Cyclophosphamide With Biochemical Progression During Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma (MM)
Cyclophosphamide With Biochemical Progression During Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma (MM)
This study evaluates the efficacy of the addiction of Cyclophosphamide to Revlimid-low dose
 dexamethasone (Rd) in relapsed/refractory Multiple Myeloma patients, who experienced a
 biochemical progression, without CRAB, during Rd treatment.
This protocol is a phase II multicenter, open label study designed to determine whether the
 addiction of Cyclophosphamide to Rd (CRd) treatment significantly increases response rates
 and prolonged the outcome (PFS, OS) in patients who experienced a biochemical relapse,
 without CRAB under Rd treatment. Patients will be evaluated at scheduled visits in up to 3
 study periods: pre-treatment, treatment and long-term follow-up (LTFU).

 The pre-treatment period includes: screening visits, performed at study entry. After
 providing written informed consent to participate in the study, patients will be evaluated
 for study eligibility. The screening period includes the availability of inclusion criteria
 described above. Subjects who meet all the inclusion criteria will be enrolled.

 The treatment period includes: administration of the combination CRd for 9 cycles. In order
 to assess the efficacy and safety of treatment, patients will attend the study center visits
 at least every 2 weeks. The response will be assessed after each cycle.

 During the LTFU period, after development of confirmed progression disease (PD), all patients
 are to be followed for survival every 1-3 months via telephone or office visit.
Inclusion Criteria:

 -  Patient with relapse/refractory multiple myeloma who experienced biochemical
 progression, without CRAB, during treatment with Rd. CRAB means the presence of organ
 damage, multiple myeloma related (renal impairment and/or anemia and/or new bone
 lesions and/or hypercalcemia). It is sufficient one of the previous signs for defining
 the presence of CRAB. Biochemical progression means: positivization of serum/urine
 immunofixation for patients who reached a complete remission with Rd treatment or at
 least 25% increment of monoclonal component in serum/urine for patients who reached at
 least a stable disease (SD).

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

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

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

 -  Female patient is either post-menopausal or surgically sterilized or, if at
 childbearing potential, must: understand that the study medication could have an
 expected teratogenic risk.

 -  Agree to use, and be able to comply with, effective contraception without
 interruption, 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 and
 continued abstinence confirmed on a monthly basis. The following are effective methods
 of contraception*:

 -  Implant**

 -  Levonorgestrel-releasing intrauterine system (IUS)**

 -  Medroxyprogesterone acetate depot

 -  Tubal sterilisation

 -  Sexual intercourse with a vasectomised male partner only; vasectomy must be
 confirmed 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 combined
 oral contraception, she must switch to one of the methods above. The increased risk of
 venous thromboembolism (VTE) continues for 4 to 6 weeks after stopping combined oral
 contraception.

 -  **prophylactic antibiotics should be considered at the time of insertion particularly
 in patients with neutropenia due to risk of infection.

 -  Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25
 mills International Units on milliliter (mIU/ml) not more than 3 days before the start
 of 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 practice
 complete and continued abstinence.

 -  Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks
 after 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 next
 treatment. This requirement also applies to women of childbearing potential who
 practice complete and continued abstinence.

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

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

 -  Male subjects must:

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

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

 -  All subjects must:

 -  Agree to abstain from donating blood while taking study drug therapy and for one
 week following discontinuation of study drug therapy.

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

 -  Patient who obtain at least a SD with Rd treatment and experienced a biochemical
 progression 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 of
 the Cyclophosphamide):

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

 -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L or ≥ 0,5 109/L x if bone marrow
 involvement 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 to
 disease (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 this
 study 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 has
 been free of the disease for ≥ 3 years. Exceptions include the following: Basal cell
 carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the
 cervix, carcinoma in situ of the breast, incidental histological finding of prostate
 cancer (TNM stage of T1a or T1b).