High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease

Accepted Manuscript Title: High Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to AL Amyloidosis and Monoclonal Immunoglobulin Deposition Disease Author: Felipe Batalini, Laura Econimo, Karen Quillen, J. Mark Sloan, Shayna Sarosiek, Dina Brauneis, Andrea Havasi, Lauren Stern, Laura Dember, Vaishali Sanchorawala PII: DOI: Reference:

S1083-8791(17)30684-5 http://dx.doi.org/doi: 10.1016/j.bbmt.2017.08.031 YBBMT 54783

To appear in:

Biology of Blood and Marrow Transplantation

Received date: Accepted date:

5-6-2017 24-8-2017

Please cite this article as: Felipe Batalini, Laura Econimo, Karen Quillen, J. Mark Sloan, Shayna Sarosiek, Dina Brauneis, Andrea Havasi, Lauren Stern, Laura Dember, Vaishali Sanchorawala, High Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to AL Amyloidosis and Monoclonal Immunoglobulin Deposition Disease, Biology of Blood and Marrow Transplantation (2017), http://dx.doi.org/doi: 10.1016/j.bbmt.2017.08.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

FULL LENGTH ARTICLE

High dose melphalan and stem cell transplantation in patients on dialysis due to AL amyloidosis and monoclonal immunoglobulin deposition disease

Felipe Batalini1, Laura Econimo4, Karen Quillen2, J. Mark Sloan1,2, Shayna Sarosiek1,2, Dina Brauneis2, Andrea Havasi1,2, Lauren Stern1,2, Laura Dember3, Vaishali Sanchorawala1,2

1

Department of Medicine, 2Amyloidosis Center and Section of Hematology and Oncology,

Boston University School of Medicine and Boston Medical Center, USA 3

Hospital of the University of Pennsylvania, USA

4

Hospital of Chiari ASST Franciacorta, Brescia, Italy

Keywords: AL amyloidosis, renal failure, end-stage renal disease, autologous stem cell transplantation, melphalan, MIDD

Running title: HDM/SCT in ESRD due to AL amyloidosis/MIDD

Corresponding Author: Vaishali Sanchorawala, MD 820 Harrison Avenue, FGH 1007 Boston, MA02118 [email protected]

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Highlights:

 HDM/SCT is valuable for selected patients with AL amyloidosis and MIDD associated ESRD  5-year OS was 54% and associated with achievement of CR after HDM/SCT  Treatment-related mortality occurred in 8% of patients  Common grade 3/4 non-hematologic toxicities were infections, mucositis and pulmonary complications

Abstract The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic responses and potential for improvement in organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicities, efficacy, hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis dependent for end stage renal disease treated at Boston Medical Center from 1994 to 2016. The most common grade 3 and 4 non-hematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%) and diarrhea (28%). Treatment related mortality (death within 100 days of SCT) occurred in 8% (3/36). A complete hematologic response was achieved in 70% of evaluable patients (19/27) at 1 year following HDM/SCT. Overall median survival after

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HDM/SCT was 5.8 years. Median overall survival was 1 year for those who did not achieve a complete hematologic response and 8 years for those who achieved a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median time of 2.4 years. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can allow these patients to be candidates for renal transplantation.

Introduction Amyloidosis is a group of diseases characterized by deposition of misfolded extracellular proteins that can generate a large array of symptoms depending on the tissue where the deposition occurs. At the molecular level, normally soluble proteins undergo conformational changes and adopt an antiparallel beta-pleated sheet configuration in the extracellular space which is toxic to tissues and organs.1 Although there are 36 human fibril proteins established by the Nomenclature Committee of the International Society of Amyloidosis in 2016, the most frequent is immunoglobulin light chain (AL) systemic amyloidosis2. Although many different organs can be involved in systemic AL amyloidosis, renal involvement is the most common clinical manifestation, affecting roughly three fourths of patients3, and 15-31% becomes dialysis-dependent, with median survival from initiation of dialysis of 8-39 months4,5.

High-dose melphalan with autologous stem cell transplantation (HDM/SCT) has been used since early 1990s as an aggressive treatment in selected patients with AL amyloidosis. HDM/SCT leads to hematologic complete response in 30-40% of patients and median overall survival of 7.60 years6.

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Due to concerns of treatment related morbidity and mortality, patients with end stage renal disease are often not considered candidates for myeloablative chemotherapy7. A previous report of 15 patients with AL amyloidosis-associated ESRD treated at Boston Medical Center from 1994 to 2000 showed no difference in treatment related mortality between patients with ESRD and nonESRD, albeit more toxicity was observed in patients on dialysis, specifically mucositis and febrile neutropenia were more common in the ESRD group8. A higher treatment related mortality (TRM) was found for patients who were not on dialysis prior to HDM, but developed acute kidney injury leading to dialysis after SCT9.

Monoclonal immunoglobulin deposition disease (MIDD) has similar pathogenesis, but in contrast to fibrillar deposits in AL amyloidosis, the specific biochemical characteristics of the immunoglobulins that lead to granular deposits, which do not bind to Congo red stain. There are limited data on the treatment of MIDD, and the usual approach is similar to multiple myeloma and/or AL amyloidosis, including chemotherapy with melphalan, bortezomib and dexamethasone10, and HDM/SCT for selected patients11,12.

Despite limited data, some studies have reported that SCT is feasible in multiple myelomaassociated ESRD, with similar hematologic response rates but increased toxicities, and transplantrelated mortality between 5-15%13. Reversal of renal failure with dialysis independence varies considerably from 0 to 15% of patients becoming dialysis-independent after SCT13-16.

The aim of the present study is to investigate tolerability, toxicities, renal response, mortality and survival outcomes of HDM/SCT in a larger population of patients on dialysis due to AL amyloidosis or MIDD-associated ESRD.

Patients and Methods 4 Page 4 of 20

Patients We performed a retrospective analysis of all patients with AL amyloidosis or MIDD-associated ESRD who underwent HDM/SCT at Boston Medical Center between July 1994 and December 2016. The prospectively maintained Amyloidosis Center database and stem cell transplant program database, along with paper and electronic medical records were used. The Institutional Review Board of Boston University Medical Campus approved the study. We included all patients who were undergoing or had a dialysis catheter placed for initiation of dialysis at the time of admission to the SCT program. All patients had at least histologic evidence of AL amyloidosis or a kidney biopsy positive for MIDD plus a diagnosis of clonal plasma cell dyscrasia (monoclonal gammopathy by serum and/or urine immunofixation electrophoresis and a clonal predominance of plasma cells in the bone marrow). Serum free light chain (FLC) concentration and ratio were obtained as part of the diagnostic testing after the assay became available in 2003. Eligibility criteria for HDM/SCT were age >18 years, Southwest Oncology Group performance status ≤2, left ventricular ejection fraction >40%, O2 saturation >95% on room air, hemodynamic stability (baseline systolic blood pressure >90 mm Hg)17. Patients with congestive heart failure NYHA class III/IV, arrhythmias or persistent pleural effusions resistant to medical management were excluded from being considered for SCT. Organ involvement was established on the basis of signs and symptoms, imaging techniques and laboratory tests according to the consensus criteria of International Society of Amyloidosis at the time of the evaluation visit18-21. Treatment protocol Our treatment protocol for HDM/SCT in dialysis patients has been described in our prior report8. Patients on peritoneal and hemodialysis were dialyzed according to their standard schedule. Stem cell mobilization was achieved by using granulocyte colony stimulating factor (GCSF) at 10-16 mcg/kg/day for 3-4 days after dialysis on dialysis days, and stem cell yield of at least > 2.5 x 106 CD 34+/kg was required to proceed to HDM. Hydration D51/2NS at 75cc/hr was given 2 hours prior and 2 hours after melphalan was administered. Since 2001, all patients received cryotherapy 5 Page 5 of 20

starting 15 minutes prior, and continued until 15 minutes post melphalan infusion. Melphalan was dosed with 70-200 mg/m2 divided over 2 days, D-3 and D-2. Dose of melphalan was selected depending on patient’s age, severity of cardiac involvement and performance status as described in our previous report17. Hemodialysis was planned on Day 0 for no earlier than 2 hours after administration of melphalan, usually on D-2. Antiemetics were repeated after dialysis on the days of melphalan administration. Hydration was used prior and post stem cell infusion (D0), and hemodialysis was planned for no earlier than 2 hours after stem cell infusion. GCSF was administered at 5 mcg/kg/day starting D +1 till neutrophil engraftment. We avoided heparin during hemodialysis when platelet count was less than 100,000/uL. On dialysis days, prophylactic medications were given after the session; we used Levofloxacin 250 mg, Acyclovir 400 mg, and Fluconazole 100 mg daily. Volume status was closely monitored; extra sessions of dialysis were given as needed, and cautious ultrafiltration was performed during periods of neutropenia. Erythropoiesis-stimulating agents were used in all patients. Febrile neutropenia was treated with Cefepime 2 g IV every 24 hr, given after dialysis on the days of dialysis, Vancomycin was dosed with 1 g IV and followed with trough levels. Protocol modifications were possible per discretion of the treating hematologist and adapted to clinical conditions. Risk-adapted approach was used to modify melphalan dose. Treatment was performed in an outpatient setting with daily evaluation in the Stem Cell Transplant Center; patients were hospitalized for management of complications. Neutrophil and platelet engraftment were defined respectively as neutrophil count >500/µL for 2 days and platelet count >20,000/µL for 2 days without transfusions in the previous 48 hours. Treatment related toxicities were graded according to The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), using the most current version at the time of the SCT. After treatment, patients were evaluated at either 3 or 6 months, and annually thereafter. Maintenance therapy was not administered routinely in patients. Laboratory and clinical data were obtained in order to define the status of the plasma cell dyscrasia and the functional organ response and progression, according to common adopted criteria. Complete hematologic response (CR) was 6 Page 6 of 20

defined by the normalization of the FLC ratio and absence of monoclonal protein on serum and urine immunofixation electrophoresis 18,20,22. Survival was recorded at the time of the last follow-up visit, last contact, or date of death. Statistical analysis A descriptive analysis of baseline patient characteristics, organ involvement, treatment received, toxicities, mortality, and survival of all patients with ESRD who underwent HDM/SCT treatment for AL amyloidosis or MIDD at Boston Medical Center between 1994 and 2017 was performed. The statistic model for survival analysis performed was the Kaplan-Meier method with a two-tailed significance value of 0.05, and we used log-rank test to compare groups. We used chi-square test for difference in proportions. Analyses were performed using R 3.3.3 using the survival, rms, and mass packages.

Results Patient characteristics Baseline characteristics of 36 patients are outlined in Table 1. The median age of the patients was 52.9 years (range 28-67), 21/36 patients (58%) were males and 18/36 (50%) had a lambda monoclonal isotype. Thirty-two patients (89%) had AL amyloidosis and 4 patients (11%) had MIDD. Two patients (5%) also had concurrent multiple myeloma. The majority of patients (30/36, 83%) were on hemodialysis, and the remainder (6/36, 17%) were on peritoneal dialysis. The median time from diagnosis to start of dialysis was 4.2 months, and the median time from dialysis to HDM/SCT was 3.7 months. Only 9/36 patients (25%) had isolated renal involvement, the heart was involved in 9/36 patients (25%), and 27/36 (75%) had involvement of 2 or more organs, the mean number of organ involvement was 2.6 (range 1-6). Measurement of cardiac biomarkers, B type natriuretic peptide (BNP) was available in 12 patients and Troponin I in 5 patients. The mean BNP was 285 pg/mL and troponin I 0.133 ng/mL. Nineteen patients (53%) received prior treatment for the underlying plasma cell dyscrasia, including oral melphalan (13 patients), immunomodulatory 7 Page 7 of 20

agents (3 patients), bortezomib (1 patient), dexamethasone (2 patients). All patients had a bone marrow biopsy showing the presence of a plasma cell dyscrasia with light chain restriction. Fineneedle aspiration of abdominal fat was performed in all patients and was positive for Congo red staining in 18/32 patients (56%) with AL amyloidosis and none of patients with MIDD, as expected. Treatment and toxicities Treatment details are provided in Table 2. Treatment related toxicities are shown in Table 3. Stem cell mobilization and collection process was mostly uneventful, with careful attention to volume status. Two patients experienced major complications during mobilization (GI bleeding and grade 4 nausea and vomiting); however, both completed treatment successfully. Mean dose of stem cell collected was 5.7 x 106 CD 34+/kg (range, 0.6-13.1), and mean dose infused was 4.8 x 106 CD 34+/kg (range, 0.4-9.7). The range of melphalan total dose was 100-140 to 200 mg/m2. One patient received only 70 mg/m2 of melphalan in one administration because of poor mobilization. Sixteen (44%) received modified dose (100-140 mg/m2), and 12 (33%) received a full dose melphalan at 200mg/m2. Several patients required modifications of dialysis schedule during treatment in order to manage fluid overload. Thirty-three patients (92%) required inpatient admission for management of treatment complications, with median inpatient stay of 11 days (range 0-123). Three patients died within 100 days of SCT, conferring a peritransplant mortality of 8%. These 3 patients received melphalan at 140mg/m2. The causes of death were respiratory failure as a result of narcotics administered for severe mucositis, sepsis secondary to pseudomembranous colitis, and invasive intestinal aspergillosis. Hematologic response and Survival Complete hematologic response (CR) after HDM/SCT was achieved by 19 of 27 evaluable patients (70%) at 12 months. This translated to a complete hematologic response of 53% on an intention-totreat analysis. In the comparison of hematologic response, 10/11 patients (91%) who received the full dose of melphalan achieved CR, and 9/16 patients (56%) achieved CR with the modified dose 8 Page 8 of 20

(p-value=0.0551). The median overall survival was 5.8 years (95% confidence interval, CI, 2.1410.8), by Kaplan-Meier survival analysis (Figure 1) and 5-year survival was 54%. Median overall survival was 8 years (95% CI=4.89-NA) for those who achieved a hematologic CR compared to 1 year (95% CI=0.23-10.4, p=0.0374) for those who did not achieve a complete hematologic response (Figure 2). Longer survival was also found for patients on hemodialysis (median 7.1 years, 95% CI=4.89-NA) versus peritoneal dialysis (median 0.9 years, 95% CI=0.04-NA, p=0.0034), and the CR rate was also different, 67% for patients on hemodialysis compared to 16% for patients on peritoneal dialysis (p=0.0225). Treatment-naïve patients also had better overall survival (median 19.7 years, CI=2.98-NA) than patients who had received prior treatments (median 3.2 years, CI=0.76-7.99, p=0.00613). Median overall survival was similar for those who received 200 mg/m2 of melphalan (5.79 years, CI 1.39-NA) compared to 100-140 mg/m2 of melphalan (5.8 years, CI 0.89-10.8, p=0.357). Patients with the kappa isotype achieved longer survival (10.8 years versus 4.0 years), but statistical significance was not reached (p=0.0516). Renal Response Two patients (6%) with AL amyloidosis became dialysis-independent, 2 and 20 months after SCT, respectively, one started dialysis 15 days prior to SCT and was off dialysis for 7 months only, the second started dialysis 3.8 months prior to SCT, and remained off dialysis permanently. Both these patients received 140 mg/m2 of HDM. The median time from initiation of dialysis to SCT was 3.7 months. Twelve patients (33%) received kidney transplants after HDM/SCT at a median of 2.4 years, they were all in CR at the time of renal transplantation. All 4 patients with MIDD who underwent HDM/SCT were able to receive kidney transplantation at a median of 2.6 years and are still alive. At the time of renal transplantation two of these patients had a CR and the other 2 patients had partial hematologic response.

Conclusions

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Our study shows that HDM/SCT is a tolerable and valuable option for selected patients with AL amyloidosis and MIDD associated ESRD. Hematologic complete response was achieved in a high proportion of patients (70%) completing and surviving HDM/SCT, and median overall survival (OS) was 5.8 years and 5-year OS was 54%. Overall survival was associated with achievement of a hematologic CR, hemodialysis modality, and the absence of prior treatments, but was not associated with the dose of melphalan (200 mg/m2 vs. 100-140 mg/m2) or kappa/lambda isotype plasma cell dyscrasia. Treatment-related mortality occurred in 8% of patients. The most common grade 3 and 4 non-hematologic toxicities were infections (75%), mucositis (42%), pulmonary complication (39%) and diarrhea (28%). These data of HDM/SCT in ESRD due to AL amyloidosis and MIDD are comparable to the full cohort of patients treated at this institution during this time frame; TRM of 7.5%, median OS 7.6 years and 5-year OS of 64%5. A large CIBMTR study including 1536 patients with AL amyloidosis treated with HDM/SCT, 5-year OS improved from 55% in 1995-2000 to 77% in 2007-2012, suggesting improved outcomes with refined patient selection, different therapeutic options and low mortality rates at centers of expertise23. This large series had no patient on dialysis undergoing HDM/SCT, but 24% had serum creatinine level of > 2.0 mg/dL. Long term outcome data on 10 patients with MIDD treated with HDM/SCT at our center (2 on hemodialysis and 8 with median serum creatinine level of 3.1 mg/dL, and median eGFR 28.5 mL/min), there was no TRM and median OS was not reached after a median follow-up of 40 months10. High dose melphalan chemotherapy is associated with significant toxicity that can be particularly severe in patients with AL amyloidosis due to underlying organ dysfunction. TRM in our series was no different (8%) than the whole cohort of 629 patients (7.5%) treated with HDM/SCT at our institution during this period. Thus, ESRD is not a predictor of increased TRM. However, ESRD patients did have increased frequency of infections, mucositis and pulmonary infections Moreover, 10 Page 10 of 20

all 3 treatment related deaths occurred due to infections and not from cardiac events, although only 28% of patients had amyloid cardiac involvement. Badros et al evaluated the outcomes of 38 patients with myeloma and ESRD treated with high dose chemotherapy and stem cell transplantation. No difference in hematologic response rates was observed in the ESRD and non-ESRD patients. Dialysis dependence had no impact on OS or event free survival13. Historically long-term renal recovery after HDM/SCT is not possible for AL amyloidosis or MIDD, however, this treatment was very successful in bridging patients to renal transplantation (33% at a median time of 2.4 years after SCT), with achievement of dialysis-independence after renal transplantation. Majority of patients (n=30) in this series were on hemodialysis and only 6 patients were on peritoneal dialysis. The hematologic CR rate was 16% in peritoneal dialysis patients compared to 67% in hemodialysis patients, and the median OS was 0.9 years compared to 7.1 years respectively. However, we believe that this difference in hematologic CR and median OS is due to low number of patients treated on peritoneal dialysis and 2 of 6 patients experiencing TRM. We make a note that NT-proBNP is important for staging, patient selection for SCT, and assessment of response for AL amyloidosis24,25, however its elimination occurs by glomerular filtration and therefore its interpretation is complicated in patients with ESRD, being in these cases associated not only with cardiac dysfunction but also with volume status and malnutrition26. Other factors such as time of testing in relation to dialysis or type of hemodialysis filter also influence the test interpretation. Thus, its use is not validated in ESRD27-29. It has been suggested that BNP, rather than NT-proBNP, should be the preferred biomarker for staging and prognosis of cardiac dysfunction in ESRD30.

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The limitations of our study include the small size of our study group which limits its generalizability. Furthermore, it is important to recognize that only those patients meeting the specified eligibility criteria were treated with HDM/SCT. Assessment of hematologic responses was difficult at times due to anuria and inability to obtain urine immunofixation electrophoresis. This may explain the higher rates of hematologic CR (70% and 53% intention-to-treat) than our full cohort of patients treated with HDM/SCT5. Although the biology and prognosis of AL amyloidosis and MIDD are different, we combined these patients on dialysis as the focus of this report is to present on the nuances of the technique and tolerability of SCT in patients on dialysis. Careful patient selection, experienced multidisciplinary team management and appropriate dialysis schedule changes may have contributed to the positive outcomes in the current study. In summary, although patients on dialysis have significant toxicities, , HDM/SCT is a reasonable and effective treatment option, if performed at centers of expertise with careful patient selection, leading to satisfactory hematologic response and survival rates, allowing these patients to become candidates for kidney transplantation. Acknowledgments Authors acknowledge the contribution of current and past members of the Amyloidosis Center, Center for Blood and Cancer disorders and Cancer clinical trials office.

Authors declare no competing financial conflicts of interest.

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References

1.

Pepys MB. Amyloidosis. Annu Rev Med. 2006;57(1):223-241. doi:10.1146/annurev.med.57.121304.131243.

2.

Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213. doi:10.1080/13506129.2016.1257986.

3.

Havasi A, Stern L, Lo S, Sun F, Sanchorawala V. Validation of new renal staging system in AL amyloidosis treated with high dose melphalan and stem cell transplantation. American Journal of Hematology. 2016;91(10):E458-E460. doi:10.1002/ajh.24464.

4.

Gertz MA, Kyle RA, O'Fallon WM. Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients. Arch Intern Med. 1992;152(11):2245-2250.

5.

Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):23252332. doi:10.1182/blood-2014-04-570010.

6.

Sanchorawala V, Sun F, Quillen K, Sloan JM, Berk JL, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood. 2015;126(20):2345-2347. doi:10.1182/blood-2015-08-662726.

7.

Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant. 2000;25(5):465-470. doi:10.1038/sj.bmt.1702178.

8.

Casserly LF, Fadia A, Sanchorawala V, et al. High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease. Kidney Int. 2003;63(3):1051-1057. doi:10.1046/j.1523-1755.2003.00813.x.

9.

Leung N, Kumar SK, Glavey SV, et al. The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation. Nephrol Dial Transplant. 2016;31(8):1284-1289. doi:10.1093/ndt/gfv328.

10.

Kastritis E, Migkou M, Gavriatopoulou M, Zirogiannis P, Hadjikonstantinou V, Dimopoulos MA. Treatment of light chain deposition disease with bortezomib and dexamethasone. Haematologica. 2009;94(2):300-302. doi:10.3324/haematol.13548.

11.

Weichman K, Dember LM, Prokaeva T, et al. Clinical and molecular characteristics of patients with non-amyloid light chain deposition disorders, and outcome following treatment with high-dose melphalan and autologous stem cell transplantation. Bone Marrow Transplant. 2006;38(5):339-343. doi:10.1038/sj.bmt.1705447.

12.

Girnius S, Seldin DC, Quillen K, Dember LM, Segal A, Sanchorawala V. Long-term outcome of patients with monoclonal Ig deposition disease treated with high-dose melphalan and stem cell transplantation. Bone Marrow Transplant. 2011;46(1):161-162. doi:10.1038/bmt.2010.82. 13 Page 13 of 20

13.

Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. British Journal of Haematology. 2001;114(4):822-829.

14.

Lee CK, Barlogie B, Zangari M, et al. Dialysis-dependent renal failure in patients with myeloma can be reversed by high-dose myeloablative therapy and autotransplant. 2002;100(11):431A–432A. doi:10.1034/j.1600-0609.2002.01572.x/full.

15.

Glavey SV, Gertz MA, Dispenzieri A, et al. Long-term outcome of patients with multiple [corrected] myeloma-related advanced renal failure following auto-SCT. Bone Marrow Transplant. 2013;48(12):1543-1547. doi:10.1038/bmt.2013.109.

16.

Bernard RS, Chodirker L, Masih-Khan E, et al. Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure. Bone Marrow Transplant. 2015;50(1):95-99. doi:10.1038/bmt.2014.226.

17.

Skinner M, Sanchorawala V, Seldin DC, et al. High-Dose Melphalan and Autologous StemCell Transplantation in Patients with AL Amyloidosis: An 8-Year Study. Ann Intern Med. 2004;140(2):85-93. doi:10.7326/0003-4819-140-2-200401200-00008.

18.

Gertz MA, Comenzo R, Falk RH, 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. In: Vol 79. Wiley Subscription Services, Inc., A Wiley Company; 2005:319-328. doi:10.1002/ajh.20381.

19.

Falk RH, Comenzo RL, Skinner M. The Systemic Amyloidoses. New England Journal of Medicine. 1997;337(13):898-909. doi:10.1056/NEJM199709253371306.

20.

Sanchorawala V. Light-chain (AL) amyloidosis: diagnosis and treatment. Clin J Am Soc Nephrol. 2006;1(6):1331-1341. doi:10.2215/CJN.02740806.

21.

Loll LC, Moinpour CM, Feigl P. Southwest Oncology Group (SWOG). J Natl Cancer Inst Monographs. 1996;(20):83-85.

22.

Quillen K, Seldin DC, Finn KT, Sanchorawala V. A second course of high-dose melphalan and auto-SCT for the treatment of relapsed AL amyloidosis. Bone Marrow Transplant. 2011;46(7):976-980. doi:10.1038/bmt.2010.239.

23.

D'Souza A, Dispenzieri A, Wirk B, et al. Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study. Journal of Clinical Oncology. 2016;33(32):3741-3749. doi:10.1200/JCO.2015.62.4015.

24.

Gertz MA, Lacy MQ, Dispenzieri A, et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 2013;48(4):557-561. doi:10.1038/bmt.2012.170.

25.

Merlini G, Lousada I, Ando Y, et al. Rationale, application and clinical qualification for NTproBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis. Leukemia. 2016;30(10):1979-1986. doi:10.1038/leu.2016.191.

26.

Ikeda M, Honda H, Takahashi K, Shishido K, Shibata T. N-Terminal Pro-B-Type Natriuretic Peptide as a Biomarker for Loss of Muscle Mass in Prevalent Hemodialysis Patients. 14 Page 14 of 20

Aguilera AI, ed. PLoS ONE. 2016;11(11):e0166804. doi:10.1371/journal.pone.0166804. 27.

C S, S H, Schwenger V, HA K, E G, M Z. Cardiac biomarkers are influenced by dialysis characteristics. Clin Nephrol. 2007;68(6):392-400.

28.

Wahl HG, Graf S, Renz H, Fassbinder W. Elimination of the Cardiac Natriuretic Peptides BType Natriuretic Peptide (BNP) and N-Terminal proBNP by Hemodialysis. Clinical Chemistry. 2004;50(6):1071-1074. doi:10.1373/clinchem.2003.030692.

29.

Booth J, Pinney J, Davenport A. N-terminal proBNP—Marker of Cardiac Dysfunction, Fluid Overload, or Malnutrition in Hemodialysis Patients? CJASN. 2010;5(6):1036-1040. doi:10.2215/CJN.09001209.

30.

Palladini G, Foli A, Milani P, et al. Best use of cardiac biomarkers in patients with AL amyloidosis and renal failure. American Journal of Hematology. 2012;87(5):465-471. doi:10.1002/ajh.23141.

Figure 1. Overall survival of 36 patients by Kaplan-Meier Survival Analysis

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Figure 2. Overall survival based on achievement of complete hematologic response after SCT per Kaplan-Meier Survival analysis

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Table 1. Baseline characteristics (n=36) Male gender; n (%)

21 (58%)

Mean age at diagnosis; years (range)

52.2 (26-66)

Mean age at transplant; years (range)

53.2 (28.4-67.1)

Time from diagnosis to dialysis; months (range) Time from dialysis to SCT; months (range)

7.7 (0.2-27.5) 6 (0.2-32.3)

Hemodialysis; n (%)

30 (83%)

Renal biopsy; n (%)

30 (83%)

Lambda monoclonal light-chain isotype; n (%)

18 (50%)

Serum free light chains (mg/L)* Patients with abnormal  to  ratio; n (%)

12/14 (86%)

Mean dFLC (range)

261.7 (22.5-569.7)

Number of organ involvement, mean (range)

2.6 (1-6)

Number of organ involvement >2; n (%)

27 (75%)

Cardiac involvement; n (%)

10 (28%)

Median bone marrow plasmacytosis, percent (range)

10 (5-80)

BNP (pg/mL)**, mean (range)

293 (26-751)

Troponin I (ng/mL)***, mean (range)

0.133 (0.033-0.324)

Albumin (g/dL), mean (range)

3.2 (1.6-4.6)

Prior treatment; n (%)

20 (56%)

* Available since 2003 ** Available since 2005 *** Available since 2008

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SCT=stem cell transplantation; dFLC=difference in involved and uninvolved serum free light chains, BNP=brain natriuretic peptide

Table 2. Treatment Characteristics Dose of melphalan; n (%) 70-140mg/m2

24 (69.4%)

200mg/m2

12 (33%)

Dose of SCC CD34+ collected, mean (range)

5.7 (0.6-13.1)

Dose of SCC CD34+ infused, mean (range)

4.8 (0.4-9.7)

Peritransplant mortality

3 (8%)

SCC=stem cell collection

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Table 3a. Toxicities*

Grade 3 minimum

Any severity

Infections/Febrile neutropenia

27/36 (75%)

28/36 (78%)

Metabolic

20/36 (56%)

28/36 (78%)

Constitutional

14/36 (39%)

21/36 (58%)

Pulmonary

14/36 (39%)

21/36 (58%)

Mucositis

15/36 (42%)

25/36 (69%)

Diarrhea

10/36 (28%)

26/36 (72%)

Nausea

8/36 (22%)

26/36 (72%)

Vomiting

5/36 (14%)

26/36 (72%)

Gastrointestinal bleeding

5/36 (14%)

9/36 (25%)

*According to CTCAE classification, version 4.03

Table 3b. Toxicities

Support

ANC <500 (days); mean+-SD, (range)

4.9+-1.5 (1-9)

Temperature>100.4 (days); mean+-SD, (range)

3.3+-7.7 (0-46)

Inpatient days; mean+-SD, (range)

16.7+-21.9 (0-123)

IV antibiotics (days); mean+-SD, (range)

6.2+-5.9 (0-32)

Neutrophil engraftment (days); mean+-SD, (range)

10.5+-1.3 (9-14)

Platelet engraftment (days); mean+-SD, (range)

16.7+-7.1 (10-46)

RBC transfused (units); mean+-SD (range)

6.5+-5.7 (0-24)

Platelets transfused (units); mean+-SD (range)

10.6+-9.0 (0-46)

FFP infused (units); mean+-SD (range)

1.3+-3.2 (0-13)

ANC=absolute neutrophil count; IV=intravenous; RBC=red blood cells; FFP=fresh frozen plasma

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