prophylactic antibiotics should be considered at the time of insertion particularlyin patients with neutropenia due to risk of infection.

• Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25mills International Units on milliliter (mIU/ml) not more than 3 days before the startof study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practicecomplete and continued abstinence.

• Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeksafter the end of study treatment, except in the case of confirmed tubal sterilization.These tests should be performed not more than 3 days before the start of nexttreatment. This requirement also applies to women of childbearing potential whopractice complete and continued abstinence.

• † A female subject or a female partner of a male subject is considered to havechildbearing potential unless she meets at least one of the following criteria: Age

≥50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancertherapy does not rule out childbearing potential), premature ovarian failure confirmedby a specialist gynaecologist, previous bilateral salpingooophorectomy orhysterectomy, xy genotype, Turner's syndrome or uterine agenesis.

• Male subjects must:

• Agree to use condoms throughout study drug therapy, during any dose interruptionand for one week after cessation of study therapy if their partner is ofchildbearing potential and has no contraception.

• Agree not to donate semen during study drug therapy and for one week after end ofstudy drug therapy.

• All subjects must:

• Agree to abstain from donating blood while taking study drug therapy and for oneweek following discontinuation of study drug therapy.

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

• Patient who obtain at least a SD with Rd treatment and experienced a biochemicalprogression without CRAB, during the treatment itself.

• Patient has a Karnofsky performance status ≥ 60%.

• Patient has a life-expectancy > 6 months.

• Patients must have a adequate cardiac function.

• Patients must have adequate pulmonary function.

• Patient has the following laboratory values within 14 days before Baseline (day 1 ofthe Cyclophosphamide):

• Platelet count ≥ 50 x 109/L or ≥ 25 109/L if bone marrow involvement is ≥ 50% ofplasma cells in bone marrow biopsy.

• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L or ≥ 0,5 109/L x if bone marrowinvolvement is ≥ 50% of plasma cells in bone marrow biopsy.

• Corrected serum calcium ≤ 14 mg/dL (3.5 mmol/L).

• Aspartate transaminase (AST): ≤ 2.5 x the upper limit of normal (ULN).

• Alanine transaminase (ALT): ≤ 2.5 x the ULN.

• Total bilirubin: ≤ 1.5 x the ULN.

• Calculated or measured creatinine clearance: ≥ 30 mL/minute.

Exclusion Criteria:

• Patients with newly diagnosed multiple myeloma.

• Patients who relapsed from multiple myeloma with signs of organ damage related todisease (CRAB).

• Any serious medical condition, including the presence of laboratory abnormalities,which places the subject at an unacceptable risk if he or she participates in thisstudy or confounds the experimental ability to interpret data from the study.

• Pregnant or lactating females.

• Prior history of malignancies, other than multiple myeloma, unless the subject hasbeen free of the disease for ≥ 3 years. Exceptions include the following: Basal cellcarcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of thecervix, carcinoma in situ of the breast, incidental histological finding of prostatecancer (TNM stage of T1a or T1b).