Approximately 70% of patients with primary light chain amyloidosis (AL) present with kidney involvement. Achievement of renal response is associated with improved overall survival (OS). OS for patients with AL treated with conventional chemotherapy ranges from 13 to 18 months1 with many progressing to end-stage renal disease and a poor long-term outcome. High-dose (HD) melphalan followed by autologous hematopoietic stem cell transplantation (auto-HCT) has been shown to improve organ function and OS by inducing high rates of both hematologic and organ responses.2 Organ response rates range from 31 to 46% and are time dependent, with a median time to best response of up to 1 year.3
In a large 8-year longitudinal study of patients undergoing HD melphalan and auto-HCT, Skinner et al.4 demonstrated an improved median OS of 4.6 years. Historically, the treatment-related mortality (TRM) of this approach has been as high as 25–40% (ref. 5). However, with better patient selection and improvements in supportive care, TRM has now decreased to <10% (ref. 3).
We studied 74 consecutive patients with AL treated with HD melphalan and auto-HCT at our center between the years 1999 and 2011. Fifty-five had renal involvement and were included in this study.
Granulocyte CSF-primed peripheral blood progenitor cells were collected using standard mobilization protocols and apheresis techniques in all patients.
All patients received HD melphalan (n=53) or melphalan-based (n=2) preparative regimens. Thirty-eight (69%) patients received melphalan 200 mg/m2, while 17 (31%) received melphalan at lower doses at the treating physician’s discretion. Filgrastim 5 μg/kg was administered daily from day +1 for those transplanted before 2010, or day +5 for those transplanted from 2010 onwards, until neutrophil engraftment. All patients received infection prophylaxis with sulfamethoxazole-trimethoprim or pentamidine and acyclovir or valacyclovir for 6 months.
Renal involvement and responses were defined according to the International Consensus Criteria, which defines renal involvement as >0.5 g of proteinuria per 24-h period.6 Renal response was defined as a 50% reduction in proteinuria in 24 h without worsening of creatinine or creatinine clearance by ⩾25% over baseline, and renal progression as a 50% increase in proteinuria in 24 h (at least 1 g/24 h) or >25% increase in creatinine or creatinine clearance.7 Patients were staged according to Palladini et al.8 and were stratified according to proteinuria >5 g/24 h and estimated glomerular filtration rate <50 mL/min. Patients with none, one or two of these parameters were stratified as stages 1, 2 or 3, respectively.
Neutrophil engraftment was defined as the first of 3 consecutive days with an ANC ⩾0.5 × 109/L. Platelet engraftment was defined as the first of 7 consecutive days with a platelet count ⩾20 × 109/L without transfusion support. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 4.
Renal responses were assessed at 6, 12 and 24 months. Hematologic responses (HRs) were determined by the International Myeloma Working Group Criteria or the revised International Society of Amyloidosis Criteria, when available9, 10 and were assessed at 1, 3, 6 and 12 months, and approximately every 3–6 months thereafter. Free light chain (FLC) assays were performed at diagnosis, before auto-HCT, and at each subsequent evaluation.
Primary endpoints were OS and PFS. Secondary endpoints were TRM, toxicity rates, hematologic and renal response rates, and the correlation between hematologic and renal responses. Predictors of OS and PFS were evaluated using Cox proportional hazards regression analysis.
Patient characteristics are summarized in Table 1. Median bone marrow plasma cell infiltration at diagnosis was 6% (range, 1–40%). Forty-one (74.5%) patients had AL with <10% bone marrow plasma cells at diagnosis (AL only). Fourteen (25.5%) patients had AL with >10% bone marrow plasma cells (PC) at diagnosis (AL+PC>10%).
In all, 42 (76%) patients received induction therapy before auto-HCT, 33 (60%) with novel agents: immunomodulatory drugs (IMiD)-based with lenalidomide in 7 (13%) patients and protieasome inhibitors (PI)-based with bortezomib in 26 (47%) patients. Nine (16%) received induction with conventional agents: dexamethasone in 5 (9%), melphalan based in 3 (5%) and cladribine in 1 (2%) patient. Median time to neutrophil and platelet engraftment was 10 (range, 7–15) and 12 (range, 6–23) days, respectively. Grade 2–4 nonhematologic toxicities included nausea in 23 (42%), infection in 18 (33%), diarrhea in 15 (26%), mucositis in 12 (22%) and cardiovascular events in 11 (20%). Renal toxicity was seen in 7 (13%) patients. Six patients died within 100 days and 7 died within 1 year, with 100-day and 1-year TRM of 11% (95% confidence interval (CI) 5–23) and 13% (95% CI 6–26), respectively. Causes of death at 1 year included infection/sepsis/multiorgan failure in 6 patients and sudden cardiac death in 1 patient. There was a significant decrease in the TRM when comparing auto-HCT performed after 2008 with those performed before 2008 (9% vs 20%).
Overall HR was observed in 43 (86%) of 50 evaluable patients after auto-HCT, with 8 (16%) CR, 12 (24%) very good partial responses (VGPR) and 23 (46%) PR. This compares with 21 of 51 patients (41%) who achieved a HR before auto-HCT. Median time to HR was 3.1 (range,1–24) months. A total of 50, 42 and 35 patients were evaluable for renal response at 6, 12 and 24 months, respectively. Renal responses were seen in 8 (16%), 13 (31%) and 17 (49%) patients at 6, 12 and 24 months, respectively. Seventeen of 35 evaluable patients achieved a renal response at 2 years. There was no difference in renal response between patients achieving >VGPR (50%), PR (50%) and <PR (33%, P=0.67). Two patients required hemodialysis before auto-HCT and remained hemodialysis dependent afterward.
With a median follow-up of 37 (range, 4–126) months, the estimated 3-year PFS and OS rates were 54% and 73%, respectively (Figure 1). At last follow-up, 31 (56%) patients were alive and in remission.
On multivariate analysis, patients not treated with IMid or PI-based induction and dFLC>26 mg/dL had significantly shorter 3-year PFS (15% vs 83%, HR=7.6, P=0.002) and significantly shorter 3-year OS (49% vs 95%, HR=9.5, P=0.004).
Our results support the role of auto-HCT by demonstrating >80% HR rate and almost 50% renal response rate at 2 years. Use of induction therapy and a lower disease burden at the time of auto-HCT, as defined by dFLC ⩽26 mg/dL, were associated with longer PFS and OS in a multivariate model.
The association of organ response with HR was not unequivocal in our study owing to small numbers and almost 30% patients being inevaluable for a response. We saw a steady improvement in renal response over 2 years, with 16%, 31% and 49% renal responses at 6, 12 and 24 months, respectively. In a similar study from Mayo Clinic, Leung et al.11 reported a renal response rate of 61% at 2 years. Although the patients were comparable, a lower response in our cohort may have been due to the inclusion of dialysis-dependent patients, use of a lower dose of melphalan in a subset of patients, a lower rate of hematologic CR and a smaller number of patients evaluable for renal response.
Huang et al.12 conducted a randomized clinical trial where patients either received induction with bortezomib+dexamethasone or no induction before HD melphalan and auto-HCT. Renal response at 2 years was 75% in the induction arm and 53% in the non-induction arm. The better renal response rate may have been due to a lower baseline serum creatinine (0.8 vs 1.2 mg/dL in our study), a higher hematologic CR in his study (68%) and the uniform use of bortezomib in patients treated on the bortezomib arm.
The role of induction therapy before auto-HCT in AL is evolving. However, several studies have failed to show improvement in outcomes. Perz et al. did not show any improvement in HR with the use of vincristine, adriamycin, dexamethasone induction before auto-HCT and the induction treatment was associated with 7% mortality.13 Some more recent studies, however, support the role of PI or IMiD-based induction in improving outcomes after auto-HCT.12 The significance of reduction of FLC as a predictor of survival was first reported by Dispenzieri et al.14 A recent report from the National Amyloidosis Center in the United Kingdom identified the magnitude of the FLC response at 6 months from baseline as a strong predictor of PFS and OS.15
HD melphalan is nephrotoxic, and some studies have reported a high risk of renal toxicity. In our study, grade 2–3 renal toxicity was seen in 7 patients (13%), and was reversible. All 7 patients had prior renal insufficiency. Forty-two (76%) patients were transplanted between 2006 and 2011, which may be one of the reasons for a relatively short median follow-up of 37 months. We showed a decrease in TRM after 2008, likely due to better patient selection, use of induction therapy and improvements in supportive care.
HD melphalan followed by auto-HCT is a safe and effective treatment option for selected patients with AL with renal involvement, with high rates of hematologic and renal responses, long PFS and OS, and acceptable rates of toxicity.
Gertz MA, Lacy MQ, Lust JA, Greipp PR, Witzig TE, Kyle RA . Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis. Med Oncol 1999; 16: 104–109.
Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood 1998; 91: 3662–3670.
Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 2011; 118: 4346–4352.
Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004; 140: 85–93.
Mollee PN, Wechalekar AD, Pereira DL, Franke N, Reece D, Chen C et al. Autologous stem cell transplantation in primary systemic amyloidosis: the impact of selection criteria on outcome. Bone Marrow Transplant 2004; 33: 271–277.
Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 2005; 79: 319–328.
Gertz MA, Leung N, Lacy MQ, Dispenzieri A . Myeloablative chemotherapy and stem cell transplantation in myeloma or primary amyloidosis with renal involvement. Kidney Int 2005; 68: 1464–1471.
Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood 2014; 124: 2325–2332.
Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012; 30: 4541–4549.
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.
Leung N, Glavey SV, Kumar S, Dispenzieri A, Buadi FK, Dingli D et al. A detailed evaluation of the current renal response criteria in AL amyloidosis: is it time for a revision? Haematologica 2013; 98: 988–992.
Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D et al. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med 2014; 12: 2.
Perz JB, Schonland SO, Hundemer M, Kristen AV, Dengler TJ, Zeier M et al. High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study. Br J Haematol 2004; 127: 543–551.
Dispenzieri A, Lacy MQ, Katzmann JA, Rajkumar SV, Abraham RS, Hayman SR et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2006; 107: 3378–3383.
Pinney JH, Lachmann HJ, Bansi L, Wechalekar AD, Gilbertson JA, Rowczenio D et al. Outcome in renal Al amyloidosis after chemotherapy. J Clin Oncol 2011; 29: 674–681.
The authors declare no conflict of interest.
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Cornelison, A., Saliba, R., Afrough, A. et al. Autologous hematopoietic stem cell transplantation in light chain amyloidosis (AL) with renal involvement. Bone Marrow Transplant 51, 307–309 (2016) doi:10.1038/bmt.2015.242
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