Lessons in Long Term Survival from AL Amyloidosis

Abstract

Patients with AL amyloidosis often encounter physicians who regard the disease as a death sentence. This opinion has historical basis in fact; only 5% of patients diagnosed prior to 1987 survived for ten years (Kyle et al, 1999). The research by Muchtar et al. (2019), published in this issue of the journal, illustrates why this nihilism is outdated and mistaken. Dr Muchtar et al detail the characteristics and treatment patterns of the 186 AL amyloidosis patients surviving 10+ years that received care at the Mayo Clinic since 2000. The foremost lesson from this paper is that long-term survival with this disease is possible and even common. Twenty five percent of patients diagnosed after 2004 survived for over a decade. This proportion of survivors is likely to increase sharply in the near future as more effective and well-tolerated treatments for AL amyloidosis are applied. Patients who fare well are often recognizable by clinical characteristics at the time of presentation. The favourable features determined by the authors are largely intuitive. They relate to the host (e.g. young age), extent of organ involvement (renal only presentation, lower Mayo cardiac stage), and tumour burden (low bone marrow plasma cell percentage, low difference in involved and uninvolved free light chains) as well as the biology of the plasma cells themselves (e.g. diploid plasma cell clone). Treatment choice appears to greatly impact the likelihood of lasting survival. The surest path to long-term survival as an AL amyloidosis patient is to qualify for and receive high dose melphalan (HDM) with autologous stem cell transplantation (ASCT). A remarkable 50% of all patients who underwent HDM survived for more than ten years. This compares favourably to those receiving bortezomib-based therapy, who had only 27% 10-year survival. Cautious interpretation of this difference is appropriate. Patients undergoing HDM treatment are generally younger and have less cardiac involvement; their prognosis is accordingly better, irrespective of therapy. More robust support for high-dose therapy comes from Muchtar et al’s analysis of time to treatment failure, a measure less influenced by patient selection bias. In this group of long-term survivors, haematological responses obtained by high dose melphalan were notably more enduring than those obtained by other means. Median treatment-free survival (TFS) was 11 7 years for patients undergoing transplant versus 6 4 years for the non-ASCT group. The improved TFS is striking considering that ASCT and other treatments, such as cyclophosphamide, bortezomib and dexamethasone (CyBorD) have similar overall haematological response rates. It is likely that in AL amyloidosis, progression free and overall survival are affected by treatment selection in a way that cannot be distinguished by merely comparing haematological response rates of different treatment modalities. Remissions in AL amyloidosis can be very durable, particularly after transplantation. Nearly half of the 10-year survivors in this cohort did not require second line treatment during 10+ years of follow-up. This calls into question the wisdom of applying lessons from maintenance therapy in Multiple Myeloma (MM) studies to AL patients. Because unmaintained first remissions are generally longer in AL compared with MM and toxicities of immunomodulatory agents are greater in AL patients, the potential benefits of maintenance therapy are usually not worth the competing risk. The organ responses in these long-term survivors were excellent; this finding perhaps explains the longevity of this group. Cardiac responses were seen in 81% of patients and renal responses in 91%. Organ responses are painfully slow in this disease, often lagging one year or more after achievement of haematological response from successful plasma cell therapy. The time to maximal organ response was over five years in these patients. This delay complicates interpretation of single arm trials of anti-fibril therapies because the slow natural history of organ improvement after plasma cell treatment may be erroneously attributed to efficacy of an anti-fibril medication under study. Haematological complete response (CR) is not always required for superior outcome; in fact, 30% of the long-term survivors did so with a very good partial response (VGPR). Reflexive pursuit of CR (or even minimal residual disease) Correspondence: Dr John Mark Sloan, Department of Medicine, Hematology & Medical Oncology, Boston University School of Medicine, 830 Harrison Ave, 3rd Floor, Suite 3200, Boston, MA 02118, USA. E-mail: [email protected] editorial comment