A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant

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.