Carfilzomib + Lenalidomide and Dexamethasone for BTK Inhibitors Relapsed-refractory or Intolerant MCL

Inclusion criteria Patient has a confirmed diagnosis of MCL according to the WHO 2017 classification; * Previous treatment with BTKi monotherapy or BTKi containing regimens with R/R disease; and/or patients who discontinued BTKi monotherapy or BTKi containing regimens for adverse events and have active disease necessitating treatment; * Previous treatment with Lenalidomide is accepted if patient resulted responsive and interrupted Lenalidomide at least 12 months before enrollment to this study; * Patient age is ≥ 18 \< 80 years; * Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2; * Understands and voluntarily signs an informed consent form; * Able to adhere to the study visit schedule and other protocol requirements; Patient has at least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan cannot be performed). Note: Patients with bone marrow involvement are eligible; * Adequate hematological counts: ANC \> 1.5 x 109/L and platelet count \> 75 x 109/L unless due to bone marrow involvement by MCL; * Conjugated bilirubin up to 2 x ULN unless due to liver involvement by MCL; * Alkaline phosphatase and transaminases up to 2 x ULN unless due to liver involvement by MCL; * Creatinine clearance ≥ 30 ml/min; a dose reduction of Lenalidomide for patients with creatinine clearance ≥ 30 mL/min but \< 50 mL/min is planned; * Patient has the ability to swallow capsules or tablets; * Life expectancy ≥ 2 months; * Male and Female patients: accordance to comply with Lenalidomide Risk Management Plan for pregnancy prevention. Exclusion criteria * Patient who have received an experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study; * Patient has a history of CNS involvement with lymphoma; * Patient with previous history of malignancies (apart MCL) ≤ 3 years before study accrual with the exception of currently treated basal cell and squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix; * History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances; * Patient has any other concurrent severe and/or uncontrolled medical condition(s) (e.g., uncontrolled diabetes mellitus, uncontrolled hypertension, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), active hemorrhage, psychiatric illness, active or uncontrolled infection that in the investigator opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form; * Creatinine clearance \< 30 ml/min; * Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment; * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib); * Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment; * Patients with LVEF \<40% * Patients with New York Health Association (NYHA) Class III and IV heart failure; myocardial infarction in the preceding 6 months; conduction abnormalities, including but not limited to atrial fibrillation, atrioventricular (AV) block, QT prolongation, sick sinus syndrome, ventricular tachycardia; * Patients with severe bradycardia (heart rate \<40 bpm, hypotension, light-headedness, syncope); * Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment; * Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment); * Patient has a known history of HIV seropositivity; * Patient has active HBV hepatitis. The following categories of HBV positive patients but with no evidence of active hepatitis may be considered for the study: * patient is HBsAg + with HBV DNA \< 2000 UI/ml (inactive carriers); HBV DNA \> 2000 UI/ml is criteria of exclusion; * patient is HBsAg - HBsAb +; * patient is HBsAg - but HBcAb + * Patient with HCV active hepatitis are excluded from the study. Patient with no evidence of active hepatitis and/or advanced chronic liver disease according to liver biopsy or fibro-scan evaluation may be included into the study; * Previous treatment with Lenalidomide if patient resulted primary refractory to Lenalidomide or interrupted Lenalidomide less than 12 months before enrollment to this study.