- Email: [email protected]
Kidney Transplantation for Kidney Failure Due to Multiple Myeloma: Case Reports
Case Report Kidney Transplantation for Kidney Failure Due to Multiple Myeloma: Case Reports Thuy X. Le, MD,1,2 Jeffrey L. Wolf, MD,3 Carmen A. Peralta, MD,1,4 and Allison B. Webber, MD 1,2 Transplantation centers have historically considered a history of multiple myeloma as a contraindication to kidney transplantation due to high recurrence rates and poor transplant survival. However, there have been significant advances in the treatment of multiple myeloma, with improved patient survival, which may allow for successful kidney transplantation in these patients. We report on 4 patients who underwent kidney transplantation at our institution between 2009 and 2015 after having achieved a very good partial response or better with chemotherapy and autologous stem cell transplantation. All 4 patients received kidneys from living donors; 2 underwent induction therapy with basiliximab, and 2, with thymoglobulin. One patient had progression of myeloma, which responded well to therapy. All had functioning transplants at 1 year after kidney transplantation. No patients experienced a rejection episode or infections with BK polyomavirus or cytomegalovirus, with follow-up ranging from 16 to 58 months after kidney transplantation. Our experience suggests that kidney transplantation is feasible in a subset of patients with multiple myeloma. Future studies are necessary to compare outcomes in these patients with other high-risk patients undergoing kidney transplantation. Am J Kidney Dis. -(-):---. ª 2017 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. INDEX WORDS: Kidney transplantation; multiple myeloma; autologous stem cell transplantation (ASCT); outcomes; end-stage renal disease (ESRD); kidney failure; renal replacement therapy (RRT); RRT modality; hematologic malignancy; light chain deposition disease (LCDD); bortezomib; remission; case report.
M
ultiple myeloma is a plasma cell dyscrasia that accounts for 1% of malignant diseases and 10% to 13% of all hematologic malignancies.1,2 Decreased kidney function is a common complication seen in almost 50% of patients with multiple myeloma, with 2% to 12% of cases progressing to kidney failure.2,3 Kidney disease related to multiple myeloma is associated with a marked increase in morbidity and mortality.2 In a retrospective study of US Renal Data System data, Abbott et al4 reported that among 375,152 patients initiated on dialysis therapy from 1992 to 1997, a total of 3,298 (0.88%) had multiple myeloma. Patients with multiple myeloma had a 2-year all-cause mortality rate of 58% versus 31% in all other dialysis patients and a 2.5 times higher relative risk for death. Survival rates remained low with conventional therapies for multiple myeloma due to poor response rates, early relapse, and poor long-term disease control. In the last decade, there have been major advances in the treatment of multiple myeloma. The integration of antimyeloma agents such as thalidomide, lenalidomide, and bortezomib into induction regimens has markedly increased the rate of response.1,5 Current practice guidelines support the use of a bortezomib-containing multiagent induction regimen followed by melphalan and autologous stem cell transplantation in eligible patients to optimize tumor reduction and long-term disease control.1,6,7 In Am J Kidney Dis. 2017;-(-):---
addition, single-agent maintenance therapy after autologous stem cell transplantation with lenalidomide, bortezomib, or thalidomide has shown promise in prolonging progression-free survival.1,8-10 We report our experience with 4 patients with multiple myeloma who successfully underwent kidney transplantation after achieving at least a very good partial response.
CASE REPORTS Patients’ demographics, clinical characteristics, and multiple myeloma treatment data are shown in Table 1. Pre– and post– kidney transplantation characteristics are shown in Table S1. Outcomes including serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR) as calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation,11 proteinuria, serum free light chains, infections, and kidney biopsy results are shown in Table 2. From the 1Division of Nephrology, Department of Medicine, Kidney Transplant Service, 3Division of Hematology and Blood and Marrow Transplantation, Department of Medicine, and 4 Kidney Health Research Collaborative, University of California, San Francisco, San Francisco, CA. Received August 22, 2016. Accepted in revised form December 26, 2016. Address correspondence to Thuy X. Le, MD, 533 Parnassus Ave, U404 Box 0532, San Francisco, CA 94143-0532. E-mail: [email protected] 2017 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.12.023 2
1
Le et al Table 1. Demographics, Clinical Characteristics, and Multiple Myeloma Treatment Course Case 1
Age at MM diagnosis, y 52 Sex Male Ethnicity/race Hispanic SFLC at diagnosis, NA mg/L Bone marrow biopsy 20% plasma cells; IgA k myeloma Renal involvement at Yes presentation Native kidney biopsy LCDD with features suggestive of cryoglobulinemic GN MM treatment course Plasmapheresis; pre-KTx thalidomide/Dex; vincristine/Doxil/Dex; CP mobilization; melphalan conditioning, then ASCT
Case 2
Case 3
Case 4
50 Male White k: 1,900; l: 1.2
50 Male White k: 2,870; l: 9.3
47 Male Other k: 59,000; l: 9
90% plasma cells; IgG k myeloma Yes
30% plasma cells; IgG k myeloma Yes
90% plasma cells; IgA k myeloma Yes
ND
LCDD
ND
MM treatment course post-KTx
None
Hematologic responsea pre-KTx Hematologic responsea post-KTx Time from remission to KTx, mo Comorbid conditions
CR
Bortezomib/Dex/ Bortezomib/Dex/ Bortezomib/Dex; lenalidomide; lenalidomide; melphalan high-cutoff dialysis; conditioning, then ASCT; CP mobilization; lenalidomide/ lenalidomide, then melphalan doxorubicin/CP/Dex; CP bortezomib maintenance conditioning, mobilization; melphalan then ASCT; conditioning, then lenalidomide tandem ASCT; maintenance bortezomib maintenance Bortezomib maintenance; Bortezomib maintenance None switched back to lenalidomide/Dex due to progression, then carfilzomid/CP/Dex, then pomalidomide/CP/Dex VGPR CR CR
CR
SD
CR
CR
66
20
32
53
Gout
HTN, HLD, GERD
HTN, HLD, CAD, PVD, gout HTN, nephrolithiasis
Abbreviations and definitions: ASCT, autologous stem cell transplantation; CAD, coronary artery disease; CP, cyclophosphamide; CR, complete remission (negative immunofixation on serum and urine, ,5% plasma cells in bone marrow); Dex, dexamethasone; GERD, gastroesophageal reflux disease; GN, glomerulonephritis; HLD, hyperlipidemia; HTN, hypertension; KTx, kidney transplantation; LCDD, light chain deposition disease; MM, multiple myeloma; NA, none available; ND, not done; PVD, peripheral vascular disease; SD, stable disease (not meeting criteria for CR, VGPR, partial response, or progressive disease); SFLC, serum free light chain; VGPR, very good partial response (serum and urine M protein detectable by immunofixation but not by electrophoresis or $90% reduction in serum M protein plus urine protein level ,100 mg/24 h). a Response was assessed using the International Myeloma Working Group uniform response criteria for multiple myeloma adapted from Durie et al.17 The pre-KTx response is hematologic status right before transplantation, and post-KTx is the most recent status obtained up to May 1, 2016.
Case 1
Case 2
A 52-year-old man presented with anemia, Scr level of 2.5 mg/ dL, proteinuria with protein excretion of 18.8 g/24 h, and a paraprotein spike on serum protein electrophoresis (SPEP). Bone marrow biopsy showed 20% plasma cells and kidney biopsy revealed light chain deposition disease (LCDD). He was treated with plasmapheresis, thalidomide, and dexamethasone, followed by vincristine, doxorubicin, and dexamethasone for 4 cycles. He achieved a complete remission 6 months later, which was followed by autologous stem cell transplantation. He underwent kidney transplantation 66 months later. He was maintained on tacrolimus, mycophenolic acid, and prednisone. A protocol transplant biopsy 6 months after kidney transplantation showed no signs of rejection. He remains in remission from multiple myeloma, off all multiple myeloma therapy, with stable transplant function 58 months after kidney transplantation, with Scr level of 1.1 mg/dL (eGFR, 73 mL/min/1.73 m2).
A 50-year-old man presented with shortness of breath, rib pain, pancytopenia, and Scr level of 1.0 mg/dL. SPEP showed a paraprotein spike and bone marrow biopsy confirmed multiple myeloma. He was started on treatment with bortezomib plus dexamethasone in addition to intensive hemodialysis with a Gambro high-cutoff filter to reduce serum free light chain levels. Despite these measures, the patient progressed to kidney failure. He was started on treatment with Doxil, cyclophosphamide, lenalidomide, and dexamethasone. He achieved a very good partial response after tandem autologous stem cell transplantation and remained on bortezomib and dexamethasone treatment for 20 months, at which time he underwent kidney transplantation from a blood group type ABO-incompatible donor (donor A Rh1 and recipient O Rh1). The University of California, San Francisco ABO-incompatible protocol was initiated, and antithymocyte globulin was used for induction therapy. He was discharged to
2
Am J Kidney Dis. 2017;-(-):---
Kidney Transplant in Multiple Myeloma Table 2. Outcomes of 4 Patients With Kidney Failure From Multiple Myeloma After Kidney Transplantation Case 1
Kidney transplant biopsya
Scr, mg/dL 6 mo 12 mo At time of writingb
Case 2
Case 3
Case 4
At 3 mo (for AKI): slight At 6 mo (per protocol): At 1 mo (for AKI): ATN, At 6 mo (per protocol): acute tubular epithelial cell minor nonspecific no rejection mild nonspecific – – injury, C4d changes, C4d At 8 mo (per protocol): changes, no – minor nonspecific rejection, C4d At 6 mo (per protocol): changes, no moderate IFTA, mild – – rejection, C4d interstitial inflammation, C4d 1.6 1.4 1.1
1.7 1.5 1.3
1.7 1.5 1.3
1.6 1.4 1.3
eGFR, mL/min/1.73 m2 6 mo 46 12 mo 55 At time of writingb 73
42 49 59
46 47 59
47 58 60
UPCR, mg/mg 6 mo 12 mo At time of writingb
0.09 0.08 1.18
0.44 0.29 0.21
0.11 0.07 0.15
0.08 0.08 0.10
SFLC, mg/L 6 mo 12 mo
NA NA
k: 282; l: 5.9 k: 822; l: 7.2
k: 9.3; l: 11.9 k: 10.4; l: 13
k: 6.8; l: 12.6 k: 11.5; l: 16.5
Bronchitis, viral URI, pneumonia
UTI (32), URI (32), bronchitis, sinusitis, pneumonia Undetectable
Otitis media, sinusitis, bacterial pneumonia
None
Undetectable
Undetectable
3 48
3 43
1 16
Infections post-KTx
BKV and CMV at Undetectable 12 mo No. of hospitalizationsb 1 Follow-up time, mob 58
Note: Conversion factor for Scr in mg/dL to mmol/L, 388. Abbreviations: AKI, acute kidney injury; ATN, acute tubular necrosis; BKV, BK polyomavirus; CMV, cytomegalovirus; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; KTx, kidney transplantation; NA, none available; SFLC, serum free light chain; Scr, serum creatinine; UPCR, urine protein-creatinine ratio; URI, upper respiratory infection; UTI, urinary tract infection. a Transplant biopsies were graded using Banff 1997 criteria adapted from Racusen et al.18 b All data were obtained up to or most recent to May 1, 2016.
home on treatment with tacrolimus, mycophenolic acid, and prednisone, as well as weekly bortezomib. Six months after kidney transplantation, he had progression of multiple myeloma based on an increase in k serum free light chains (to 516 mg/L) and was switched to treatment with lenalidomide plus dexamethasone. His protocol transplant biopsy showed no rejection or recurrence of multiple myeloma. He was later switched to treatment with carfilzomib, cyclophosphamide, and dexamethasone because of disease progression. He tolerated his treatments well, with stable disease, but was nonadherent to his medical regimen. Scr level was 1.3 mg/dL (eGFR, 59 mL/min/1.73 m2) 48 months after kidney transplantation.
Case 3 A 50-year-old man presented with anemia and Scr level of 6.5 mg/dL. Bone marrow biopsy confirmed multiple myeloma. A kidney biopsy showed LCDD. He was treated with bortezomib, lenalidomide, and dexamethasone and reached a very good partial response after 5 cycles. Nonetheless, he progressed to kidney failure. He underwent autologous stem cell transplantation and continued on lenalidomide maintenance therapy. Lenalidomide was switched to bortezomib due to side effects. He underwent kidney transplantation 32 months after achieving a very good Am J Kidney Dis. 2017;-(-):---
partial response and 3 months after achieving a complete remission. He is maintained on treatment with tacrolimus, mycophenolic acid, and prednisone in addition to monthly bortezomib. Transplant function remained stable with Scr level of 1.3 mg/dL (eGFR, 59 mL/min/1.73 m2) 43 months after kidney transplantation.
Case 4 A 47-year-old man presented with rib pain, and workup revealed a paraprotein spike on SPEP and proteinuria with protein excretion of 5 g/24 h. Bone marrow biopsy showed 8% plasma cells, consistent with monoclonal gammopathy of undetermined significance. He was subsequently lost to follow-up and presented a year later with kidney failure requiring dialysis. Bone marrow biopsy showed 90% plasma cells. He received bortezomib, lenalidomide, and dexamethasone for 6 cycles and lenalidomide as maintenance therapy thereafter. A repeat bone marrow biopsy showed ,5% plasma cells with normal cytogenetics. Three months later, he underwent autologous stem cell transplantation and remained in complete remission for 53 months before undergoing successful kidney transplantation. Induction therapy was with basiliximab, and he was maintained on a steroid-free regimen of tacrolimus and mycophenolic acid. A protocol transplant biopsy 6 months later 3
Le et al showed no rejection. He remained in complete remission off all multiple myeloma therapy, with Scr level of 1.3 mg/dL (eGFR, 60 mL/min/1.73 m2) 16 months after kidney transplantation.
DISCUSSION In this case series, we describe 4 patients with multiple myeloma leading to kidney failure who, after contemporary treatment of myeloma, underwent successful kidney transplantation. Currently, there is little experience with kidney transplantation in patients with multiple myeloma because it has historically precluded patients from transplantation. The European Registry Study provided data for 2,453 (1.54%) patients with multiple myeloma who were started on dialysis therapy from 1986 to 2005, of whom only 35 (1.4%) underwent transplantation, compared to 23.6% of patients with kidney failure from other causes.12 Leung et al13 reported the outcomes of 7 patients with LCDD who underwent kidney transplantation. LCDD recurred in 5 patients after a median of 33.3 months. Four of these 5 patients died and 1 remained on dialysis therapy. The study concluded that kidney transplantation should not be an option for these patients given such poor outcomes. However, because this was prior to 2004, these patients received older multiple myeloma therapies without autologous stem cell transplantation. More recently, Hassoun et al14 reported on 2 patients with kidney failure from LCDD who underwent kidney transplantation at 14.1 and 45.7 months after achieving hematologic complete remission with thalidomide, dexamethasone, melphalan, and doxorubicin followed by autologous stem cell transplantation. Both had normal eGFRs without recurrence up to 24.1 months after kidney transplantation. Quintana et al15 reported that 2 patients with multiple myeloma underwent kidney transplantation after being treated with lenalidomide and autologous stem cell transplantation and achieving a very good partial response to complete remission. Myeloma recurrence was not observed at 36 months of follow-up. Both were young recipients who achieved and maintained their response for more than 4 years before kidney transplantation. The 4 cases we have reported here are of patients with multiple myeloma who achieved at least a very good partial response with bortezomib, lenalidomide, cyclophosphamide, thalidomide, or combinations plus autologous stem cell transplantation. Three patients underwent transplantation within 5 years, and one, within 2 years of achieving remission. All underwent successful kidney transplantation with minor infectious complications despite receiving standard immunosuppression regimens. To date, there have been no rejections and all cases have excellent kidney function up to 58 months after kidney transplantation. 4
Although there are no specific guidelines with regard to maintenance therapy in multiple myeloma, particularly after kidney transplantation, 2 of 4 patients remained on maintenance therapy after kidney transplantation with either lenalidomide or bortezomib and had excellent disease control. One patient experienced a relapse but later re-established disease control with a different chemotherapeutic regimen. Lenalidomide remains the most commonly used agent for maintenance therapy, but bortezomib may be an excellent choice in patients after kidney transplantation given its role in the treatment of antibodymediated rejection.16 In conclusion, our experience supports the feasibility of kidney transplantation in patients with multiple myeloma who have achieved at least a very good partial response or better with induction chemotherapies and autologous stem cell transplantation. Because sustained periods of disease remission are possible with advances in multiple myeloma treatments with improved overall survival, multiple myeloma may no longer preclude patients with kidney failure from kidney transplantation. In addition, waiting 2 to 5 years from the time of remission to kidney transplantation could be reconsidered if benefits are to be maximized. A reasonable approach is to evaluate each individual case, assessing cancer type and staging, treatment response, risk for progression and recurrence, age, comorbid conditions, and performance status prior to referral for kidney transplantation. More research is needed to identify which subset of patients with multiple myeloma would benefit most from kidney transplantation.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by 3 external peer reviewers, a CoEditor, and Editor-in-Chief Levey.
SUPPLEMENTARY MATERIAL Table S1: Pre– and post–kidney transplantation characteristics. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2016.12.023) is available at www.ajkd.org
REFERENCES 1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060. 2. Korbet SM, Schwartz MM. Multiple myeloma. J Am Soc Nephrol. 2006;17(9):2533-2545. 3. Bansal T, Garg A, Snowden JA, McKane W. Defining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias. Nephron Clin Pract. 2012;120(4):c228-c235. 4. Abbott KC, Agodoa LY. Multiple myeloma and light chainassociated nephropathy at end-stage renal disease in the United Am J Kidney Dis. 2017;-(-):---
Kidney Transplant in Multiple Myeloma States: patient characteristics and survival. Clin Nephrol. 2001;56(3):207-210. 5. Nayak L, Lazarus HM. Renal allografts in plasma cell myeloma hematopoietic cell graft recipients: on the verge of an explosion? Bone Marrow Transplant. 2013;48(3):338-345. 6. Anderson KC, Alsina M, Bensinger W, et al. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw. 2009;7(9):908-942. 7. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27): 5436-5443. 8. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791. 9. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. 10. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955. 11. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612.
Am J Kidney Dis. 2017;-(-):---
12. Tsakiris DJ, Stel VS, Finne P, et al. Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry study. Nephrol Dial Transplant. 2010;25(4): 1200-1206. 13. Leung N, Lager DJ, Gertz MA, Wilson K, Kanakiriya S, Fervenza FC. Long-term outcome of renal transplantation in light-chain deposition disease. Am J Kidney Dis. 2004;43(1): 147-153. 14. Hassoun H, Flombaum C, D’Agati VD, et al. High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease. Bone Marrow Transplant. 2008;42(6):405-412. 15. Quintana AS, Rull PR, Atienza JB, McDonnell CN. Renal transplant in plasma cell dyscrasias with lenalidomide treatment after autologous stem cell transplantation. Nephrology. 2013;18(9):641-643. 16. Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation. 2008;86(12):1754-1761. 17. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473. 18. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55(2):713-723.
5
M
ultiple myeloma is a plasma cell dyscrasia that accounts for 1% of malignant diseases and 10% to 13% of all hematologic malignancies.1,2 Decreased kidney function is a common complication seen in almost 50% of patients with multiple myeloma, with 2% to 12% of cases progressing to kidney failure.2,3 Kidney disease related to multiple myeloma is associated with a marked increase in morbidity and mortality.2 In a retrospective study of US Renal Data System data, Abbott et al4 reported that among 375,152 patients initiated on dialysis therapy from 1992 to 1997, a total of 3,298 (0.88%) had multiple myeloma. Patients with multiple myeloma had a 2-year all-cause mortality rate of 58% versus 31% in all other dialysis patients and a 2.5 times higher relative risk for death. Survival rates remained low with conventional therapies for multiple myeloma due to poor response rates, early relapse, and poor long-term disease control. In the last decade, there have been major advances in the treatment of multiple myeloma. The integration of antimyeloma agents such as thalidomide, lenalidomide, and bortezomib into induction regimens has markedly increased the rate of response.1,5 Current practice guidelines support the use of a bortezomib-containing multiagent induction regimen followed by melphalan and autologous stem cell transplantation in eligible patients to optimize tumor reduction and long-term disease control.1,6,7 In Am J Kidney Dis. 2017;-(-):---
addition, single-agent maintenance therapy after autologous stem cell transplantation with lenalidomide, bortezomib, or thalidomide has shown promise in prolonging progression-free survival.1,8-10 We report our experience with 4 patients with multiple myeloma who successfully underwent kidney transplantation after achieving at least a very good partial response.
CASE REPORTS Patients’ demographics, clinical characteristics, and multiple myeloma treatment data are shown in Table 1. Pre– and post– kidney transplantation characteristics are shown in Table S1. Outcomes including serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR) as calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation,11 proteinuria, serum free light chains, infections, and kidney biopsy results are shown in Table 2. From the 1Division of Nephrology, Department of Medicine, Kidney Transplant Service, 3Division of Hematology and Blood and Marrow Transplantation, Department of Medicine, and 4 Kidney Health Research Collaborative, University of California, San Francisco, San Francisco, CA. Received August 22, 2016. Accepted in revised form December 26, 2016. Address correspondence to Thuy X. Le, MD, 533 Parnassus Ave, U404 Box 0532, San Francisco, CA 94143-0532. E-mail: [email protected] 2017 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.12.023 2
1
Le et al Table 1. Demographics, Clinical Characteristics, and Multiple Myeloma Treatment Course Case 1
Age at MM diagnosis, y 52 Sex Male Ethnicity/race Hispanic SFLC at diagnosis, NA mg/L Bone marrow biopsy 20% plasma cells; IgA k myeloma Renal involvement at Yes presentation Native kidney biopsy LCDD with features suggestive of cryoglobulinemic GN MM treatment course Plasmapheresis; pre-KTx thalidomide/Dex; vincristine/Doxil/Dex; CP mobilization; melphalan conditioning, then ASCT
Case 2
Case 3
Case 4
50 Male White k: 1,900; l: 1.2
50 Male White k: 2,870; l: 9.3
47 Male Other k: 59,000; l: 9
90% plasma cells; IgG k myeloma Yes
30% plasma cells; IgG k myeloma Yes
90% plasma cells; IgA k myeloma Yes
ND
LCDD
ND
MM treatment course post-KTx
None
Hematologic responsea pre-KTx Hematologic responsea post-KTx Time from remission to KTx, mo Comorbid conditions
CR
Bortezomib/Dex/ Bortezomib/Dex/ Bortezomib/Dex; lenalidomide; lenalidomide; melphalan high-cutoff dialysis; conditioning, then ASCT; CP mobilization; lenalidomide/ lenalidomide, then melphalan doxorubicin/CP/Dex; CP bortezomib maintenance conditioning, mobilization; melphalan then ASCT; conditioning, then lenalidomide tandem ASCT; maintenance bortezomib maintenance Bortezomib maintenance; Bortezomib maintenance None switched back to lenalidomide/Dex due to progression, then carfilzomid/CP/Dex, then pomalidomide/CP/Dex VGPR CR CR
CR
SD
CR
CR
66
20
32
53
Gout
HTN, HLD, GERD
HTN, HLD, CAD, PVD, gout HTN, nephrolithiasis
Abbreviations and definitions: ASCT, autologous stem cell transplantation; CAD, coronary artery disease; CP, cyclophosphamide; CR, complete remission (negative immunofixation on serum and urine, ,5% plasma cells in bone marrow); Dex, dexamethasone; GERD, gastroesophageal reflux disease; GN, glomerulonephritis; HLD, hyperlipidemia; HTN, hypertension; KTx, kidney transplantation; LCDD, light chain deposition disease; MM, multiple myeloma; NA, none available; ND, not done; PVD, peripheral vascular disease; SD, stable disease (not meeting criteria for CR, VGPR, partial response, or progressive disease); SFLC, serum free light chain; VGPR, very good partial response (serum and urine M protein detectable by immunofixation but not by electrophoresis or $90% reduction in serum M protein plus urine protein level ,100 mg/24 h). a Response was assessed using the International Myeloma Working Group uniform response criteria for multiple myeloma adapted from Durie et al.17 The pre-KTx response is hematologic status right before transplantation, and post-KTx is the most recent status obtained up to May 1, 2016.
Case 1
Case 2
A 52-year-old man presented with anemia, Scr level of 2.5 mg/ dL, proteinuria with protein excretion of 18.8 g/24 h, and a paraprotein spike on serum protein electrophoresis (SPEP). Bone marrow biopsy showed 20% plasma cells and kidney biopsy revealed light chain deposition disease (LCDD). He was treated with plasmapheresis, thalidomide, and dexamethasone, followed by vincristine, doxorubicin, and dexamethasone for 4 cycles. He achieved a complete remission 6 months later, which was followed by autologous stem cell transplantation. He underwent kidney transplantation 66 months later. He was maintained on tacrolimus, mycophenolic acid, and prednisone. A protocol transplant biopsy 6 months after kidney transplantation showed no signs of rejection. He remains in remission from multiple myeloma, off all multiple myeloma therapy, with stable transplant function 58 months after kidney transplantation, with Scr level of 1.1 mg/dL (eGFR, 73 mL/min/1.73 m2).
A 50-year-old man presented with shortness of breath, rib pain, pancytopenia, and Scr level of 1.0 mg/dL. SPEP showed a paraprotein spike and bone marrow biopsy confirmed multiple myeloma. He was started on treatment with bortezomib plus dexamethasone in addition to intensive hemodialysis with a Gambro high-cutoff filter to reduce serum free light chain levels. Despite these measures, the patient progressed to kidney failure. He was started on treatment with Doxil, cyclophosphamide, lenalidomide, and dexamethasone. He achieved a very good partial response after tandem autologous stem cell transplantation and remained on bortezomib and dexamethasone treatment for 20 months, at which time he underwent kidney transplantation from a blood group type ABO-incompatible donor (donor A Rh1 and recipient O Rh1). The University of California, San Francisco ABO-incompatible protocol was initiated, and antithymocyte globulin was used for induction therapy. He was discharged to
2
Am J Kidney Dis. 2017;-(-):---
Kidney Transplant in Multiple Myeloma Table 2. Outcomes of 4 Patients With Kidney Failure From Multiple Myeloma After Kidney Transplantation Case 1
Kidney transplant biopsya
Scr, mg/dL 6 mo 12 mo At time of writingb
Case 2
Case 3
Case 4
At 3 mo (for AKI): slight At 6 mo (per protocol): At 1 mo (for AKI): ATN, At 6 mo (per protocol): acute tubular epithelial cell minor nonspecific no rejection mild nonspecific – – injury, C4d changes, C4d At 8 mo (per protocol): changes, no – minor nonspecific rejection, C4d At 6 mo (per protocol): changes, no moderate IFTA, mild – – rejection, C4d interstitial inflammation, C4d 1.6 1.4 1.1
1.7 1.5 1.3
1.7 1.5 1.3
1.6 1.4 1.3
eGFR, mL/min/1.73 m2 6 mo 46 12 mo 55 At time of writingb 73
42 49 59
46 47 59
47 58 60
UPCR, mg/mg 6 mo 12 mo At time of writingb
0.09 0.08 1.18
0.44 0.29 0.21
0.11 0.07 0.15
0.08 0.08 0.10
SFLC, mg/L 6 mo 12 mo
NA NA
k: 282; l: 5.9 k: 822; l: 7.2
k: 9.3; l: 11.9 k: 10.4; l: 13
k: 6.8; l: 12.6 k: 11.5; l: 16.5
Bronchitis, viral URI, pneumonia
UTI (32), URI (32), bronchitis, sinusitis, pneumonia Undetectable
Otitis media, sinusitis, bacterial pneumonia
None
Undetectable
Undetectable
3 48
3 43
1 16
Infections post-KTx
BKV and CMV at Undetectable 12 mo No. of hospitalizationsb 1 Follow-up time, mob 58
Note: Conversion factor for Scr in mg/dL to mmol/L, 388. Abbreviations: AKI, acute kidney injury; ATN, acute tubular necrosis; BKV, BK polyomavirus; CMV, cytomegalovirus; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; KTx, kidney transplantation; NA, none available; SFLC, serum free light chain; Scr, serum creatinine; UPCR, urine protein-creatinine ratio; URI, upper respiratory infection; UTI, urinary tract infection. a Transplant biopsies were graded using Banff 1997 criteria adapted from Racusen et al.18 b All data were obtained up to or most recent to May 1, 2016.
home on treatment with tacrolimus, mycophenolic acid, and prednisone, as well as weekly bortezomib. Six months after kidney transplantation, he had progression of multiple myeloma based on an increase in k serum free light chains (to 516 mg/L) and was switched to treatment with lenalidomide plus dexamethasone. His protocol transplant biopsy showed no rejection or recurrence of multiple myeloma. He was later switched to treatment with carfilzomib, cyclophosphamide, and dexamethasone because of disease progression. He tolerated his treatments well, with stable disease, but was nonadherent to his medical regimen. Scr level was 1.3 mg/dL (eGFR, 59 mL/min/1.73 m2) 48 months after kidney transplantation.
Case 3 A 50-year-old man presented with anemia and Scr level of 6.5 mg/dL. Bone marrow biopsy confirmed multiple myeloma. A kidney biopsy showed LCDD. He was treated with bortezomib, lenalidomide, and dexamethasone and reached a very good partial response after 5 cycles. Nonetheless, he progressed to kidney failure. He underwent autologous stem cell transplantation and continued on lenalidomide maintenance therapy. Lenalidomide was switched to bortezomib due to side effects. He underwent kidney transplantation 32 months after achieving a very good Am J Kidney Dis. 2017;-(-):---
partial response and 3 months after achieving a complete remission. He is maintained on treatment with tacrolimus, mycophenolic acid, and prednisone in addition to monthly bortezomib. Transplant function remained stable with Scr level of 1.3 mg/dL (eGFR, 59 mL/min/1.73 m2) 43 months after kidney transplantation.
Case 4 A 47-year-old man presented with rib pain, and workup revealed a paraprotein spike on SPEP and proteinuria with protein excretion of 5 g/24 h. Bone marrow biopsy showed 8% plasma cells, consistent with monoclonal gammopathy of undetermined significance. He was subsequently lost to follow-up and presented a year later with kidney failure requiring dialysis. Bone marrow biopsy showed 90% plasma cells. He received bortezomib, lenalidomide, and dexamethasone for 6 cycles and lenalidomide as maintenance therapy thereafter. A repeat bone marrow biopsy showed ,5% plasma cells with normal cytogenetics. Three months later, he underwent autologous stem cell transplantation and remained in complete remission for 53 months before undergoing successful kidney transplantation. Induction therapy was with basiliximab, and he was maintained on a steroid-free regimen of tacrolimus and mycophenolic acid. A protocol transplant biopsy 6 months later 3
Le et al showed no rejection. He remained in complete remission off all multiple myeloma therapy, with Scr level of 1.3 mg/dL (eGFR, 60 mL/min/1.73 m2) 16 months after kidney transplantation.
DISCUSSION In this case series, we describe 4 patients with multiple myeloma leading to kidney failure who, after contemporary treatment of myeloma, underwent successful kidney transplantation. Currently, there is little experience with kidney transplantation in patients with multiple myeloma because it has historically precluded patients from transplantation. The European Registry Study provided data for 2,453 (1.54%) patients with multiple myeloma who were started on dialysis therapy from 1986 to 2005, of whom only 35 (1.4%) underwent transplantation, compared to 23.6% of patients with kidney failure from other causes.12 Leung et al13 reported the outcomes of 7 patients with LCDD who underwent kidney transplantation. LCDD recurred in 5 patients after a median of 33.3 months. Four of these 5 patients died and 1 remained on dialysis therapy. The study concluded that kidney transplantation should not be an option for these patients given such poor outcomes. However, because this was prior to 2004, these patients received older multiple myeloma therapies without autologous stem cell transplantation. More recently, Hassoun et al14 reported on 2 patients with kidney failure from LCDD who underwent kidney transplantation at 14.1 and 45.7 months after achieving hematologic complete remission with thalidomide, dexamethasone, melphalan, and doxorubicin followed by autologous stem cell transplantation. Both had normal eGFRs without recurrence up to 24.1 months after kidney transplantation. Quintana et al15 reported that 2 patients with multiple myeloma underwent kidney transplantation after being treated with lenalidomide and autologous stem cell transplantation and achieving a very good partial response to complete remission. Myeloma recurrence was not observed at 36 months of follow-up. Both were young recipients who achieved and maintained their response for more than 4 years before kidney transplantation. The 4 cases we have reported here are of patients with multiple myeloma who achieved at least a very good partial response with bortezomib, lenalidomide, cyclophosphamide, thalidomide, or combinations plus autologous stem cell transplantation. Three patients underwent transplantation within 5 years, and one, within 2 years of achieving remission. All underwent successful kidney transplantation with minor infectious complications despite receiving standard immunosuppression regimens. To date, there have been no rejections and all cases have excellent kidney function up to 58 months after kidney transplantation. 4
Although there are no specific guidelines with regard to maintenance therapy in multiple myeloma, particularly after kidney transplantation, 2 of 4 patients remained on maintenance therapy after kidney transplantation with either lenalidomide or bortezomib and had excellent disease control. One patient experienced a relapse but later re-established disease control with a different chemotherapeutic regimen. Lenalidomide remains the most commonly used agent for maintenance therapy, but bortezomib may be an excellent choice in patients after kidney transplantation given its role in the treatment of antibodymediated rejection.16 In conclusion, our experience supports the feasibility of kidney transplantation in patients with multiple myeloma who have achieved at least a very good partial response or better with induction chemotherapies and autologous stem cell transplantation. Because sustained periods of disease remission are possible with advances in multiple myeloma treatments with improved overall survival, multiple myeloma may no longer preclude patients with kidney failure from kidney transplantation. In addition, waiting 2 to 5 years from the time of remission to kidney transplantation could be reconsidered if benefits are to be maximized. A reasonable approach is to evaluate each individual case, assessing cancer type and staging, treatment response, risk for progression and recurrence, age, comorbid conditions, and performance status prior to referral for kidney transplantation. More research is needed to identify which subset of patients with multiple myeloma would benefit most from kidney transplantation.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by 3 external peer reviewers, a CoEditor, and Editor-in-Chief Levey.
SUPPLEMENTARY MATERIAL Table S1: Pre– and post–kidney transplantation characteristics. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2016.12.023) is available at www.ajkd.org
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