A multicenter, randomized phase III study of bortezomib and ...

HOVON 104 AL AMYLOIDOSIS Clinical trial protocol version 7, 27 November 2012
5 Introduction and rationale
5.1 AL Amyloidosis and current treatment
Disease
AL amyloidosis is caused by a small monoclonal population of plasma cells in the bone marrow,
synthesizing monoclonal light chains that undergo conformational modifications and aggregate into
amyloid fibrils that form extracellular deposits in one or more vital organs, most frequently the kidney,
heart, liver and peripheral and autonomic nervous system.
The disease is rare with an estimated incidence of 0.8 per 100,000 person years. The median age is
60 years with a male predominance (57%). If untreated, AL amyloidosis is a progressive disease and
is usually fatal within 2 years. 1
Patients can present with nephrotic syndrome, renal failure, hepatosplenomegaly, congestive heart
failure, arrythmias, postural hypotension, syncope, and pseudo-obstruction of the gastro-intestinal
tract. Highly suggestive physical findings are macroglossia and periorbital purpura. Approximately
70% of patients present with 2 or more organs involved.
Diagnosis & Prognosis
The diagnosis of AL amyloidosis is based on a clinical suspicion and confirmed by a tissue biopsy,
usually of an involved organ. The type of amyloid must then be determined. Patients with AL
amyloidosis will have a clonal plasma cell dyscrasia.
Since the extent of cardiac involvement is the most important determinant of clinical outcome, a
staging system to evaluate the cardiac injury has been developed. 2 This system uses the serum
markers N-terminal fragment of pro-brain natriuretic peptide (NT-ProBNP) and troponin T or I. NT-
ProBNP is produced when there is increased wall stress of the heart and the cardiac tropinins are
highly specific sensitive markers of cardiac injury.
A very helpful tool in the diagnosis and response assessment is the serum free light chain (FLC)
immunoassay which consists of a polyclonal latex-conjugated anti-free light chain antibody with high
specificity and affinity for serum free light chains. This assay has improved the diagnosis and
monitoring of AL Amyloidosis patients. M-proteins can be detected in the serum or urine in only 50%
of patients, whereas the FLC assay can detect and quantify light chains in about 90% of patients.
Many studies have demonstrated that achieving a hematological response is closely related with
survival. This is not only demonstrated after high dose therapy 3;4 but also after standard dose
therapy. 5;6
The quality of hematological response is also very important; patients achieving a complete
hematological remission (CHR) having the best survival and therefore hematological response is a
valid endpoint in clinical trials. 7
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