Bortezomib for AL amyloidosis: moving forward.

Small plasma cell clones can cause big problems2; this could be the outline for AL amyloidosis. AL amyloidosis is the most common form of systemic amyloidosis, a protein misfolding disease that is characterized by the failure of the amyloidogenic monoclonal light chain to adopt a soluble conformation. This misfolding leads to the formation of a precursor protein that tends to form highly organized fibrils that acquire a pleated secondary structure and form amyloid fibrils that are deposited in various tissues and organs. The formation and deposition of amyloid fibrils is a complex procedure that involves cellular quality control mechanisms, local physicochemical conditions, extracellular matrix, and the specific properties of the amyloidogenic protein, related to its primary aminoacid sequence.3 The plasma cell clone is usually small or modest, relatively indolent, and often produces very small amounts of monoclonal light chains. The resulting clinical syndromes are related to the pattern of amyloidotic organ involvement and the amyloid load in involved organs. Patients who die of AL amyloidosis do so because of complications related to amyloidotic organ involvement. Based on our current knowledge of the disease, treatment for AL amyloidosis should aim at 3 different processes: the production of the amyloidogenic protein, the formation of the amyloid fibril, and the reabsorption of the deposited amyloid fibrils. So far, there are no clinically available treatments that target the latter 2 processes. Thus, targeting the production of the amyloidogenic protein has been the mainstay of treatment for AL amyloidosis. Therapies based on alkylating agents with standard-dose corticosteroids have not been very effective. For a subset of patients, high-dose melphalan with autologous stem cell transplantation results in long-lasting remission and often in significant improvement in the function of involved organs.2,4 The combination of melphalan and dexamethasone is considered a form of standard treatment for AL amyloidosis today. However, the treatment of this disease is not satisfactory. Several peculiarities make the management of AL amyloidosis challenging. AL amyloidosis is a rare disease, and large, randomized studies are extremely difficult to conduct. The management of patients with AL amyloidosis is a challenge for every physician. Most patients present with impaired function of 1 or more organs and if A small plasma cell clone produces poor quality amyloidogenic light chains that, mostly outside the plasma cell, tend to misfold and form amyloid fibrils (A). Inside the plasma cell the increased protein load induces ER stress and mechanisms to retain homeostasis require the rapid clearance of these proteins. The degradation of these poor quality proteins is largely dependent on proteasome activity. Bortezomib blocks proteasome degradation of proteins and increases poor quality protein load within ER thus inducing ER stress beyond the capacity of the control mechanisms and resulting in plasma cell apoptosis (B).