A Trial for Systemic Light-chain (AL) Amyloidosis (EMN-03)

Inclusion Criteria:

• Histologic diagnosis of amyloidosis.
• Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of kappa or lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement.
• Not eligible for ASCT with melphalan 200 mg/m2. Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
• Patients must be 18 years of age.
• ECOG performance status 0,1 or 2.
• Measurable disease; al least one of the following criteria:
• monoclonal protein >10 g/L in serum,
• amyloid-forming (involved) FLC >75 mg/L with an abnormal K/L ratio,
• difference between involved and uninvolved FLC >50 mg/L,
• bone marrow with a clonal predominance.
• Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system). Definition of organ involvement is defined.
• Hemoglobin ≥11 g/dL, absolute neutrophil count ≥1500/mikroL, platelets ≥140,000/mikroL.
• Total bilirubin <2.5 mg/dL, alkaline phosphatase <5 × u.l.n., ALT <3 × u.l.n..
• Estimated glomerular filtration rate (eGFR) by the MDRD formula >30 ml/min.
• Only patients who are informed of the investigational nature of this study and sign and give written informed consent in accordance with institutional, national and European guidelines are eligible to participate.
• Women must be either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
• Men must agree to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

• Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis.
• Isolated soft tissue involvement.
• Presence of non-AL amyloidosis.
• Previous treatment for plasma cell disease. A single previous cycle of dexamethasone or steroid equivalent (maximum cumulative dexamethasone dose 160 mg) is allowed; in this case baseline data must be obtained after steroid administration. Previous stem cell harvest is allowed, provided that mobilization is performed with G-CSF only.
• Bone marrow plasma cells >30%.
• Cardiac stage III disease: both cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL) AND simultaneous NT-proBNP >332 ng/L. These subject can be enrolled in the ancillary phase II study.
• Repetitive ventricular arrhythmias on 24h Holter ECG in spite of anti-arrhythmic treatment.
• Chronic atrial fibrillation
• Supine systolic blood pressure <100 mmHg or symptomatic orthostatic hypotension or clinically important autonomic disease
• Grade 3 sensory or grade 1 painful peripheral neuropathy.
• Patients with AL who are eligible for ASCT with 200 mg/m2 of melphalan. These are patients <65 years of age, without cardiac involvement (determined according to the consensus criteria), with eGFR >51mL/min, left ventricular ejection fraction >45%, and bilirubin <2.0 mg/dL. Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
• Pregnant or nursing women.
• Clinically overt multiple myeloma with lytic bone lesions
• Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
• Patients with medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure, or myocardial infarction within the previous 6 months are not eligible.
• HIV positive.
• Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Patients with hypersensitivity to bortezomib, boron or mannitol.