Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study

Lahuerta, Juan José; Mateos, M. V.; Martínez‐López, Joaquín; Grande, Carlos; Rubia, Javier de la; Rosiñol, Laura; Sureda, A; García-Laraña, José; Dı́az-Mediavilla, Joaquı́n; Hernández-García, M; Carrera, Dolores; Besalduch, Joan; Arriba, Felipe de; Oriol, Albert; Escoda, Lourdes; García-Frade, Javier; Rivas-González, Concepción; Alegre, Adrián; Bladé, Joan; Miguel, Jesús F. San

doi:10.3324/haematol.2010.028027

Cited by 103 publications

(72 citation statements)

References 46 publications

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“…The median number of days with ANC ⩽ 0.1, ⩽ 0.5 and ⩽ 1 × 10 9 /L was 3 (range 2-8), 5 (range 3-10) and 6 (range 3-13), respectively. The median duration of hospitalization after stem cell infusion was 16 days (range [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The engraftment kinetics observed for BENDA plus HDM conditioning at second transplant were similar to those reported previously with the first HDM (200 mg/m 2 ) conditioning regimen ( Table 2).…”

Section: Study Populationsupporting

confidence: 72%

“…3,14 HDM at a dose of 200 mg/m 2 is considered to be the standard conditioning regimen. 14,17,18,30 However, a variety of strategies has been explored with the aim of improving the results of HDM 200 mg/m 2 , including dose escalation, 22 addition of other agents such as busulfan, thiotepa or TBI 14,15,[17][18][19][20][21][22] or, conversely, dose reduction as part of a tandem auto-SCT procedure, 20 with overall mixed results. Further evidence is however necessary on the best conditioning regimen.…”

Section: Discussionmentioning

confidence: 99%

“…Although many studies have been performed in the induction, consolidation and maintenance settings, few trials have been dedicated to conditioning regimens before ASCT; [14][15][16][17][18][19][20][21][22] and the current standard conditioning regimen is considered high-dose melphalan (HDM). 14 Bendamustine (BENDA) (Ribomustin/Levact; Mundipharma International Ltd, and Treanda; Cephalon) is a synthetic chemotherapeutic agent that combines the alkylating properties of a mustard group with the antimetabolic activity of a purine analog.…”

Section: Introductionmentioning

confidence: 99%

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A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

Martino

Tripepi

Messina

et al. 2016

Bone Marrow Transplant

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This phase II trial evaluates, for the first time, the safety and efficacy of bendamustine plus high-dose melphalan (HDM) as a conditioning regimen before the second autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM) patients. In total, 32 ASCT patients received HDM (200 mg/m 2 ) as conditioning for the first ASCT. After 3-6 months from the first ASCT, responding patients underwent a second ASCT following bendamustine (200 mg/m 2 ) and HDM (140 mg/m 2 ). High-dose chemotherapy and ASCT were performed with complete neutrophil and platelet recovery in all patients. The median number of days to neutrophil and platelet engraftment was 11 (range 9-15) and 12 (range 10-19), respectively. Only one subject experienced grade 3 diarrhea; the rate of mucositis and vomiting was significantly lower with the bendamustine plus HDM regimen compared with the HDM-only regimen (81.2 vs 96.9%, P = 0.025 and 78.1 vs 100%, P = 0.008). Overall response rate (ORR) was 81.2% after the first transplant, and 90.6% after the second, while complete response rates were 46.8 and 62.5%, respectively (P = 0.016). Actuarial 2-year PFS and OS were 79% (95% confidence interval (CI), 60-98) and 97% (95% CI, 91-100), respectively. Bendamustine+HDM is feasible as the conditioning regimen for second ASCT in MM patients. The present study may pave the way for phase III studies specifically aimed at further investigating this combination strategy. The role of this combination in MM for conditioning regimen in a first or single ASCT setting should be also investigated.

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Section: Study Populationsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

Martino

Tripepi

Messina

et al. 2016

Bone Marrow Transplant

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“…Regarding alkylating agents in combination with melphalan: oral busulfan is demonstrably too toxic, as 8% of patients in a Spanish study developed veno-occlusive disease, with a case fatality rate of 25% (Lahuerta et al, 2010). The intravenous busulfan formulation introduced in 2003 reduces hepatic exposure via the portal circulation, and a non-randomized study (n=153) comparing mel140 plus busulfan 9.6mg/kg i.v.…”

Section: Melphalan and Chemotherapeutic Agent Combinationsmentioning

confidence: 99%

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

Maybury

Cook

Pratt

et al. 2016

Biology of Blood and Marrow Transplantation

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SummaryConsolidation with high dose chemotherapy and autologous stem cell transplantation (ASCT) is the standard of care for transplant eligible patients with multiple myeloma, based on randomised trials showing improved progression free survival with autologous transplantation following combination chemotherapy induction. These trials were performed before novel agents were introduced, and subsequently combinations of immunomodulatory drugs (IMiDs) and proteasome inhibitors as induction therapy have significantly improved rates and depth of response. Ongoing randomised trials are testing whether conventional autologous transplantation continues to improve responses following novel agent induction. While these results are awaited, it is important to review strategies for improving outcomes following ASCT. Conditioning prior to ASCT with higher doses of melphalan, and combinations of melphalan with other agents, including radiopharmaceuticals have been explored. Tandem ASCT, consolidation and maintenance therapy following ASCT have been investigated in phase III trials. Experimental cellular therapies using ex vivo primed dendritic cells , ex vivo expanded autologous lymphocytes, KIR-mismatched allogeneic NK cells, and genetically modified T cells are also in phase I trials to augment ASCT. This review summarises these strategies and highlights the importance of exploring strategies to augment ASCT even in the era of novel agent induction.

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“…72 Although the introduction of i.v. BU may lower the TRM, 73 perhaps adult physicians can learn from the neuroblastoma experience.…”

Section: Addition Of Other Agentsmentioning

confidence: 99%

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

Shaw

Nath

Lazarus

2014

Bone Marrow Transplant

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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...

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Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study

Cited by 103 publications

References 46 publications

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

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

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