Ixazomib, Lenalidomide, Dexamethasone Induction and Extended Consolidation Plus Lenalidomide Maintenance in Multiple Myeloma

Evaluation of Ixazomib, Lenalidomide, Dexamethasone Induction and Extended Consolidation Followed by Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma Patients ≤65 Years Eligible for High Dose Therapy

Open-label study to evaluate the safety and efficacy of Ixazomib in combination with Lenalidomide and Dexamethasone in patients with newly diagnosed multiple myeloma (MM). The patient population will consist of adult men and women up to 65 years, who have a confirmed diagnosis of MM who meet eligibility criteria.

Patients will receive induction therapy, comprising three cycles with Ixazomib, plus Lenalidomide and Dexamethasone.

Peripheral Blood Stem Cells (PBSC) will be mobilized within 2 weeks (+/- 1 week) after the last dose of Lenalidomide, with Cyclophosphamide plus G-CSF or Granulocyte-CSF(Colony Stimulating Factor).

Intensification: High Dose Melphalan (HDM) will be performed within 3 weeks +/- 1 week following stem cell harvest.

After Peripheral Blood Stem Cell Transplantation, patient will enter in the consolidation phase:

Early consolidation (consolidation part 1) will start 2 months after transplantation and will comprise 2 cycles of MLN - Rd (MLN R identical to induction therapy but low dose of Dexamethasone).

Late consolidation (consolidation part 2) will consist in 6 additional cycles of Ixazomib plus Lenalidomide. No Dexamethasone.

Maintenance therapy will start within 28 days after the last dose of Lenalidomide in last cycle of Late Consolidation for thirteen 28-day cycles (approximately 12 months duration) Patients will be seen at regular treatment cycle intervals while they are participating in the study.

Response will be assessed according to the International Myeloma Working Group (IMWG) criteria until disease progression. All patients will be followed for survival after progression.

Inclusion Criteria:

• Multiple myeloma based on the new IMWG Diagnostic Criteria for plasma cells disorders

• Symptomatic myeloma with CRAB criteria

• Measurable disease requiring systemic therapy defined by serum M-component ≥ 5g/l or urine M-component ≥ 200 mg/24h or serum FLC ≥ 100 mg/l.

• Subjects must not have been treated previously with any systemic therapy for multiple myeloma.

• Eligibility for high dose therapy.

• Life expectancy ≥ 3 months

• ECOG performance status 0, 1 or 2

• Patients must meet the following clinical laboratory criteria:

  • Adequate hepatic function,
  • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to enrollment.
  • Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to enrollment
  • Platelet count ≥ 75 × 109/L eRenal eGFR ≥ 50 mL/minute within 7 days

Exclusion Criteria:

• Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening

• Evidence of mucosal or internal bleeding and/or platelet refractory.

• Prior myeloma systemic therapy

• Major surgery within 14 days before first dose of study drug.

• Radiotherapy within 14 days before first dose of study drug.

• Corticosteroids if exceed the equivalent of 160 mg of dexamethasone within 14 days before first dose of study drug

• Central nervous system involvement

• Growth factors within 7 days of screening

• Transfusion within 7 days of screening

• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to first dose of study drug

• Infection .

• Evidence of current uncontrolled cardiovascular conditions,

• Systemic treatment, within 14 days before first dose of study drug, with strong inhibitors of CYP1A2 , strong inhibitors of CYP3A or use of Ginkgo biloba or St. John's wort.

• Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis and history of hepatitis B or C virus hepatitis.

  15. Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

• Psychiatric illness/social situation that would limit compliance with study requirements.

• Known allergy to any of the study medications,

• Contraindication to any of the required concomitant drugs

• Diagnosed or treated for another malignancy within 5 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease.

• Patient has significant neuropathy