TREATMENT Al Amyloidosis
Extensive multisystemic involvement typifies AL amyloidosis, and the median survival period without treatment is usually only ~1–2 years from the time of diagnosis. Current therapies target the clonal bone-marrow plasma cells, using approaches employed for multiple myeloma. Treatment with oral melphalan and prednisone can decrease the plasma cell burden but rarely leads to complete hematologic remission, meaningful organ responses, or improved survival and is no longer widely used. The substitution of dexamethasone for prednisone produces a higher response rate and more durable remissions, although dexamethasone is not always well tolerated by patients with significant edema or cardiac disease. High-dose IV melphalan followed by autologous stem cell transplantation (HDM/SCT) produces complete hematologic responses in ~40% of treated patients, as determined by loss of clonal plasma cells in the bone marrow and disappearance of the monoclonal LC, as determined by SIFE/UIFE and free LC quantitation. Hematologic responses can be followed in the subsequent 6–12 months as improvements in organ function and quality of life. Hematologic responses appear to be more durable after HDM/SCT than in multiple myeloma, with remissions continuing in some patients beyond 15 years without additional treatment. Unfortunately, only about half of AL amyloidosis patients are suitable for aggressive treatment, and, even at specialized treatment centers, transplantation-related mortality rates are higher than those for other hematologic diseases because of impaired organ function. Amyloid cardiomyopathy, poor nutritional and performance status, and multiorgan disease contribute to excess morbidity and mortality. A bleeding diathesis resulting from adsorption of clotting factor X to amyloid fibrils also increases mortality rates; however, this syndrome occurs in only 5–10% of patients. A randomized multicenter trial conducted in France compared oral melphalan and dexamethasone with HDM/SCT and failed to show a benefit of dose-intensive treatment, although the transplantation-related mortality rate in this study was very high. It has become clear that careful selection of patients and expert peritransplantation management are essential in reducing transplantation-related mortality.
For patients with impaired cardiac function or arrhythmias due to amyloid involvement of the myocardium, the median survival period is only ~6 months without treatment. In these patients, cardiac transplantation can be performed and followed by HDM/SCT to eliminate the noxious clone and prevent amyloid deposition in the transplanted heart or other organs.
Novel anti–plasma cell agents have been investigated for treatment of plasma cell diseases. The immunomodulators thalidomide, lenalidomide, and pomalidomide display activity; dosing may need to be adjusted compared to their usage for myeloma. The proteasome inhibitor bortezomib has also been found to be effective in single-center and multicenter trials. Anti-fibril small molecules and humanized monoclonal antibodies are also being tested. Clinical trials are essential in improving therapy for this rare disease.
Supportive care is important for patients with any type of amyloidosis. For nephrotic syndrome, diuretics and supportive stockings can ameliorate edema; angiotensin-converting enzyme inhibitors should be used with caution and have not been shown to slow renal disease progression. Effective diuresis can be facilitated with albumin infusions to raise intravascular oncotic pressure. Congestive heart failure due to amyloid cardiomyopathy is best treated with diuretics; it is important to note that digitalis, calcium channel blockers, and beta blockers are relatively contraindicated as they can interact with amyloid fibrils and produce heart block and worsening heart failure. Amiodarone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators have reduced effectiveness due to the thickened myocardium, but they may benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid cardiomyopathy and is an indication for anticoagulation even in the absence of atrial fibrillation. Autonomic neuropathy can be treated with α agonists such as midodrine to support the blood pressure; gastrointestinal dysfunction may respond to motility or bulk agents. Nutritional supplementation, either oral or parenteral, is also important.
In localized AL disease, amyloid deposits can be produced by clonal plasma cells infiltrating local sites in the airways, bladder, skin, or lymph nodes (Table 19-1). These deposits may respond to surgical intervention or low-dose radiation therapy (typically only 20 Gy); systemic treatment generally is not appropriate. Patients should be referred to a center familiar with management of these rare manifestations of amyloidosis.