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This is a multicenter, randomized, blinded, 2-arm phase IIb trial that will compare the efficacy and safety of Lenalidomide maintenance after Bortezomib/Melphalan/Prednison (VMP) induction to VMP without maintenance (Placebo). In addition the trial will assess the treatment of Revlimid/low dose Dexamethasone (Rd) as Salvage after VMP without sufficient response (less than PR) in an observational arm. Key eligibility criteria include patients with newly diagnosed multiple myeloma and who are 65 years of age or older or are not candidates for high-dose chemotherapy and autologous stem cell transplantation. Patients with poor performance status or serious coexistent medical conditions will be excluded from this study. After registration all patients receive 6 cycles VMP (modified according to Mateos et al.). Patients who receive at least a PR and completed VMP can be randomized to either Lenalidomide 10 mg/d continuously maintenance or to placebo. Randomization will be stratified according to the quality of response after VMP induction (PR vs. VGPR + stringent complete remission [sCR] + CR). Patients that are not able to complete VMP due to toxicity but reached at least a PR after a minimum of four cycles of therapy should immediately proceed to randomization. Blinded phase continues until progression or end of study. After unblinding, patients who received placebo should be treated with Rd.
Patients that do not reach PR after induction with VMP or are progressive during treatment with VMP should not be randomized, but switched to the observation arm and treated with Rd immediately. The study treatment ends with the confirmed progression on maintenance treatment (Lenalidomide or placebo) for patients that reached PR with induction treatment, or with the confirmed progression on second-line therapy with Revlimid® and Dexamethasone for patients that did not reach PR on induction treatment. All patients will be followed up every 3 months after end of study treatment, until end of study. The study ends two years after Last Patient In (i.e. randomization for maintenance) if sufficient events for the primary endpoint were received, but not later than 8 years after trial initiation (whatever comes first).
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Inclusion criteria
Must understand and voluntarily sign an informed consent form.
Must be ≥18 years of age at the time of signing the informed consent form.
Must be able to adhere to the study visit schedule and other protocol requirements.
Previously untreated, symptomatic multiple myeloma as defined by the 3 criteria below:
Multiple Myeloma (MM) diagnostic criteria (all 3 required):
Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma
Monoclonal protein present in the serum and/or urine
Myeloma-related organ dysfunction (at least one of the following):
AND have measurable disease by protein electrophoresis analyses as defined by the following:
AND are at least 65 years of age or older or, if younger than 65 years of age, are not candidates for stem cell transplantation because:
OR:
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
Female of childbearing potential (FCBP) † must:
Understand the potential teratogenic risk to the unborn child
Understand the need for effective contraception, without interruption, 4 weeks before starting study treatment, throughout the entire duration of study treatment, dose interruption and 28 days after the end of study treatment
Be capable of complying with effective contraceptive measures and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual 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 method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
Highly effective methods*:
Additional effective methods:
(*)Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking Lenalidomide and Dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception she should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with Dexamethasone.
(**)Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
Be informed about and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
Agree to have two medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml (milli-International Units per milliliter) prior to starting Lenalidomide. The first pregnancy test must be performed within 10 to 14 days prior to the start Lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of Lenalidomide. The patient will receive Lenalidomide only after the study doctor has verified that the results of these pregnancy tests are negative. She must understand the need to commence the study treatment as soon as study drug is dispensed following the second negative pregnancy test. This requirement also applies to FCBP who practice complete and continued abstinence.
Must understand the need and accepts to undergo pregnancy testing in the frequency as follows: FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following study drug discontinuation. This requirement also applies to FCBP who practice complete and continued abstinence.
Females must agree to abstain from breastfeeding during study participation and for at least 28 days after study drug discontinuation.
A FCBP † is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months).
Male subjects must:
All subjects must:
Exclusion criteria
Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [i.e., less than or equal to the equivalent of Dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of registration]).
Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, patient with unstable cardiac disease as defined by: Cardiac events such as MI within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; patients with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
Pregnant or breast feeding females.
Any of the following laboratory abnormalities within 1 week prior to registration:
Renal failure with creatinine clearance (CLCR)< 15 ml/min or requiring hemodialysis or peritoneal dialysis.
Psychiatric illness that would prevent the subject from signing the informed consent form or from completion of treatment according to the protocol.
Patient currently is enrolled in another clinical research study or has been enrolled in such a study within 4 weeks before randomization/registration and/or is receiving an investigational agent for any reason or has received such an agent within 4 weeks before registration.
Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for 3 years. Exceptions include the following, if treated with curative intent:
Known positive for HIV or active hepatitis A, B or C viral infection.
Immunotherapy or antibody therapy within 8 weeks before registration.
Major surgery within 4 weeks before registration.
Any severe systemic infection requiring treatment.
Patients who are unable or unwilling to undergo antithrombotic therapy.
Peripheral neuropathy of ≥ grade 3 severity or grade 2 severity with pain.
Primary AL (amyloid light chain) amyloidosis and myeloma complicated by amyloidosis.
Primary purpose
Allocation
Interventional model
Masking
85 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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