Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Data on the effectiveness and toxicity of high-dose melphalan in patients with renal impairment (RI) are lacking. We evaluated the impact of RI on outcomes of patients with multiple myeloma treated with melphalan 200 mg/m 2 (Mel200) and autologous stem cell transplantation. Similar baseline characteristics were seen among 46 patients with creatinine clearance (CrCl) o 60 mL/min (median 50 mL/min, range 20-59) and 103 patients with CrCl ⩾ 60 mL/min (median 83 mL/min, range 60-128). Patients with CrCl o60 mL/min had longer time to neutrophil (P = 0.008) and platelet engraftment (P o 0.001). Diarrhea, duration of total parenteral nutrition use and infection were significantly higher in the CrCl o 60 mL/min group. With a median follow-up of 35 months (range 2-132) in the CrCl o60 mL/min group and 47 months (range 1-45) in the CrCl ⩾ 60 mL/min group, overall survival was comparable between the two groups. Median treatment-free survival was longer in the RI group (37 vs 17 months, P = 0.0025). Multivariate analysis showed CrCl o 60 mL/min (hazard ratio (HR) 3.5), and prior proteasome inhibitor therapy (HR 2.441) both predicted longer treatment-free survival. We consider Mel200 safe and effective in patients with CrCl between 30 and 60 mL/min.

Section: Discussionmentioning

confidence: 99%

Section: Baseline Characteristicsmentioning

confidence: 99%

Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival

Sweiss

Patel

Culos

et al. 2016

“…In summary, high melphalan dose (expressed as mg/kg or mg/m 2 ) and/or renal impairment are significant risk factors for severe oral mucositis. [16][17][18][19][20] However, high-dose intensity also is associated with improved disease response. 21,22 Palumbo et al 23 reported improved PFS with melphalan 200 mg/m 2 rather than melphalan 100 mg/m 2 , but increased gastrointestinal toxicity was noted.…”

Section: Indirect Indicators Of Melphalan Pharmacodynamicsmentioning

confidence: 99%

“…33 Badros et al 20 examined melphalan toxicity in 81 subjects undergoing autotransplantation in the setting of renal failure, including 38 patients receiving dialysis. Sixty patients (27 undergoing dialysis) received melphalan 200 mg/m 2 ; 21 (11 on dialysis) subsequently were treated at a lower melphalan dose of 140 mg/m 2 .…”

Section: Dosing In Renal Impairmentmentioning

confidence: 99%

Not too little, not too much—just right! (Better ways to give high dose melphalan)

Shaw

Nath

Lazarus

2014

Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m 2 , but at these doses it is cardiac, rather than gut, toxicity that is doselimiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies. To best assess the contribution that the dose of drug makes to clinically meaningful endpoints in haematopoietic cell transplantation (HCT), one would choose one drug, ideally used as monotherapy, for one disease and with one source of haematopoietic progenitor cells (HPC). Although this approach may appear quite restrictive, these criteria are fulfilled when high-dose melphalan is used in the context of autologous HCT for plasma cell myeloma. Indeed, melphalan, which has been in use for 60 years, has been used in this way for 30 years. One might think we would know all there is to know about the use of this agent for this indication. However, in fact, we know very little. Several years ago, we briefly reviewed this subject, but the focus was on the various settings in which high-dose melphalan and autologous HCT were used. 1 In this present review, we will not discuss the role of high-dose melphalan in HCT but would direct readers to an excellent recent review on this topic. 2 Instead, we will use that review as our starting point for what we know about the pharmacokinetics (PK) of melphalan for high-dose therapy, in particular for myeloma, and how we may move forward. EARLY WORKHigh-dose melphalan has been in use for decades. The relatively few and reversible non-hematologic toxic effects make it suitable for high-dose therapy, whereas its profound marrow toxicity makes it unsuitable for repeated low-dose exposures. Today, most patients are naïve to melphalan exposure as it is only infrequently used as initial cancer therapy. The toxicity profile means that infusion of HPC can rescue or protect against most of the toxicity of the drug-hence, melphalan is the ideal agent for high-dose therapy with rescue by autologous HCT.Amongst the variety of solid tumours for which subjects first underwent HCT using melphalan were paediatric patients with neuroblastoma; these early reports garnered the inte...

“…Moreover, very few data on the outpatient ASCT management of MM patients with impaired renal function or other comorbidities are reported. 49,50 The expert panel selected a list of major criteria to enroll patients in an outpatient ASCT program. A set of specific questions was answered by each panel members and the results with the final list of inclusion/exclusion criteria are reported in the Supplementary File.…”

Section: Operative Questionsmentioning

confidence: 99%

Italian consensus conference for the outpatient autologous stem cell transplantation management in multiple myeloma

Martino¹,

Lemoli

Girmenia

et al. 2016

Multiple myeloma (MM) is the leading indication for autologous stem cell transplantation (ASCT) worldwide. The safety and efficacy of reducing hospital stay for MM patients undergoing ASCT have been widely explored, and different outpatient models have been proposed. However, there is no agreement on the criteria for selecting patients eligible for this strategy as well as the standards for their clinical management. On the basis of this rationale, the Italian Group for Stem Cell Transplantation (GITMO) endorsed a project to develop guidelines for the management of outpatient ASCT in MM, using evidence-based knowledge and consensus-formation techniques. An expert panel convened to discuss the currently available data on the practice of outpatient ASCT management and formulated recommendations according to the supporting evidence. Evidence gaps were filled with consensus-based statements. Three main topics were addressed: (1) the identification of criteria for selecting MM patients eligible for outpatient ASCT management; (2) the definition of standard procedures for performing outpatient ASCT (model, supportive care and monitoring during the aplastic phase); (3) the definition of the standard criteria and procedures for re-hospitalization during the aplastic phase at home. Herein, we report the summary and the results of the discussion and the consensus. INTRODUCTIONMultiple myeloma (MM) remains the leading indication for highdose chemotherapy and autologous stem cell transplantation (ASCT) worldwide 1,2 and the International Guidelines recommend that ASCT should be offered at some point during the treatment program for a medically fit patient. 3,4 High-dose melphalan (HDM) at 200 mg/m 2 is the standard conditioning for ASCT 5,6 and, today, the treatment should be considered a safe procedure with a very low transplant-related mortality (TRM). 7-9 The significant increase in the waiting lists generated concerns about the appropriate use of health care resources and, over the past years, some studies have investigated the safety, efficacy and potential cost advantages of reducing hospital stay for patients undergoing ASCT. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] The ease of administering HDM, the relatively low extra-hematological toxicity and the short period of neutropenia 5,6 make MM patients ideal candidates for outpatient ASCT programs. Standardization of criteria for the outpatient ASCT policy is a relevant goal of the Italian hematology and transplant community and may facilitate comparison of retrospective and prospective data. The Italian Group for Stem Cell Transplantation (GITMO) endorsed a panel of 10 experts in the transplant field (MMa, RML, CG, LC, BB, MO, IL, MMo, GM and AO) to propose a consensus for the selection criteria and management of MM patients for ASCT procedure in the outpatient setting. METHODSA working group of 10 experts from 7 GITMO centers, with specific expertise in the field of ASCT, convened four times to: (a) identify common criteria for selecti...