Sequential, Autologous Hematopoietic Stem Cell Transplant Followed by Renal Transplant in Multiple Myeloma

Introduction

Plasma cell dyscrasia is one of the common malignancies, especially in the elderly, although it may also afflict the young adults. About half of these patients have some renal dysfunction at presentation and about 10% require hemodialysis.[1] Occasionally, patients present to the nephrologist for evaluation of unexplained renal failure and investigations reveal plasma cell dyscrasia. We present a similar clinical scenario in a female who had hypertension, pulmonary edema and presented with rapidly progressive renal failure (RPRF). Investigations revealed cast nephropathy. She underwent autologous hematopoietic stem cell transplant while on maintenance hemodialysis and subsequently successful live related renal transplantation. To the best of our knowledge, this is the first such reported case from India.

Case Report

A 30-year-old female presented to the Renal Clinic of our hospital in January 2012 for the investigation of rapidly progressive renal failure (RPRF). Her illness started in October 2011 with headache and weakness. Subsequently, she developed exertional dyspnea and orthopnea. She was detected to have anemia and increased blood pressure of 160/90 mmHg. She was initially admitted to a private hospital, with features suggestive of pulmonary edema. Investigations there revealed hemoglobin (Hb) 9 g%, total leukocyte count 13,100, blood urea 253 mg%, creatinine 13.9 mg%, Na 131 mEq/L, K 6.2 mEq/L, calcium 11.9 mg%, phosphate 6.8 mEq/L, uric acid 9.5 mEq/L, intact parathyroid hormone 27.6 pg/ml. Urine routine revealed 2+ proteins, 30–35 red blood cells (RBCs), and 10–12 white blood cell. Urine protein-creatinine ratio was 3.9. There was no history of reduced urine output, hematuria, dysuria, fever, nonsteroidal anti-inflammatory drug use, alternative drug use, calcium supplementation, oral ulcers, skin rash, Raynaud's phenomenon, photosensitivity, hemoptysis, or epistaxis.

She was initiated there on hemodialysis and stabilized. Further evaluation of RPRF was done. The hemogram showed no schistocytes, and serum lactate dehydrogenase was 872 U/L (normal for her renal function). Serum antinuclear antibody, double-stranded DNA, and anti-neutrophil cytoplasmic antibody were negative; C₃ was 98 mg/dL. Serum protein electrophoresis was normal. Serum immunofixation electrophoresis (IFE) revealed a monoclonal gammopathy, with elevated kappa chain. Urine IFE too showed kappa light chains. Serum β2 microglobulin was 38.72 mcg/ml. X-rays of the skull, pelvis, and dorsolumbar spine were normal.

Kidney biopsy was done there and reported as prominent tubular hyaline casts with mild to moderate acute interstitial nephritis. She was given intravenous pulses of steroid and cyclophosphamide. Subsequently, she came to Renal Clinic at our hospital. The serum free light chain assay revealed kappa 381.14 mg/dl, lambda 58.31 mg/dl, with a kappa/lambda ratio 6.54 (0.26–1.65). Bone marrow examination revealed 15% plasma cells. The kidney biopsy slides were reviewed. It showed five glomeruli, which were unremarkable. The tubules showed fractured casts with giant cell reaction. There was significant interstitial atrophy. The pathologic diagnosis was myeloma cast nephropathy (kappa light-chain restricted), with chronic kidney disease.

Maintenance hemodialysis was continued and she was referred to medical oncology. There, she received induction therapy with bortezomib and dexamethasone. Six cycles were given from January to June 2012. She achieved complete remission. The serum and urine protein electrophoresis became negative for gammopathy. Bone marrow aspiration showed 1%–2% plasma cells. Maintenance bortezomib was continued till May 2014 when she was planned for autologous bone marrow transplantation. Autologous hematopoietic stem cell transplantation was performed on June 6, 2014. Melphalan was administered at the dose of 100 mg/m²; total of 150 mg; and CD34+ 4.34 × 10⁶/kg cells were infused. Posttransplant complications included febrile neutropenia and gastrointestinal (GI) toxicity, which settled down with time.

On follow-up, serum protein electrophoresis (SPEP) and bone marrow were normal. The free light chain ratio was 2.9 (WNL for her renal functions). After bone marrow transplant, monthly, bortezomib was continued until April 2015 when it was stopped in view of thrombocytopenia. It was treated with steroids for 2 months. Throughout the period, maintenance hemodialysis through arteriovenous fistula in the right forearm was continued. Hb was maintained at around 10 g% with injection erythropoietin 6000 units/week. In December 2014, renal transplantation was planned with father (59 years) as donor. Sensitization history included two units packed RBC infusion in June 2014 and two pregnancies. The complement-dependent cytotoxicity and flow cross-matches were negative. Her Hb was 10.9 g%, total leukocyte count 3700/mm³, and platelets 98,000/mm³. Hence, pretransplant mycophenolate was withheld. No induction therapy was given. Renal transplant was performed on January 4, 2016, with immunosuppression consisting of prednisolone and tacrolimus. Subsequently, mycophenolate was added. She achieved a serum creatinine of 0.6 mg% on day 4. Posttransplantation course was uneventful. Currently, she was 4½ months postrenal transplant. She was receiving tablet prednisolone 7.5 mg, mycophenolate 500 mg TDS, and tacrolimus 5.5 mg BD (tacrolimus level 5.5 ng/ml).

Discussion

Renal dysfunction is very common in patients with plasma cell dyscrasia. It affects the kidney by three mechanisms: cast nephropathy, also called myeloma kidney, is most common (40%–63%), followed by monoclonal immunodeposition disease (19%–26%) and amyloid light-chain amyloidosis (7%–30%).[2] Renal dysfunction with multiple myeloma is associated with increased morbidity and mortality.[3] In the period, before novel agents and stem cell transplantation, the median survival of patients of cast nephropathy on dialysis was dismal 6 months.[2] There has been significant improvement in survival of patients with renal dysfunction in the past decade due to the use of thalidomide and bortezomib.[4] Currently, the initial aim is to achieve remission with chemotherapy, followed by high-dose melphalan therapy and autologous stem cell transplantation (ASCT) in suitable patients. However, patients on dialysis are usually not considered for stem cell transplantation.[56] Dosage of the conditioning agents is problematic: under-dosing increases the risk of recurrent disease, while overdosing can cause toxicity to the GI mucosa, heart, and lungs, besides infection.[7] Subsequent renal transplantation is even rarer but has been reported from few centers in younger patients with good performance status.[8910]

Our patient presented with RPRF. Laboratory investigations showed anemia, hypercalcemia, and hyperuricemia. There was no evidence of hemolysis or vasculitis. The screening tests for multiple myeloma, viz., SPEP and skeletal survey, were negative. However, serum IFE revealed monoclonal gammopathy with elevated kappa chain, and kidney biopsy showed classic cast nephropathy. She achieved complete hematologic remission, with the induction treatment consisting of bortezomib and dexamethasone. However, her renal function did not improve with chemotherapy and she continued to remain dialysis dependent. After remaining in remission for about 2 years, she underwent successful autologous hematopoietic stem cell transplantation. A sustained remission is advised before renal transplantation as there are chances of recurrence of multiple myeloma postrenal transplant due to the effect of immunosuppression.[11] In our patient, the total waiting period after remission was about 2½ years. The major issue before renal transplant was thrombocytopenia, which was thought to be due to immune thrombocytopenia, and was treated with steroids. Mycophenolate was introduced after the renal transplant. There were no problems in the posttransplant period.

Every patient of multiple myeloma with end-stage renal failure is not a candidate for ASCT; ASCT is indicated in patients with <65 years of age with no severe comorbidities. Although ASCT is feasible with renal failure, toxicities of high-dose chemotherapy are more frequent and more severe. The dose of melphalan should be reduced to 100 mg/m² instead of 200 mg/m². To the best of our knowledge, this is the first such case reported from India. This case highlights appropriate evaluation of RPRF, followed by close interaction of medical oncology and nephrology. We feel that sequential ASCT followed by renal transplantation is an appropriate modality of care of patients, with plasma cell dyscrasia with renal failure in young and otherwise fit patients.