The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.

Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).

Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.

All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.

Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

Inclusion Criteria:

• Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of clonal bone marrow plasma cells plus CRAB defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy:

  • 60% or greater clonal plasma cells on bone marrow examination;
  • Serum involved/uninvolved free light chain (FLC) ratio of 100 or greater;
  • More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size.

• Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).

• Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score

• Patient has given voluntary written informed consent.

• Patient is able to be compliant with hospital visits and procedures required per protocol.

• Patient agrees to use acceptable methods for contraception.

• Patient has measurable disease according to IMWG criteria.

• Patient has ECOG (Eastern Cooperative Oncology Group) performance status < 3.

• Pre-treatment clinical laboratory values within 30 days before randomization:

  • 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 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

• Pre-treatment blood pressure value < 140/90 mmHg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable.

• Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding.

• FBCP must follow the Pregnancy Prevention Plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs*

• Males must use an effective barrier method of contraception if sexually active with FCBP during the treatment and for at least 90 days after the last administration of study drug/s. Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.

Exclusion Criteria:

• Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.

• Patient defined as frail according to the IMWG frailty score.

• 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).

• 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
  • Pulmonary hypertension and interstitial lung disease
  • Uncontrolled arrhythmias or history of QT prolongation
  • Myocardial infarction or unstable angina ≤ 6 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) 5.0 (Appendix A)
  • Uncontrolled hypertension defined as persistent hypertension (>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.

• Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.

• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).

• Invasive malignancy within the past 3 years.

• Administration of any experimental drug within 4 weeks prior the baseline or within 5 drug half-lives.