Finishing off fibrils

In this issue of Blood, Reece and colleagues report a phase 1/2 study of bortezomib in the treatment of immunoglobulin light chain amyloidosis (AL).¹  The authors report hematologic responses in 15 of 30 evaluable patients, 20% of which were complete, achieved at a median of 1.2 months. The activity of bortezomib, producing hematologic responses in AL, should not be surprising, given the high activity of the agent in multiple myeloma,²  the neoplastic counterpart of the clonal plasma cell dyscrasia AL. Virtually all chemotherapeutic stratagems for AL have been derived from the treatment of multiple myeloma and have included melphalan-based therapies, dexamethasone, thalidomide, and lenalidomide. High-dose therapy with autologous stem cell replacement is widely used for the treatment of AL, but this therapy is unsuitable for high-risk patients with the disease.³  The high prevalence of cardiomyopathy makes high-dose therapy excessively toxic for many patients with AL, necessitating the use of alternatives. In a retrospective report of bortezomib, combined with dexamethasone⁴  in 90%, hematologic response was achieved in 71% of patients including complete response in 25%. An organ response was observed in 30% of patients. In this issue of Blood, the first prospective study of bortezomib is reported.

What are the strengths of this study? In the current paper, dexamethasone was not administered with bortezomib. One can, therefore, confidently conclude that bortezomib alone is responsible for the reported benefit. A second strength is the high frequency of rapidly achieved hematologic responses occurring at virtually all dose levels and both schedules of bortezomib, suggesting that the maximum tolerated dose may not be the same as the lowest effective dose. Rapid response may reduce the organ damage the toxic light chains produce over time.

What are the weaknesses of this paper? The results may not be generalizable, since the median time from AL diagnosis to study enrollment was 32 months. In an unselected amyloidosis population, 70% will have succumbed to the disease at this time point, and the remaining patients have a much better prognosis than the oft-quoted 12 to 18 months median survival. Patients with New York Heart Association class III and class IV heart failure, found in a quarter of patients with amyloidosis, were excluded from this protocol. The impact of excluding these patients, since cardiomyopathy is the leading cause of death in amyloidosis, may make it difficult to generalize the outcomes to an unselected population of patients with AL. The failure to report cardiac biomarkers, troponin, and NT-pro-BNP is a weakness, since it is difficult to assess the severity of cardiomyopathy in enrolled patients. Moreover, NT-pro-BNP has been used to measure cardiac response so estimates of cardiac benefit in a subsequent report may be inaccurate. This manuscript fails to report organ response, admittedly an often delayed end point, but hematologic responses that do not ultimately produce organ responses may not be of value to this patient population.

What are the unanswered and new questions this report generates? Will the drug be of use in patients with moderate amyloid cardiomyopathy since bortezomib can dysregulate the ubiquitin-proteasome system predisposing to cardiac failure?^5,6  Fifteen percent of patients with AL have peripheral and autonomic neuropathy; can the agent be used safely in this subgroup? Now that bortezomib is established to have activity in amyloidosis, will the responses be durable when administered to a broader cohort of patients, or will we see rapid, perhaps deep responses that are short-lived?⁷  Will bortezomib in combination regimens previously proven to be effective for multiple myeloma⁸  provide even higher response rates in AL patients? Will there be an opportunity to combine bortezomib with stem cell transplantation? Two such variations would be to use bortezomib induction either in an attempt to improve organ function and render patients suitable for high-dose therapy, or to reduce the risk of fatal complications associated with high-dose therapy. Alternatively, risk-adapted stem cell transplantation with posttransplantation adjuvant thalidomide has been shown to be beneficial,⁹  and the potential of bortezomib to suppress residual disease after stem cell transplantation in the hope of achieving a complete response may be achievable in a significant proportion of patients.

Amyloidosis is a difficult disorder to treat. The dropout rates in studies are generally high. In this protocol, 12 of the 30 patients discontinued therapy and grade 3 to 4 adverse events were seen in 50%. Nonetheless, the authors are to be congratulated for a meticulously conducted study in a single-agent setting in a devastating disorder.