The Use of Novel Agents in the Treatment of Light-Chain Amyloidosis
When thalidomide(Drug information on thalidomide) (Thalomid) was used as a single agent in combination with corticosteroids, hematologic responses were seen in 48% of patients, with no complete responses. The treatment-related toxicity of thalidomide in amyloidosis is high; the agent is not well tolerated; and the starting dose is generally lower than that in patients with multiple myeloma, often 50 mg/day. Thalidomide has been combined with cyclophosphamide(Drug information on cyclophosphamide) and dexamethasone(Drug information on dexamethasone). The reported hematologic response rate for this regimen is 74%, with complete responses seen in 21%. Reported median overall survival from the start of therapy was 41 months, with a treatment-related mortality of 3%. The use of cyclophosphamide-thalidomide-dexamethasone has the advantage of being all-oral. In addition to the usual treatment-related toxicities seen with thalidomide in patients with myeloma—somnolence, constipation, and peripheral neuropathy—patients with amyloidosis are also particularly prone to bradycardia and worsening fluid retention.
Lenalidomide (Revlimid) has been combined with dexamethasone in the treatment of light-chain amyloidosis. The associated toxicities include cytopenias, rash, fatigue, cramps, and renal dysfunction. In one study, the hematologic response rate was 41%. The median overall survival was 31 months. In an update of this study, progression-free survival in patients who achieved a hematologic complete response was 49.8 months. Lenalidomide in combination with dexamethasone produced a hematologic complete response in 16% of previously treated patients, and 60% of the complete responses were durable. A second study of lenalidomide with dexamethasone had a response rate of 67% in the patients with renal involvement; 41% of patients with renal involvement had a decrease in urinary protein excretion. High-risk patients were less likely to respond.
In a phase I/II dose escalation study, lenalidomide was combined with melphalan(Drug information on melphalan) and dexamethasone for patients with newly diagnosed amyloidosis. The maximum tolerated dose of lenalidomide when combined with melphalan and dexamethasone was 15 mg/day. Hematologic responses were seen in 58%, with complete responses in 42%; 2-year event-free survival was 54%, and overall survival was 81%. Lenalidomide has also been combined with cyclophosphamide and dexamethasone. The hematologic response rate was 60%, and in patients evaluable for response (those who received four or more cycles), the hematologic response rate was 87%.
Use of pomalidomide, a derivative of thalidomide with structural similaritiesto both thalidomide and lenalidomide, has been reported in 26 patients. All patients were previously treated with alkylating agents, autologous stem-cell transplantation, and in 13, prior lenalidomide or thalidomide. Nineteen patients evaluable for hematologic response had a response rate of 35%, with two confirmed and four unconfirmed organ responses.
Pomalidomide in combination with dexamethasone is a promising therapy for light-chain amyloidosis.
In an early study of bortezomib(Drug information on bortezomib) (Velcade), 80% of evaluable patients had a hematologic response. A subsequent study of 18 patients reported hematologic responses in 77% and complete responses in 16%. A phase I/II dose-escalation study of bortezomib that specifically excluded corticosteroids and that used both a biweekly and a weekly administration schedule of bortezomib reported hematologic responses in 50% of patients, 20% complete, with a median time to response of 1.2 months. One-year duration of response was 67%, and 2-year duration was 45%. Patients with New York Heart Association class III/IV heart disease were excluded from the study. Bortezomib and dexamethasone have been used after stem-cell transplantation to improve the depth of response for patients who achieved less than a very good partial response. Nineteen of 28 patients received post-transplant bortezomib and dexamethasone; 67% of these achieved a complete response, 60% organ responses. In a multinational survey study reporting on 94 patients who received bortezomib with or without dexamethasone, a hematologic response was seen in 71%, a complete response in 25%. A cardiac response was seen in 29%. Addition of bortezomib to the high-dose melphalan (HDM) used as a conditioning regimen prior to stem-cell transplantation is feasible and well-tolerated by patients with AL amyloidosis. The combination resulted in no increase in adverse events beyond what is typically seen with HDM alone.
Active Clinical Trials in the Management of Amyloidosis
Based on the recognized single-agent activity of cyclophosphamide, melphalan, lenalidomide, bortezomib, and dexamethasone in the management of amyloidosis, a number of clinical trials are now exploring these agents in combination. These trials are listed in Table 3 and warrant specific comment. An important phase III study that is being conducted in the United States and Europe randomly assigns patients either to melphalan + dexamethasone, which is currently considered the default standard of care for non–transplant-eligible patients, or to melphalan-dexamethasone-bortezomib, based on the activity of bortezomib as a single agent as described above. Dosing of these agents is given in Table 3.
Lenalidomide is being explored in three phase II trials, combined with the alkylating agent cyclophosphamide in two and with melphalan in one. In one of the lenalidomide studies, the primary outcome is maximum tolerated dose, with the lenalidomide being increased from 5 to 25 mg/day, and cyclophosphamide from 50 to 100 mg/day. In the other lenalidomide study, which is a phase II study, the lenalidomide dose is fixed at 15 mg/day, and cyclophosphamide is fixed at 500 mg weekly.
Bortezomib is being explored as part of the induction therapy prior to stem-cell transplantation. In standard doses, bortezomib is combined with cyclophosphamide and dexamethasone (CyBorD) in an attempt to combine the rapid response rate of proteasome inhibitors with the effectiveness of alkylators. The oral proteasome inhibitor MLN9708 is also being explored in a phase I trial to determine the maximum tolerated dose and to assess whether the activity is comparable to that of bortezomib but with the added convenience of an oral regimen. Bendamustine (Treanda), which has shown activity in the treatment of multiple myeloma and low-grade lymphoma, is also being explored in combination with dexamethasone in a phase II trial in standard doses for patients with preserved renal function. Bendamustine is not approved for use in patients whose creatinine clearance is below 40 mL/min.
Relationship Between Hematologic Response and Organ Response
The endpoint of hematologic response is used primarily for rapid assessment of drug activity. Clinical benefit, however, is not dependent on hematologic response. Clinical benefit requires organ response. Reduction of urinary protein loss, improvement in echocardiographic changes, and clinically relevant reductions in NT-proBNP levels have been reported with stem-cell transplantation as well as with combination chemotherapy.[43,60] Using stem-cell transplantation, urinary protein levels as high as 21 g/24-hour period have fallen to < 0.2 g/day, a result associated with a survival of 72+ months (Gertz, unpublished). Others have reported similar organ responses. Most investigators believe that an organ response cannot occur in the absence of a significant hematologic response; studies have shown that complete responders survive better than very good partial responders and that hematologic response is the best predictor of organ response and survival. It is not known whether the amyloid deposits actually regress. It is believed that amyloid deposits may remain, yet significant organ healing nonetheless occurs, suggesting that soluble toxic intermediates may play a role in producing the organ dysfunction of amyloidosis.[62,63] If this is in fact the case, reduction of the free light chain level would directly impact organ dysfunction.
When light-chain amyloidosis is diagnosed prior to the development of advanced cardiomyopathy, systemic therapy is capable of producing hematologic responses that will translate into organ responses and prolonged survival. When a patient is seen with a compatible clinical syndrome, studies to confirm light-chain amyloidosis should be performed, and the deposits must be verified as being both systemic and light chain–derived. Some patients are appropriate candidates for stem-cell transplantation. Advances in the management of multiple myeloma are currently being translated into a variety of clinical trials designed to improve the quality of life and survival of patients with light-chain amyloidosis.
Financial Disclosure: Dr. Gertz receives honoraria from Millennium, Binding Site, and Celgene. Dr. Dispenzieri reports clinical trials for Celgene and Millennium, and has also served as an unpaid member of Millennium’s advisory board; she received a travel award from Binding Site.