Melphalan and Dexamethasone Is Less Effective for Patients with Immunoglobulin Light Chain Amyloidosis (AL) with High Bone Marrow Plasmacytosis.
Authors: Leung Nelson , Gunderson Heidi D , Tan Tow S , Dispenzieri Angela , Gertz Morie A , Zeldenrust Steven R , Lacy Martha Q , Buadi Francis K , Hayman Suzanne R. , Kumar Shaji 
Published: April 2020

Abstract
Introduction: Currently, the most extensively tested treatments for immunoglobulin light chain amyloidosis (AL) are high dose melphalan followed by autologous stem cell transplantation (ASCT) and melphalan and dexamethasone (MDex). A recent randomized controlled trial comparing the two regimens showed MDex is at least equivalent if not superior to ASCT. Most patients with symptomatic systemic AL have a low plasma cell load; however, approximately 30% have bone marrow plasmacytosis greater than 20% but do not meet criteria for multiple myeloma with significant anemia or lytic bone disease. This leads to the speculation that the plasma cell biology (and therefore outcomes) might differ between low and high plasma cell burden AL. We undertook this study to address whether these two standard regimens are equally effective in AL patients with low and high plasma cell burden.
Methods: Patients with confirmed AL treated with MDex were recruited for this study. Some of the patients treated were not ASCT candidates while others were eligible but favored MDex. Hematologic response was defined as 50% reduction in serum M-protein or 90% reduction in urine M-protein if one was present, otherwise a 50% reduction in serum free light chain levels was used. Organ involvement was defined according to the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. Patients were separated into a high and a low marrow plasma cells (PC) group based on their percentage of bone marrow plasma cells. Cutoff for the bone marrow plasmacytosis was calculated using receiver-operator characteristic (ROC) curve. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier method. OS was also calculated for 342 AL patients treated with ASCT for comparison.
Results: Seventy-three patients with AL received MDex between 05/01 and 05/07. Median follow-up was 16.8 months. At the time of the study, 42.5% had died. Calculating for OS and PFS, the best cutoff for bone marrow plasmacytosis was found to be 20%. In our cohort, 28.8% had &gt;20% bone marrow plasmacytosis. Age (64.8 yr vs 61.0 yr, p = 0.61) and sex (81% male vs 63.4% male, p = 0.13) were similarly distributed between patients with high and low PC. Cardiac troponin T (cTnT) was also comparable between the 2 groups (0.03 ng/ml (high) vs 0.06 ng/ml (low), p = 0.41). Cardiac involvement were similar between high and low PC groups (78.9% vs 85.7% respectively, p = 0.49) but renal involvement was less common in the high PC group (70.6% vs 38.1%, p = 0.01). No differences were noted in the gastrointestinal and neurological involvement. Patients with high PC received a median of 4 cycles of MDex vs 5 in the low PC group (p = 0.68). Hematologic response was achieved in 75% of patients with high PC and 54.9% of the low’s (p = 0.11). A significant difference was noted in the PFS and OS between the 2 groups. The PFS and OS were 13.5m and 15.3m, respectively for patients with high PC but neither was reached in those with &lt; 20% plasmacytosis (p=0.02 and p = 0.03 respectively). In the multivariate analysis, hematologic response, cardiac involvement and plasmacytosis &gt;20% were independent predictors of PFS and OS. To determine if plasmacytosis had the same affect on survival of ASCT treated patients, 342 patients were analyzed. No relationship between OS and % of plasmacytosis was found.
Conclusion: Our study suggests that ASCT and MDex may not be equivalent for all AL patients. Even though hematologic response rates were similar, patients with plasmacytosis &gt;20% had a worse OS and PFS when treated with MDex. This disparity in survival was not evident in patients treated with ASCT. This effect was independent of cardiac involvement. If confirmed, this could have a significant impact on the choice of therapy for AL patients. The best therapy may be determined by the extent of marrow plasmacytosis, with higher plasma cells favoring high dose therapy.