Evaluation of the Safety and the Efficacy of Carfilzomib Combined With Cyclophosphamide and Dexamethasone (CCyd) or Lenalidomide and Dex (CRd) Followed by ASCT or 12 Cycles of Carf Combined With Dex and Len for Patients Eligible for ASCT With Newly Diagnosed Multiple Myeloma.

Study Overview
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Brief Summary
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This study will evaluate the safety and the efficacy of carfilzomib combined with cyclophosphamide and dexamethasone (CCyd) or lenalidomide and dexamethasone (CRd) followed by autologous transplantation ASCT or 12 cycles of carfilzomib combined with dexamethasone and lenalidomide for patients eligible for ASCT with newly diagnosed multiple myeloma. As a secondary endpoint this study will evaluate the best maintenance treatment between lenalidomide and lenalidomide combined with carfilzomib. Four hundred seventy-seven patients, males and females aged > 18 years, enrolled in several sites, will take part in this study. The duration of the study is approximately 5 years.

Official Title
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A MULTICENTER, RANDOMIZED, OPEN LABEL PHASE II STUDY OF CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (CCyd) as Pre Transplant INDUCTION and Post Transplant Consolidation or CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (CRd) as Pre Transplant INDUCTION and Post Transplant Consolidation or Continuous Treatment With CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (12 Cycles) Without Transplant, All Followed by MAINTENANCE With LENALIDOMIDE (R) Versus LENALIDOMIDE AND CARFILZOMIB (CR) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS ELEGIBLE FOR AUTOLOGOUS TRANSPLANT

Conditions
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MULTIPLE MYELOMA (MM)

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Cyclophosphamide
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Newly diagnosed MM based on standard CRAB criteria (see appendix B). Patient < 65 years eligible for ASCT. Patient has measurable disease according to IMWG (International Myeloma Working Group) criteria. Patient has given voluntary written informed consent. Patient agrees to use acceptable methods for contraception. Patient has a Karnofsky performance status ≥ 60% Pretreatment clinical laboratory values within 30 days of enrolment: Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is > 50%) Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors Corrected serum calcium ≤14 mg/dL (3.5 mmol/L) Alanine transaminase (ALT): ≤ 3 x the Upper Limit Normal (ULN) Total bilirubin: ≤ 2 x the ULN Calculated or measured creatinine clearance: ≥ 30 mL/minute. LVEF≥40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available Life expectancy ≥ 3 months Exclusion Criteria: Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid < to the equivalent of dexamethasone 40 mg/day for 4 days) Patients with non-secretory MM unless serum free-light chains are present and the ratio is abnormal or a plasmocytoma with minimum largest diameters of > 2 cm Patients ineligible for autologous transplantation Pregnant or lactating females Presence of: Clinical active infectious hepatitis type A, B, C or HIV Acute active infection requiring antibiotics or infiltrative pulmonary disease Myocardial infarction or unstable angina ≤ 4 months or other clinically significant heart disease Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0 Known history of allergy to Captisol ® (a cyclodextrin derivative used to solubilize carfilzomib) Contraindication to any of the required drugs or supportive treatments Invasive malignancy within the past 3 years Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCyd<br>Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment. After the end of consolidation all patients will be randomized to receive: Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance. | Drug: Carfilzomib<br> <br> Drug: Cyclophosphamide<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: CRd<br>Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment. After the end of consolidation all patients will be randomized to receive: Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance. | Drug: Carfilzomib<br> <br> Drug: Lenalidomide<br> <br> * Other names: Revlimid;Drug: Dexamethasone<br> <br> |
| Experimental: CRd long treatment<br>Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. Stem cells collection will be performed. Carfilzomib Lenalidomide and Dexamethasone administered for 8 28-day cycles. After that all patients will be randomized to receive: Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance. | Drug: Carfilzomib<br> <br> Drug: Lenalidomide<br> <br> * Other names: Revlimid;Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy in term of at least Very Good Partial Response (VGPR) | The efficacy, in term of at least VGPR, of the combination of carfilzomib, dexamethasone with cyclophosphamide or lenalidomide after 4 cycles of induction treatment in newly diagnosed MM patients eligible for ASCT. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| sCR rate | the stringent complete response (sCR) rate in the 3 arms after complete primary therapy (induction, ASCT and consolidation for the transplant arms and after 12 cycles in the long treatment arm) in an explorative manner. | up to 1 year | 
| Safety as incidence of grade 3/4 adverse events | the safety in the 3 induction/consolidation arms and in the 2 maintenance arms. | Up to 3 years | 
| Survival | the survival in the 3 induction/consolidation arms and in the 2 maintenance arms. | Up to 5 years | 
| Correlation between tumor response and outcome with baseline prognostic factors. |  | up to 5 years | 
| Minimal Residual Disease (MRD) | Minimal Residual Disease | up to 5 years | 
| Survival after relapse | the survival after relapse | up to 7 years |