Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

Abstract

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

Clarification on the definition of complete haematologic response in light-chain (AL) amyloidosis

“…One of them compared ixazomib/dexamethasone versus physician's best choice in relapsed/refractory patients with AL amyloidosis, and no significant difference in the primary endpoint was observed between the two arms [2]. The other study compared oral melphalan/dexamethasone (MDex) with the same regimen with the addition of bortezomib (BMDex) [3]. In this study, there was a significant advantage in OHR rate in favour of BMDex, that was associated with prolonged overall survival [3].…”

“…The other study compared oral melphalan/dexamethasone (MDex) with the same regimen with the addition of bortezomib (BMDex) [3]. In this study, there was a significant advantage in OHR rate in favour of BMDex, that was associated with prolonged overall survival [3]. A more recent trial compared cyclophosphamide/bortezomib/dexamethasone (CyBorD) with CyBorD plus daratumumab [4].…”

“…The primary endpoint of this trial was CR, and overall and profound haematologic response rates were significantly higher in the experimental arm. Because modern therapies generate very high OHR rates (81% with BMDex and 92% with CyBorD plus daratumumab) [3,4], clinical trials need to use a more rigorous primary endpoint, CR rate rather than OHR rate, to demonstrate a meaningful improvement over the comparator.…”

“…Complete haematologic response requires absence of monoclonal protein by immunofixation electrophoreses of both serum and urine as well as a normal FLC ratio (FLCr), based on the published ISA criteria. During the validation of the response criteria for the original study, [1] and in subsequent studies, including the two phase-III trials mentioned above [2,3], for the purpose of CR assessment, FLCr was considered not only when the FLCr was normalised to within the reference range, but it was also considered when it was altered in favour of the non-amyloidogenic, uninvolved FLC (uFLC), even though the ratio may not have been normalised. Whilst this was very apparent to the authors of the original paper and was used in the validation analyses, the methods section and the tables in the original paper do not explicitly state this latter point.…”

Cardiac Amyloidosis

“…For these patients, the most common initial chemotherapy regimens used nowadays are bortezomibbased, such as combinations with cyclophosphamide and dexamethasone (CyBorD) or melphalan and dexamethasone (BMDex). These regimens have a significantly higher hematological response rate, a longer progression-free period and increased overall survival compared to the older regimen of dexamethasone and prednisone, which has been the standard of care for many years in these subjects [79,80].…”