Approximately 20–40% of patients with plasma cell disorders have renal impairment at the time of diagnosis, and up to 2–3% of patients will require dialysis during their disease course [1, 2]. Patients who require dialysis are reported to have a poor prognosis. Although several studies have shown equivalent response rates to conventional chemotherapy in patients with mild to moderate renal insufficiency compared to those with normal renal function, the survival of myeloma patients with renal impairment is still significantly shorter. This can be attributed to an increased risk of early death, association of renal dysfunction with advanced disease, and also in part to reluctance in the use of intensive chemotherapy. Therefore, patients with dialysis-dependent renal failure are frequently considered unfit for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) [3-8]. There are limited data about patients with dialysis-dependent renal failure undergoing ASCT. It is encouraging, however, that even in patients with severe renal failure, improvements in renal function following transplantation can be observed. However, this treatment approach was associated with higher rates of toxicity and transplant-related mortality [5-15]. We aimed to demonstrate that, in patients with plasma cell disorders and dialysis-dependent renal failure, ASCT is feasible and can improve disease response.
We retrospectively analyzed our transplant database from 2004 to June 2017 to identify all myeloma and AL (light chain amyloidosis) patients who received ASCT while they were dialysis dependent. We identified 7 patients with advanced renal failure due to plasma cell disorder who required dialysis during ASCT. At diagnosis, patients received induction therapy according to the standard regimens used in plasma cell disorders. In the majority (6 out of 7 patients), bortezomib-based regimens were administered. Peripheral blood stem cells (PBSC) were mobilized using different mobilization factors: 2 patients with granulocyte colony-stimulating factor (lenograstim 5 μg/kg subcutaneous [sc] b.i.d. for 4 days), 4 patients with high-dose cyclophosphamide (CTX-HD) i.v. day 1 (1 patient 2 g/m2, 3 patients 3 g/m2), and G-CSF (lenograstim 5 μg/kg/day sc day 4–9 then b.i.d. until apheresis collection has been completed), 1 patient with CTX-HD i.v. day 1 (2 g/m2), G-CSF (lenograstim 5 μg/kg/day sc day 4–9 then b.i.d. until hematopoietic stem cell [HSC] apheresis collection has been completed), and plerixafor (0.16 mg/kg/day sc after 10 days of G-CSF treatment until HSC apheresis collection has been completed). Plerixafor was administered on demand because the peak CD34+ cell preapheresis count was less than 20 cells/μL. The patient required plerixafor dose escalation to 0.24 mg/kg/day with subsequent successful mobilization. No plerixafor-related toxicities were reported. A minimum of 2 × 106 CD34+ cells/kg were required to proceed to ASCT. The conditioning regimen for all patients consisted of melphalan (cumulative dose depending on age and clinical status). Patients received G-CSF 5 μg/kg sc daily from the day after PBSC infusion until an absolute neutrophil count > 1,000/μL. Antiemetic prophylaxis was administered. Patients were routinely transfused for Hb < 8 g/dL or PLT < 20.000/μL. Neutrophil engraftment was defined as the first of 3 consecutive days on which the absolute neutrophil count exceeded 500/μL. Response and progression were measured according to the “International Myeloma Working Group consensus criteria for response and minimal residual assessment in multiple myeloma” and according to the 2011–2012 guidelines for amyloidosis from the University of Pavia. Response to ASCT was assessed at approximately 100 days post-ASCT. Toxicity was measured according to the Common Terminology Criteria for Adverse Events version 4.0.
Treatment-related mortality was defined as any death not related to relapse, within approximately 100 days of transplant and at 6 and 12 months after the transplant. Overall survival was calculated from the date of ASCT to the date of death due to any cause, with living patients censored on the last follow-up date. Progression-free survival was calculated from the date of ASCT to the date of progression or date of death; patients alive without progression were censored on the date of last follow-up.
The patient characteristics are outlined in Table 1. Six patients were receiving hemodialysis and 1 was receiving peritoneal dialysis. In 1 case a renal biopsy diagnosed renal AL amyloidosis. In the other 6 patients we assumed that the causes of renal failure were light-chain cast nephropathy and/or light-chain deposition disease, excluding other comorbidities as causes of renal impairment and considering the concomitant increasing of the monoclonal protein and the renal impairment onset. One patient received full-dose melphalan (200 mg/m2) as the conditioning regimen; 1 received a reduced melphalan dose of 140 mg/m2. The other 5 patients received a nonmyeloablative conditioning regimen with a melphalan dose of 100 mg/m2 (n = 4) or 75 mg/m2 (n = 1). The median number of PBSC infused was 3.1 × 106 cells/kg (range 2.14–4.41 × 106 cells/kg). The median time to neutrophil engraftment was 10 days. Bedside dialysis treatment was done on the day before and on the day after melphalan administration. Hemodialysis treatment was always done at the bedside during the period of neutropenia post- ASCT. Treatment-related mortality was 0%. At the time of the last follow-up, 4 patients were still alive without disease progression and 3 were lost to follow-up. The nonhematologic toxicities (all grades) were mucositis, febrile neutropenia, delirium, and atrial dysrhythmias. Documented infections included Staphylococcus epidermidis and Enterobacter cloacae bacteremia (n = 2, only 1 microbiologically documented infection was catheter related), and Clostridium difficile diarrhea (n = 1). One patient developed neutropenic enterocolitis. The 100-day and the 6, and 12-month treatment-related mortality was 0%.
The overall response rate was 100%, including: complete response (CR), n = 2; very good partial response (VGPR), n = 2, and partial response (PR), n = 2. All the patients confirmed or improved their previous response after ASCT treatment, as listed in Figure 1. One patient reduced peritoneal dialysis requirements from 6 times a week to 3 times a week after ASCT. After a median follow-up of 2.1 years (7 months to 5 years), no patients have progressive disease.
Renal failure in myeloma patients is a frequently encountered problem. The prognosis is generally poor and these patients are often considered unfit for high-dose therapy and ASCT. We did not observe any impediment to hematopoietic progenitor cell mobilization by dialysis. All patients in our study were able to collect a sufficient number of PBSC for ASCT. This is in line with our historical experience with nondialysis patients. Though our study is retrospective in nature and with a small sample size, we are able to demonstrate that in patients with plasma cell disorders and dialysis-dependent renal failure, ASCT is feasible and can improve disease response. Dialysis should not constitute a parameter for exclusion from high-dose therapy and ASCT. Prospective randomized trials in patients with severe renal failure are mandatory in order to further optimize treatment-related toxicity and improve the outcome of this frequently neglected group of patients.
The authors declare no conflicts of interest.