Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65 (DFCI 10-106)

• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To compare the response rates (RR) between the two arms.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To compare time to progression (TTP) between the two arms.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To compare the overall survival (OS) between the two arms.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: Yes ]
  To compare toxicity between the two arms.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To define genetic prognostic groups evaluateed by gene expression profiling (GEP).
• Secondary Outcomes [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To examine the best treatment in each GEP-defined prognostic group.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To compare quality of life (QOL) between the two arms.
• Secondary Outcome [ Time Frame: Up to 6 years or until progression ] [ Designated as safety issue: No ]
  To collect medical resource utilization (MRU) information which may be used in economic evaluation models.

The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma.

In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.

After screening procedures determine if a patient is eligible for this research study, the patient will be randomized into one of the study groups: lenalidomide, bortezomib and dexamethasone without autologous stem cell transplantation, followed by lenalidomide maintenance (Arm A) or lenalidomide, bortezomib and dexamethasone with autologous stem cell transplantation, followed by lenalidomide maintenance (Arm B). There is an equal chance of being placed in either group.

All participants will receive one cycle of lenalidomide, bortezomib and dexamethasone treatment before being randomized to Arm A or Arm B.

Participants in Arm A will receive two additional cycles of lenalidomide, bortezomib and dexamethasone prior to stem cell collection. If randomized to Arm A, the subject will undergo stem cell collection, followed by five cycles of lenalidomide, bortezomib and dexamethasone. This will be followed by twelve months of lenalidomide treatment.

Participants in Arm B will receive two additional cycles of lenalidomide, bortezomib and dexamethasone prior to stem cell collection. If randomized to Arm B, the subject will undergo stem cell collection and autologous stem cell transplantation, followed by two cycles of lenalidomide, bortezomib and dexamethasone. This will be followed by twelve months of lenalidomide treatment.

• Drug: Lenalidomide

  Oral, 25 mg/day, days 1-14 for 8 total cycles for Arm A. Oral, 25 mg/day, days 1-14 for 5 total cycles for Arm B.

  Oral, 10-15 mg/day, daily for 12 months in maintenance for Arm A and Arm B.

  Other Name: CC-5013
• Drug: Bortezomib
  IV, days 1, 4, 8 and 11 for 8 total cycles for Arm A. IV, days 1, 4, 8 and 11 for 5 total cycles for Arm B.
  Other Names:

  • PS-341
  • Velcade
• Drug: Dexamethasone

  Oral, days 1, 2, 4, 5, 8, 9, 11 and 12 for 8 total cycles for Arm A. Oral, days 1, 2, 4, 5, 8, 9, 11 and 12 for 5 total cycles for Arm B.

  Dose of 20 mg/day for first 3 cycles. Dose of 10 mg/day for remaining cycles.

  Other Name: Decadron
• Procedure: Autologous Stem Cell Transplant
  Stem cell transplant

• Active Comparator: High Dose Treatment
  Lenalidomide, bortezomib, dexamethasone. Stem cell collection. Maintenance Lenalidomide.
  Interventions:

  • Drug: Lenalidomide
  • Drug: Bortezomib
  • Drug: Dexamethasone
• Experimental: High Dose Treatment with SCT
  Lenalidomide, bortezomib, dexamethasone. Stem cell collection. Autologous Stem Cell Transplant. Maintenance Lenalidomide.
  Interventions:

  • Drug: Lenalidomide
  • Drug: Bortezomib
  • Drug: Dexamethasone
  • Procedure: Autologous Stem Cell Transplant

Inclusion Criteria:

• Diagnosis of Multiple Myeloma, according to the International Myeloma Foundation 2003 Diagnostic Criteria
• Documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration
• Myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains.
• ECOG performance status </= 2
• Negative HIV blood test
• Voluntary written informed consent

Exclusion Criteria:

• Pregnant or lactating female
• Prior systemic therapy for MM (localized radiotherapy allowed if >/= 2 weeks before study entry, corticosteroids allowed if dose </= equivalent of 160 mg dexamethasone over 2 weeks)
• Primary amyloidosis (AL) or myeloma complicated by amylosis
• Receiving any other investigational agents
• Known brain metastases
• Poor tolerability or allergy to any of the study drugs or compounds of similar composition
• Platelet count <50,000/mm3, within 21 days of registration
• ANC <1,000 cells/mm3, within 21 days of registration
• Hemoglobin <8 g/dL, within 21 days of registration
• Hepatic impairment (>/= 1.5 x institutional ULN or AST (SGOT), ALT (SGPT), or alkaline phosphatase >2 x ULN). Patients with benign hyperbilirubinemia are eligible.
• Renal insufficiency (serum creatinine >2.5 mg/dl or creatinine clearance <60 ml/min, within 21 days of registration)
• Respiratory compromise (DLCO < 50%)
• Clinical signs of heart or coronary failure or LVEF < 40%. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities
• Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements
• Previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer
• Inability to comply with an anti-thrombotic treatment regimen
• Peripheral neuropathy >/= Grade 2

• Celgene Corporation
• Millennium Pharmaceuticals, Inc.
• Massachusetts General Hospital
• Beth Israel Deaconess Medical Center
• Emory University
• University of Michigan
• Fox Chase Cancer Center
• Memorial Sloan-Kettering Cancer Center
• Fred Hutchinson Cancer Research Center
• Barbara Ann Karmanos Cancer Institute
• Duke University
• University of California, San Francisco
• University of Chicago
• M.D. Anderson Cancer Center
• UNC Lineberger Comprehensive Cancer Center