Bone Marrow Transplantation (2014) 49, 1457–1465 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt

REVIEW

Not too little, not too much—just right! (Better ways to give high dose melphalan) PJ Shaw1,2, CE Nath1,3 and HM Lazarus4 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/m2, 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. Bone Marrow Transplantation (2014) 49, 1457–1465; doi:10.1038/bmt.2014.186; published online 18 August 2014

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 WORK High-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 interest of both paediatric and adult transplanters in its broader application.3–6 Interestingly, the initial report of its use in myeloma was 30 years ago, and was to support a second course of melphalan 140 mg/m2.7 High-dose melphalan is relatively well tolerated as a single agent at a total dose of 200 mg/m2. Myeloablation requires doses of 180 mg/ m2 or more, as patients ultimately will recover haematopoietic (and gut) function within 30 days of exposure to 140 mg/m2 without HPC rescue.7–9 The dose of 200 mg/m2 that was adopted by the Arkansas group is now widely used.10

MELPHALAN ELIMINATION Melphalan is eliminated by both renal excretion and spontaneous chemical degradation to its mono- and di-hydroxy metabolites.11,12 The latter pathway is a relatively minor contributor (o 5%) because plasma protein binding retards the hydrolysis rate of melphalan.13 However, melphalan undergoes rapid decomposition in urine, leading to a highly variable percentage of a dose that can be recovered from urine over a 24-h collection period. This has led to some confusion about the role of renal function in melphalan elimination. The fact that it was possible to recover more than 60% of the dose in three (of nine) patients in one study suggests that renal excretion is likely to be the major elimination pathway for melphalan.12 Population PK analyses have also identified renal function as a significant determinant of melphalan clearance,14,15 with renal clearance estimated to be approximately 40%.15

1 Departments of Oncology The Children’s Hospital at Westmead, Westmead, New South Wales, Australia; 2The Department of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia; 3Biochemistry The Children’s Hospital at Westmead, Westmead, New South Wales, Australia and 4Department of Medicine, Division of Haematology-Oncology, University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Cleveland, OH, USA. Correspondence: Professor PJ Shaw, Head, BMT Unit, Department of Oncology, The Children’s Hospital at Westmead, Westmead, New South Wales, 2145, Australia. E-mail: [email protected] Received 15 October 2013; revised 6 June 2014; accepted 18 June 2014; published online 18 August 2014

Bone Marrow Transplantation (2014) 1457 – 1465

Standard high-dose melphalan improved disease response compared with lower doses as a risk adjustment strategy Melphalan 200 mg/m2 dose associated with more mucositis and better PFS than 100 mg/m2 dose Abbreviation: HCT = haematopoietic cell transplantation.

298 Plasma cell myeloma 23

22

Amyloidosis

171

High- and intermediate-dose melphalan (100–200 mg/m2) High- and intermediate-dose melphalan (100–200 mg/m2) Melphalan 200 mg/m2 versus 100 mg/m2 421 Amyloidosis 21

High-dose melphalan (200 mg/m2) 96 Plasma cell myeloma 19

27

80

Diffuse large B cell lymphoma Plasma cell myeloma 18

16

17

High-dose melphalan (220 mg/m2)

High mg/kg melphalan dose and high serum creatinine were identified as significant risk factors for the development of severe (grade 3 or 4) oral mucositis Mucositis worse and hospitalisation longer in patients whose melphalan dose was 43.6mg/kg Melphalan 220mg/m2 (with forced diuresis) associated with more mucositis than seen with lower dose Impaired renal function gave significantly higher incidence severe oral mucositis, diarrhoea and infection OS, EFS and CR rate better with melphalan 200 mg/m2 than 100 or 140 mg/m2 High-dose melphalan (200 mg/m2, reduced to 140 mg/m2 for serum creatinine 43 mg/dL BEAM prior to autologous HCT 381

Melphalan 200 and 140 mg/m2 81

Plasma cell myeloma with renal failure Plasma cell myeloma

Details of conditioning Number of patients Reference Disease

Indirect indicators of melphalan pharmacodynamics

UNDER-UTILIZATION OF PK STUDIES The data summarised above, and in Tables 1 and 2, support the hypothesis that low melphalan blood concentrations will be associated with less toxicity but less efficacy, whereas it is plausible that high concentrations will result in the reverse. This observation is in the context of a generally accepted ‘limit’ of 200–220 mg/m2 with haematopoietic growth factor support after autologous HCT. As some of these PK studies for melphalan extend over 25 years, why are there so few? In part, as the toxicity of this drug is relatively mild, there was little impetus to refine the dose for safety reasons, in contrast to drugs such as BU, for example. In essence, BU is the only agent used in myeloablative regimens for HCT for which therapeutic drug monitoring has been widely used, because of significant intra- and inter-patient variations in PK behaviour, as well as marked differences in blood concentration when comparing oral with i.v. administration.35 Further, BU is given on multiple days in the conditioning regimens, unlike the one or two doses of high-dose melphalan. So, despite the melphalan assay being relatively reproducible and easy to perform (see below) compared with the BU assay, there are far more reports of BU PK monitoring in transplantation than of melphalan.

Comment

PK STUDIES There are also a number of PK studies on melphalan that have related high melphalan exposure with either increased toxicity,6,14,15,24 improved efficacy25 or no obvious discernable effect;26–28 these studies are summarised in Table 2. Kühne et al.15 studied 84 adults with mixed diagnoses (but mainly myeloma) at melphalan doses ranging from 10 to 200 mg/m2. They found that melphalan area under the concentration-time curve (AUC) was significantly associated with the development of oral mucositis and diarrhoea. In our study of 100 myeloma patients, all treated at high doses, melphalan AUC was significantly higher in patients with ⩾ grade 3 oral mucositis and those with long hospital admissions.14 Many of the PK studies summarised in Table 2 report wide variability in melphalan clearance. Up to a sixfold variation in the AUC results was noted in patients receiving the same mg/m2 dose.14,15,25,26,29 Renal function affects melphalan clearance,14,12,29 and PK interactions have been reported with carboplatin30,31 and furosemide,32 both drugs that are eliminated by renal excretion. In patients with severe renal insufficiency (creatinine clearance o 40 ml/min), haemodialysis ensures that melphalan clearance is similar to those with normal renal function.33 Many other studies and observations tell us that patients with renal impairment can receive high-dose melphalan relatively safely. In fact, some subjects even showed improved renal function subsequently, but none of these reports included PK analysis that allows us to comment on what drug exposure was achieved.34

20

INDIRECT INDICATORS OF MELPHALAN PHARMACODYNAMICS As melphalan dose and renal function are both determinants of melphalan exposure, those studies identifying these factors as important determinants of outcome or toxicity are indirect indicators of melphalan PK. The results from key studies are presented in Table 1. In summary, high melphalan dose (expressed as mg/kg or mg/m2) and/or renal impairment are significant risk factors for severe oral mucositis.16–20 However, high-dose intensity also is associated with improved disease response.21,22 Palumbo et al.23 reported improved PFS with melphalan 200 mg/m2 rather than melphalan 100 mg/m2, but increased gastrointestinal toxicity was noted.

Table 1.

1458

More organ toxicities after 200 mg/m2 melphalan

Better ways to give high dose melphalan PJ Shaw et al

© 2014 Macmillan Publishers Limited

Better ways to give high dose melphalan PJ Shaw et al

150 or 180

21 adults

9 children

Various cancers

Solid tumours 28

20–40

20 adults Various cancers

27

26

64 adults Various cancers 25

7.9– 30.2 mg (mg/m2 dose not given) 20–30 24-h i.v. infusion 140 7 adults 24

10–200 84 adults

Myeloma lymphoma, other Ovarian cancer 15

115–216 100 adults Myeloma 14

© 2014 Macmillan Publishers Limited

Abbreviations: AUC = area under the concentration-time curve; CI = confidence interval; CV= coefficient of variation; GI = gastrointestinal; PSA = prostate specific antigen.

High melphalan AUC associated with haematologic recovery and GI toxicity High AUC associated with ⩾ grade 3 oral mucositis and long hospitalisations 33.06 L/h (95% CI: 25.8–42.3) Linear relationship with dose. AUC associated with development of mucositis and Values not given diarrhoea Not determined AUC within ± 15% target values of AUC correlated with relative leucocyte decrease between 0.5 and 1.25 mg/L.h 20.1 L/h (45.3%) AUC normalised to 40 mg dose was High AUC associated with larger decreases in PSA 2.03 mg/L.h levels in patients with prostatic adenoma 32.9 ± 18 L/h/1.73 m2 8.9 ± 3.4 range: 2.9–18.1 No association between myelosuppression or nonhaematologic toxicities and AUC Dose CL mg/m2 L/h/m2 20 Dose AUC mg/m2 mg/L.h 20 No association between AUC and haematologic 11.5 ± 3.8 30 10.7 ± 2.3 40 8.5 ± 2.4 1.9 ± 0.6 30 2.9 ± 0.9 40 5.1 ± 1.5 toxicity 21.4 ± 5.9 L/h/m2 Survivors had lower clearance than patients who died (Po0.05)

Course 1: 18.3 ± 3.4 L/h/m2 Course Course 1: 5.7 ± 1.1 Course 2: 2: 20.8 ± 5.3 L/h/m2 5.0 ± 1.1 27.8 L/h (34%) median: 14.4 L/h/m2 Median: 12.8 range: 4.9–24.4 21 children 100 Solid tumours 6

Melphalan clearance mean ± s.d. (% CV) Melphalan dose (mg/m2) No. Pts Reference Disease

Table 2.

A summary of key pharmacokinetic/pharmacodynamic studies on intravenous melphalan

Melphalan exposure, AUC (mg/L.h) mean ± s.d.

Melphalan exposure-outcome associations

1459 Attempting to apply therapeutic drug monitoring to melphalan in myeloma is limited by the absence of repeated exposure to the drug over long periods of time, with opportunities to look at the dose–response or dose–toxicity profile and modify accordingly. For a single dose of melphalan where this is not applicable, the only option is to use a test dose strategy. This approach has also been used in the past, so it could be considered in myeloma, if it was believed to be of benefit. This strategy requires: (1) High-dose melphalan continues to be required in the therapeutic regimen, particularly in myeloma. (2) Suggestion of benefit in avoiding low, or high blood concentrations, or both. (3) A linear association between melphalan dose and AUC, which is reproducible between the administration of the test and full doses. (4) An assay for determination of plasma melphalan concentrations which is rapid, sensitive and simple at the levels expected after a test dose. These requirements raise corresponding questions, to which we offer answers here.

(1) Does high-dose melphalan still have a role in myeloma? If its use is about to die out, we need not start this endeavour. As mentioned in many current reviews, even in responding patients, high-dose melphalan provides an additional benefit to most patients and the most recent review even suggests targeting exposure is worthwhile.2 Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) show us that the use of high-dose melphalan, most often as a single agent, continues to be used in thousands of patients every year, with no suggestion of a reduction over time. (Tables 3a and 3b) (2) Are there hard data to suggest that higher dose exposure is beneficial—is there a therapeutic window? A previous review in this journal had suggested there was no clear association between any PK parameter and the occurrence of nonhaematological side effects at high doses of melphalan.36 The preceding non-PK work summarised above and in Table 2 suggests a relationship between dose and toxicity. Our own work, only published in abstract form to date, has shown that if one analyses a cohort of 115 patients with myeloma by exposure, then there was slightly more mucositis in those exposed to higher doses. So finally, hard data support what was assumed from looking at dose measured by mg/kg administered. Importantly, the EFS was 20% higher at 3 years in those exposed to more than the median value.37 (3) Is there a linear and reproducible association between melphalan dose and AUC? In a paediatric patient population, there was a linear association (r2 = 0.98) between mg/m2 dose (dose range: 10–180 mg/m2) and mean melphalan AUC.38 However, for a test dose strategy of melphalan dose Table 3a. Use of melphalan conditioning for autologous HCT in patients transplanted for plasma cell dyscrasias registered with the CIBMTR between 2010 and 2012, by year of transplant Year

2010

2011

2012

Total number

4650

5146

5186

Melphalan for conditioning Yes, single agent high dosea Yes, single agent low dose Yes, multiple agents No

3818 570 203 59

(82) (12) (4) (1)

Number (%) 4141 (80) 4094 (79) 686 (13) 753 (15) 260 (5) 313 (6) 59 (1) 26 (1)

High dose melphalan is defined as ⩾ 150 mg/m2.

a

Bone Marrow Transplantation (2014) 1457 – 1465

Better ways to give high dose melphalan PJ Shaw et al

1460 Table 3b. Distribution of melphalan conditioning for autologous HCT in patients transplanted for plasma cell dyscrasias registered with the CIBMTR between 2010 and 2012, by location of transplant center and year of transplant US centersa

Total number Melphalan for conditioning Yes, single agent high doseb Yes, single agent low dose Yes, multiple agents No

Non-US centers

2010

2011

4059

4567

3292 520 191 56

(81) (13) (5) (1)

3620 656 236 55

(79) (14) (5) (1)

2012

2010

2011

2012

4660

591

579

526

Number (%) 3645 (78) 703 (15) 293 (6) 19 ( o1)

526 50 12 3

(89) (8) (2) (1)

521 30 24 4

(90) (5) (4) (1)

449 50 20 7

(85) (10) (4) (1)

The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committee of the CIBMTR. aReporting of autologous transplants by US centers is voluntary; it is estimated the CIBMTR database includes 80% of the autologous transplants performed in the US between 2010 and 2012. bHigh-dose melphalan is defined as ⩾ 150 mg/m2.

optimisation to be successful, melphalan clearance needs to remain constant throughout the period from test dose to high dose. This means that the factors that affect melphalan clearance need to be controlled. Previous attempts at a test dose strategy failed when linearity between test and full dose was not achieved in patients receiving carboplatin,31,38 possibly because its use leads to daily changes in renal function. In an earlier study, successful predictions of full dose AUC values could only be obtained after modifying the protocol to ensure consistent use of furosemide, consistent melphalan infusion times and having the same individual collect all of the blood samples.39 Therefore, a test dose can be used to predict the AUC of a full dose of melphalan but only when renal function and concomitant medications are constant throughout the treatment period. Drugs identified as having a PK interaction with high-dose melphalan are listed in Table 4. Because both melphalan and carboplatin continue to be given together, detailed PK studies are still needed, and may also be needed for other drugs, in particular those eliminated mainly by the kidney. We are currently performing a pilot study examining whether test dose melphalan PK can be used to predict high-dose PK in patients with plasma cell myeloma and it includes collection of concomitant medication information (Trial number: ACTRN12613000487718 at www. anzctr.org.au) This requires a dose be given as a test dose and followed by a full dose. Although melphalan is frequently given over 2 days, there is a recent note of caution. Parmar et al.40 reported a single center, retrospective analysis examining melphalan given over 1 versus 2 days. They observed no significant differences in PFS or OS but noted that grade 3 or higher mucositis was significantly more frequent (13.5 versus 5.4%, P = 0.03) in the 2-day group. (4) Is there an accurate, precise, reliable, sensitive and simple assay for melphalan? There are numerous published highperformance liquid chromatographic assay methods for measuring melphalan concentrations in plasma.41–46 These have detection limits ranging from 10 to 100 ng/mL, depending on the specifics of the method of detection. Sensitive liquid chromatography–tandem mass spectrometric assays are now available, with detection limits less than 10 ng/mL.47 When embarking on a test dose strategy, it is critical that the assay is sensitive and reproducible at the low levels used for a test dose when compared with the full dose. The sensitivity is not as important if, for example, one built on those protocols that split the 200 mg/m2 into two days of 100 mg/m2, but nonetheless, a rapid reliable assay is still essential. Bone Marrow Transplantation (2014) 1457 – 1465

Therefore, if we are able to demonstrate a split dose or test dose strategy that allows targeting of a desired melphalan exposure and this is associated with an optimal outcome, then we will have established a method for optimising high-dose melphalan in myeloma. Once we have achieved that goal, where next? If we do accumulate a larger cohort of adults with myeloma given single agent melphalan with PK analysis, then this data set could go a long way towards answering continuing questions regarding optimal dosing for patients in high-risk populations. DOSING IN HIGH-RISK POPULATIONS There are three situations where a PK-guided dose may assist patient management; dosing in renal impairment, in obese patients and in older patients. DOSING IN RENAL IMPAIRMENT As cited above, we know that renal function affects melphalan clearance,14,12 and haemodialysis restores normal melphalan clearance.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/m2; 21 (11 on dialysis) subsequently were treated at a lower melphalan dose of 140 mg/m2. Dialysis dependence and melphalan dose did not affect EFS or OS. The investigators noted that the lower melphalan dose had an acceptable toxicity and appeared equally effective as melphalan 200 mg/m2. Grazziutti et al.17 observed increased melphalan exposure with increased dose in the setting of renal insufficiency; such a situation led to an increased risk of severe mucositis. In both of these studies, accompanying PK data would provide a better guide to dose modification in the face of renal impairment. Equally, a PK-guided dose may reveal under-dosing of patients with normal, or good, renal function. DOSING IN OBESE PATIENTS This issue is of particular importance with our current epidemic of obesity and the fact that plasma cell myeloma is recognised as an ‘obesity-associated malignancy’. In an observational database of 1087 myeloma autotransplant recipients given high-dose melphalan, with or without TBI, obese patients were more likely to receive a reduced melphalan dose, but this manoeuvre did not appear to affect PFS.48 These authors concluded, as did Bubalo et al.,49 that further research is necessary to optimise dosing of © 2014 Macmillan Publishers Limited

Better ways to give high dose melphalan PJ Shaw et al

1461

PHARMACOGENOMICS Although melphalan is subject to conjugation by glutathione S-transferases, because of its high level of spontaneous degradation and renal excretion, there is less likely to be a role for this conjugation to determine toxicity or response than, for example, the conjugation of BU. Melphalan is conjugated by glutathione S-transferases that have polymorphisms; there is a polymorphism in GSTP1 that modulates outcome of myeloma with a low-dose melphalan containing regimen, but not high-dose melphalan.52 Kühne et al.15 found little evidence of any association between glutathione S-transferase polymorphisms and gut toxicity. Polymorphisms of transporters of melphalan into the cell were also not correlated with toxicity or PK.53 As published in this journal, Dumontet et al.54 studied 209 SNPs in 95 genes involved in drug metabolism, DNA repair, apoptosis and cell cycle regulation in 169 patients with myeloma and found polymorphisms in genes associated with disease response, severe mucositis or death after high-dose melphalan. There is much interest in genetic variations that might impact on treatment in myeloma (reviewed in Vangsted et al.55) and so long as future studies include PK analysis of melphalan with these genomic studies, we will be well placed to assess the contribution of these polymorphisms to melphalan exposure. BUILDING ON A PLATFORM OF HIGH-DOSE MELPHALAN Discussion of interventions such as high-dose melphalan in tandem versus single autografts, further high-dose melphalan after relapse (after prior autograft) and allogeneic transplant are well beyond the scope of this brief review. But we can comment further on what building blocks may add to the foundation of high-dose melphalan and HCT.

Table 4. Agent

0.18 0.16 0.14 0.12 0.1 0.08 0.06 0.04 0.02 0 pts.

181 83 87 112 99 102 123 111 143 155 173 187 173 214 214 227 177 204 183 174 194

DOSING IN ELDERLY PATIENTS In a preliminary communication, Sharma et al.51 also used registry data to explore the issues relating to adjusting melphalan dose according to age by comparing relative transplant efficacy in three cohorts: age ⩾ 70 years (n = 946); age 60–69 years (n = 4666) and age 18–59 years (n = 5818). The older age cohort was more likely to receive melphalan dose reduction as 42% received o180 mg/m2. Although transplants were performed less frequently in the older patients, efficacy was equivalent to the other agent groups and was associated with low non-relapse mortality. Survival differences were driven partly by higher co-morbidities and lower post-relapse survival; yet, outcomes were similar when older patients were appropriately selected for aggressive therapy. So again, PK-guided studies may optimise therapy in this increasing patient population.

Melphalan for injection has marginal solubility and limited chemical stability upon reconstitution and dilution. Further, the propylene glycol solubilizer potentially can contribute to side effects including renal dysfunction, arrhythmias, hyperosmolality, increased anion gap metabolic acidosis and sepsis-like syndrome; these effects limit the ability to deliver higher doses of melphalan. One strategy to improve drug safety and efficacy is to reformulate melphalan using a proprietary (Captisol) brand of β-cyclodextrin sulfobutyl ethers that have been used in other medications such as voriconazole and amiodarone. In a preliminary communication, Aljitawi et al.56 demonstrated in a recent phase IIa open-label, randomised, cross-over design study that the PKs of propylene glycol-free melphalan was statistically bioequivalent (using geometric means of AUC) to melphalan in myeloma patients undergoing autologous HCT. Potentially, the reformulated melphalan agent has improved stability and can be administered using slower infusion rates and longer administration durations. An additional benefit may be the avoidance of the rare melphalan recall reaction occasionally seen in AL amyloid patients and those myeloma patients undergoing second, salvage transplants; this adverse event may be related to the propylene glycol and, in theory, could be avoided.57 From the paediatric literature, we can already see what can be achieved in building on a platform of single-agent high-dose melphalan in neuroblastoma, the commonest paediatric indication for autologous HCT. Modern, cisplatin-based chemotherapy provided for relatively poor long-term survival in neuroblastoma,58 but this result was improved significantly with the addition of a single high-dose of melphalan and HCT.59 Attempts to intensify the melphalan were associated with what was a high TRM, when this was a ‘kill or cure’ strategy (Lodenstein et al. 60 Figure 1), but a subsequent randomised controlled trial confirmed the value of a melphalan-based combination including TBI, when compared to three courses of intensive multiagent chemotherapy.61 This study also confirmed the benefit of the randomised addition of retinoid therapy post transplant, confirmed with much longer follow-up.62 Subsequent studies simplified the intensity of the conditioning; dropping the TBI and using two or three drugs.63,64 As the importance of the high-dose block of therapy has evolved from a ‘kill or cure’ approach to a cytoreductive cassette in overall therapy, the TRM has fallen from over 10% in an earlier era to the current 2%.63 100-day cumulative incidence of transplant related mortality

chemotherapy in obese patients. Within our own patient cohort, we demonstrated that across a broad range of BMI, in a subset of patients with normal renal function, use of actual body weight to calculate a surface-area-based dose was at least as accurate as any other technique of capping or modifying dose for the patients’ weight.50

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 Year of HDT

Figure 1. 100-day TRM and year of high-dose procedure for neuroblastoma (with permission, from Ladenstein et al.60).

Pharmacokinetic drug Interactions with high-dose i.v. melphalan Effect

Mechanism

Reference

Carboplatin Increases plasma concentrations of melphalan Reduces melphalan clearance, possibly by reducing renal clearance Cisplatin Increases plasma concentrations of melphalan Cisplatin induces renal dysfunction, which reduces melphalan clearance Furosemide Decreases plasma concentrations of melphalan Increases melphalan clearance, possibly by increasing renal clearance

30,31

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83 32

Bone Marrow Transplantation (2014) 1457 – 1465

Better ways to give high dose melphalan PJ Shaw et al

1462 In myeloma, because we are starting with what by transplant standards, is a ‘safe’ treatment, this lends itself to serve as a platform for additional therapies. Initial escalation of ‘high’ dose from 140 to 180 mg/m2, with HPC rescue, was associated with the usual pattern of mucositis. Escalation of melphalan dose under the protection of amifostine led to rapidly reversible marrow toxicity and mucosal toxicity was significant, but not dose-limiting in most cases.65 The occurrence of atrial fibrillation and hepatic toxicity in a small number of cases at a dose of ⩾ 280 mg/m2 led the authors to suggest that a dose of 280 mg/m2 was relatively safe. The rate of overt cardiac toxicity is low with standard melphalan 200 mg/ m2 in myeloma,23,66 even with repeated doses, although subtle abnormalities are detectable with sophisticated testing.67,68 In the absence of amifostine, two patients treated at 220 mg/m2 had (reversible) atrial fibrillation18 and, with the addition of palifermin, dose-limiting cardiac toxicity in two of six patients at a dose of 280 mg/m2.69 Thus, with use of gut-protecting agents, cardiotoxicity at doses beyond 200 mg/m2 seems to be dose-limiting. Although these studies show that higher doses of melphalan can be given, it is unfortunate that these studies did not include PK analysis, so we do not know if the amifostine or palifermin had any Table 5.

effects on the exposure to melphalan and whether these other toxicities were related to exposure or not. Thus further studies combining such protectants with PK may still be worth exploring. Simply increasing the dose without PK control is probably too unsophisticated for us to tease out the benefit of more subtly modifying melphalan exposure. ADDITION OF OTHER AGENTS Another strategy that is already widely employed in autologous HCT is adding additional agents to melphalan. Although this approach is still relatively unused in myeloma (Tables 3a and 3b), there is already a strong track record, for example, of combining BU with melphalan in Non-Hodgkin's Lymphoma, as well as myeloma, and even building additional agents onto a BU–melphalan backbone. This topic has been reviewed recently, so we will not discuss it in detail here.70,71 However, even if we achieve dose optimisation of melphalan, as it is such a welltolerated conditioning regimen, the additional 5% TRM from, for example, oral BU plus i.v. melphalan, is probably too much in a disease (myeloma) that has so many developing pre- and post-

Agents that have been combined with high-dose MEL in conditioning

Agent

Action

Pazopanib

Inhibitor of VEGF receptor. Low doses demonstrate synergistic cytotoxicity with MEL in vitro

84

Proteasome inhibitor. Potential synergy with alkylating agents in inducing plasma cell apoptosis

78

Bortezomib

Reference Results

85

86

87

79

88

In mouse xenograft model for myeloma, pazopanib increases apoptosis of human myeloma cells No activity as single agent in relapsed/refractory myeloma In vitro cytotoxicity better when MEL preceded bortezomib Matched pairs analysis of 46 patients given bortezomib pre and post MEL 200 mg/m2 showed higher CR rate than 115 controls Phase I/II dose escalation of bortezomib preceded by MEL 100 mg/m2 × 2 days. Planned dose of 1.3mg/m2 well tolerated. Bortezomib downregulated mRNA expression in DNA repair pathway FANC F and BRCA2 Bortezomib pre high dose MEL in 17 patients compared with 17 controls. Bortezomib group had no more toxicity and more likely to show VGPR BU/MEL/bortezomib (n = 43) as BU i.v. target AUC 20 000 mM* min plus MEL 140 mg/m2 and bortezomib 1.6 mg/m2 Improved NRM, relapse and PFS at 1 year but similar 2-year OS compared with contemporaneous registry cohort (n = 162) receiving MEL 200 mg/m2 Cell lines and SCID model, no clinical cases

Histone deacetylases Irradiation

Vorinostat enhances effects of MEL in MM cell lines and a murine xenograft model Addition of TBI too toxic

82 66

MEL 200 mg/m2 was less toxic than MEL 140 mg/m2 combined with 8Gy TBI

Radionuclides

166

89

166 Ho given with MEL 140 or 200 mg/m2 or 140 mg/m2 with TBI 8Gy. Nephrotoxiciy and bladder toxicity associated with high dose exposure 166 Ho given 7–10 days prior to MEL 200 mg/m2 (+/ − 8Gy TBI) versus 63 patients given MEL 200 mg/m2 alone. Outcome appeared better when the radiation dose received was lower ( o2400 mCi) 46 patients treated with a dose of 153Sm targeted to provide a red marrow dose of 40Gy, combined with MEL 200 mg/m2 compared with 102 treated with high-dose MEL alone; similar toxicity and outcome 48 myeloma patients given MEL 200 mg/m2+AA+ATO. No DLT

Ho localises to the skeleton

90

153

91

ATO induces apoptosis of myeloma cell lines through generation of ROS; enhanced in presence of AA. Helps overcome resistance to MEL

92

Sm localises to bone

Arsenic

93

58 patients given MEL 200 mg/m2+AA+ATO and graded bortezomib; safe and well tolerated

Abbreviations: AA = ascorbic acid; ATO = Arsenic trioxide; AUC = area under the concentration-time curve; DLT = dose limiting toxicity; 166Ho = 166Holmium; NRM = non-relapse mortality; MEL = melphalan; ROS = reactive oxygen species; 153Sm = 153Sumarium; VGPR = very good PR.

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consolidation therapies.72 Although the introduction of i.v. BU may lower the TRM,73 perhaps adult physicians can learn from the neuroblastoma experience. To bypass the phase of escalating consolidation therapy (with accompanying mortality) would keep the autograft as safe as possible. Logic says that keeping the patient in good shape will allow him/her to benefit from the array of biological therapies that have the best chance of working when we have achieved a state of minimal residual disease. Again returning to our neuroblastoma model, the addition of post-HCT immunotherapy has increased 2-year EFS by 20%.74 Furthermore, the patient’s rapid recovery from the effects of high-dose melphalan allows introduction of novel therapies very early post HCT. Specifically, the immunodepletion that occurs early post HCT opens a window for immunotherapy,75 using monoclonal Ab therapy for myeloma76 as well as cellular immunotherapy, which has been reviewed recently in this journal.77 What about radiotherapy? The lack of superiority and additional toxicity when conventional irradiation is given as TBI means this has fallen out of favour,66 as it has in neuroblastoma. However, more sophisticated use of irradiation is being explored (Moreau et al.71 and Table 5). Retrospective comparison data suggest these treatments are feasible and safe; whether they add to the outcome resulting from the high-dose melphalan alone remains to be tested in prospective studies. And whether these treatments permit, or delay, the possibility of introducing additional therapies post HCT remains to be explored. Therefore, rather than adding to the intensity of the melphalan conditioning, are other therapies synergistic? Again, it is not our role to discuss the lengthy series of agents that are used post HCT. Candidate agents that could be given during the high-dose therapy procedure are shown in Table 5. For example, as well as its role in induction and relapse therapy, we know that bortezomib can be given in conjunction with high-dose melphalan, without adding to the toxicity. Studies show evidence of enhanced plasma cell apoptosis,78 and perhaps even a suggestion that patients may be more likely to achieve very good PR.79 These studies also considered the schedule dependency of the apoptosis induced by melphalan, with better results when the bortezomib was given after the melphalan78,80 although the former downregulates the DNA repair pathways. One might expect prior bortezomib therapy to be optimal; some protocols use bortezomib both pre and post melphalan—clearly an area for further study. Although histone deactylase inhibitors (reviewed in Kaufman et al.81) also enhance the effects of melphalan in myeloma cell lines and murine xenograft models,82 it remains to be tested whether this approach will result in a meaningful benefit in the context of the high-dose melphalan therapy. WHERE DO WE GO FROM HERE? Despite the growth of multiple new drugs targeting myeloma, the simple fact is that in the US in 2010 to 2012, of 13 286 autologous HCTs for plasma cell disorders reported to the CIBMTR, 10 557 of these procedures used single-agent, high-dose melphalan (Tables 3a and 3b). In addition to multiple drugs being used as maintenance and minimal residual disease treatments, cytoreduction continues to play an important role in the overall treatment plan. With other therapies available, it is important we keep the melphalan autograft as safe as possible; however, it is also valuable to maximise the effectiveness of this agent. New strategies appear to include improving the safety of melphalan, either by use of a less toxic propylene glycol-free preparation, or by tailoring drug delivery to the individual patient, through knowledge of it’s PK and pharmacogenomics. It seems incongruous that after 30 years of clinical use, at a time when new drugs are available, we are still trying to work out how best to use the first drug. Let us hope that, despite our attention being drawn to these new, expensive, agents, we can still © 2014 Macmillan Publishers Limited

1463 maximise the benefit of our oldest, cheapest, treatment. When we have achieved this goal, we will be in the best position possible to use emerging drugs and technologies to push the survival curve of myeloma even higher, with the goal of making this disease-free survival, rather than simply OS. CONFLICT OF INTEREST Dr Shaw and Dr Nath have received funding from the National Heath and Research Council for their work on melphalan pharmacokinetics in myeloma Dr Lazarus declares no conflict of interest

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