UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission

Study Overview
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Brief Summary
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The purpose of this study is to improve the clinical outcomes of research subjects with high-risk multiple myeloma in the context of the immediately preceding Total therapy 5 trial 2008-02 and Total therapy 3 trials 2003-33 and 2006-66.

Detailed Description
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Total therapy 5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission by reducing host-imposed toxicity and facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib. This will result in avoiding multiple myeloma re-growth that, we postulate, ensued in Total therapy 3 during recovery phases from severe de-conditioning. It is speculated that the incidence of positive minimal residual disease will be reduced with the addition of one cycle of consolidation therapy. The following approach will be implemented: apply a 4-day fractionated lower dose melphalan (80 mg/m2) together with CFZ-TD-PACE regimen in MEL80-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE as a hopefully less toxic and more effective transplant regimen interspersed with 1 cycle of non-transplant supported MEL-20-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE (in lower doses than with transplant) inter-therapy (reduced from two cycles due to prolonged thrombocytopenia) followed by CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE consolidation therapy post transplant #2 CFZ-RD (carfilzomib, lenalidomide and dexamethasone) maintenance for 1 year followed by CFZ-D for an additional year

Official Title
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A Phase II Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission (AS-CR) by Applying Non-Host-Exhausting and Timely Dose-Reduced Mel-80-CFZ-TD-Pace Transplant(s) With Interspersed Mel-20-CFZ-TD-Pace With CFZ-RD and CFZ-D Maintenance

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Device: myPRS
* Drug: Induction 1 - MEL-10+CFZ-TD-PACE
* Drug: First Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)
* Drug: Inter-Therapy - MEL-20+CFZ-TD-PACE (75%)
* Drug: Second Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)
* Drug: Consolidation - CFZ-TD-PACE
* Drug: Maintenance - CFZ-R(T)-D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy. Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation. Participants must have high-risk disease, as defined by GEP70 risk score of ≥ 0.66 Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease. Patients must have a platelet count of ≥ 50,000/μL, unless lower levels are explained by extensive bone marrow plasmacytosis. Patients must be at least 18 years of age and not older than 75 years of age at the time of registration. Participants must have preserved renal function as defined by a serum creatinine level of < 3 mg/dL. Participants must have an ejection fraction by ECHO or MUGA scan ≥ 45% Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy. Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB. Exclusion Criteria: Does not have high-risk disease Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol. Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years. Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Total Therapy 5b<br>Induction, optional bridging, first transplant, optional bridging, inter-therapy, optional bridging, second transplant, optional bridging, consolidation, maintenance | Device: myPRS<br>* Genome expression profiling used to identify high-risk and low-risk multiple myeloma<br>* Other names: Gep70;Drug: Induction 1 - MEL-10+CFZ-TD-PACE<br>* Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days 1, 5, & 6; MEL 10mg/m2 on day 3; T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 400 mg/m2/d, and E 40 mg/m2/d on days 5-8; G-CSF 10 mcg/kg/day from day 11 through end of Peripheral Blood Stem Cell (PBSC) collection. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until 1st transplant.<br>* Other names: Granulocyte colony-stimulating factor (G-CSF), filgrastim (Neupogen®);Drug: First Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)<br>* Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days -5 & -4; MEL 20 mg/m2/d, T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 100 mg/m2/d, and E 80 mg/m2/d on days -5 & -2; PBSC transplant on day 0. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until inter-therapy.<br>* Other names: Etoposide (VP-16) (Vepesid®);Drug: Inter-Therapy - MEL-20+CFZ-TD-PACE (75%)<br>* Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 27 mg/m2 on days 1-2; MEL 5 mg/m2/d, T 200 mg/d, D 20 mg/d, P 7.5 mg/m2/d, A 7.5 mg/m2/d, C 75 mg/m2/d, and E 60 mg/m2/d on days 1-4. Optional Bridging with T 50 mg/d and D 20 mg on day 1-4 every 21 days until 2nd transplant.<br>* Other names: Etoposide (VP-16) (Vepesid®);Drug: Second Transplant - MEL-80+CFZ-TD-PACE + PBSC (biologic)<br>* Melphalan (MEL) and Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and Dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), Adriamycin (A), Cyclophosphamide (C) and Etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. After completion of the continuous chemotherapy, Granulocyte colony-stimulating factor (G-CSF), a shot just under the skin to help the bone marrow and blood counts recover more quickly after chemotherapy, will be given. Regimen: CFZ 20 mg/m2 on days -5 & -4; MEL 20 mg/m2/d, T 200 mg/d, D 40 mg/d, P 10 mg/m2/d, A 10 mg/m2/d, C 100 mg/m2/d, and E 80 mg/m2/d on days -5 & -2; PBSC transplant on day 0. Optional Bridging with T 50mg/d and D 20 mg on day 1-4 every 21 days until consolidation.<br>* Other names: Etoposide (VP-16) (Vepesid®);Drug: Consolidation - CFZ-TD-PACE<br>* Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) is a capsule and dexamethasone (D) is a pill; both will be taken by mouth. Cisplatin (P), adriamycin (A), cyclophosphamide (C) and etoposide (E) are all given into the vein (IV) by a continuous infusion through a central catheter. Regimen: CFZ 27 mg/m2 on days 1-2; T 200 mg/d, D 40 mg/d, P 7.5 mg/m2/d, A 7.5 mg/m2/d, C 300 mg/m2/d, and E 30 mg/m2/d on days 1-4.<br>* Other names: Etoposide (VP-16) (Vepesid®);Drug: Maintenance - CFZ-R(T)-D<br>* Carfilzomib (CFZ) will be given into a central venous catheter. Thalidomide (T) and lenalidomide (R) are capsules and dexamethasone (D) is a pill; all will be taken by mouth. Regimen: For Cycles 1-12 CFZ 27 mg/m2/wk and D 12 mg/wk on days 1, 8, 15, & 22; lenalidomide (R) 15 mg/d on days 1-21. For Cycles 13-24 CFZ 27 mg/m2/wk and D 12 mg/wk on days 1, 8, 15, & 22. T may be substituted for R at 100 mg/day at the treating physician's discretion.<br>* Other names: Thalidomide (Thalomid®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Remission Rate for Participants With High-risk Myeloma | Toward improving the clinical outcomes of research subjects with high-risk MM (HR-MM) in the context of the immediately preceding TT5 trial 2008-02 and TT3 trials 2003-33 and 2006-66, TT5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission (AS-CR-2) by reducing host-imposed toxicity and thus facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib (CFZ). This will result in avoiding MM re-growth that, we postulate, ensued in TT3 during recovery phases from severe de-conditioning. Furthermore, we speculate that the incidence of positive minimal residual disease (MRD) will be reduced with the addition of one cycle of consolidation therapy. | from baseline to either death or study completion for each subject (up to approximately 48 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High-Risk, Carfilzomib