Health Policy Advisory Committee on Technology

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1 Health Policy Advisory Committee on Technology Technology Brief Update Theralite for renal failure in patients with multiple myeloma November 2014

2 State of Queensland (Queensland Department of Health) 2014 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD HealthPACT@health.qld.gov.au Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, ip_officer@health.qld.gov.au, phone (07) Electronic copies can be obtained from: DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or cost-effectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This brief was prepared by Dr. Vicki Foerster for the Australian Safety and Efficacy Register of New Interventional Procedures Surgical (ASERNIP-S).

3 Technology, Company and Licensing TECHNOLOGY BRIEF UPDATE 2014 Register ID Technology name Patient indication WP094 Theralite Treatment of renal failure in patients with multiple myeloma Reason for assessment In 2012, a Technology Brief was completed to investigate the use Theralite filters for the removal of free light chains in patients with multiple myeloma (MM). In light of developing evidence on the subject, the Brief recommended that this technology be monitored for further evidence in 24 months. In line with this recommendation, the purpose of the current Update is to consider the evidence that has emerged since 2012, and determine whether this new evidence may provide additional information to inform policy decisions. Background Plasma cells are an important part of the immune system, and produce immunoglobulins that help to fight infections and disease. MM is a progressive cancer of the plasma cells, characterised by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact immunoglobulins (IgG, IgA, IgD or IgE) or free light chains (FLCs) (Gambro 2010). In healthy people, FLCs are rapidly removed from the circulation by renal clearance but in patients with MM, serum concentrations of FLCs may be several thousand times higher than normal. These high concentrations of FLCs cannot be effectively cleared by the kidney. They co-precipitate with local proteins to form waxy casts, block the flow of urine, cause interstitial inflammation, and result in cast nephropathy or myeloma kidney (Hutchison et al 2009). Up to 50 per cent of patients with MM have renal impairment at presentation, and 10 to 20 per cent become dependent on dialysis, most requiring dialysis long-term. Unfortunately, traditional haemodialysis (HD) is minimally effective, as FLCs are too large to move through the pores of standard dialysis membranes. Therefore, the management options for the severe renal failure experienced by 10 to 20 per cent of patients with MM are limited. Researchers from the University of Birmingham tested seven types of dialysers in vitro and found the Gambro HCO1100 to be superior. Model calculations suggested that the device might remove 90 percent of FLCs over 3-weeks, so the device was then evaluated Theralite for renal failure in patients with multiple myeloma update: November

4 in eight patients (in combination with chemotherapy); serum FLCs dropped by 35 to 70 per cent within two hours (Hutchison et al 2007). The Gambro device uses a unique membrane technology to target FLCs and other plasma components with a molecular weight of up to 45 kda, while ensuring effective retention of larger proteins with molecular weights greater than 60 kda such as clotting factors and immunoglobulins. The device is used with a HD machine, and one new device per treatment session is required (Gambro 2011). Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Australian Therapeutic Goods Administration approval Yes ARTG number (s): No Not applicable 2014 International utilisation COUNTRY Austria Australia Brazil Denmark Europe b Finland France Germany Italy New Zealand Slovenia Spain Sweden LEVEL OF USE Trials underway Limited use Widely diffused or completed a a Nine of these 15 countries contributed to a database reported by Hutchison et al (2012). b From the 2012 report: According to Grima et al (2011) in a cost-effectiveness analysis, [This] technology is commercially available and currently used in regular clinical practice in Europe and other parts of the world. Theralite for renal failure in patients with multiple myeloma update: November

5 Switzerland United Kingdom 2014 Evidence and Policy 2014 Safety and effectiveness Six case series studies were located evaluating Theralite (originally Gambro AB, Lund, Sweden; since mid-2013, Baxter International Inc., Deerfield, IL, USA) in patients with multiple myeloma (MM) and renal failure who are on dialysis. 1-6 The two largest studies 2, 4 are included in this update, along with two small case series from Australasia (n=4 to 6 patients) that have particular relevance to the local context (Table 1). 3, 6 The study by Marn-Pernat et al (2014) 4 was only available in a conference abstract, but it is included here because it was the second largest case series available at the time of writing. Table 1 Characteristics of included studies evaluating Theralite in patients with MM and renal failure Study/ Location, Treatment years Design (evidence level) N Patients; treatment Outcomes tracked; length of follow-up Conflict of interest Marn-Pernat Slovenia Tan et al New Zealand Khalafallah et al Australia Hutchison et al Australia & 8 European countries Case series (IV); unclear if prospective or retrospective Case series (IV); retrospective chart review Case series (IV); prospective Case series (IV); patient data submitted to an international database; assumed prospective 22 Patients with MM & renal failure who were dialysisdependent with FLC concentrations >500 mg/l; treatment included chemotherapy & HCO-HD with regional citrate anticoagulation 6 Patients with MM & renal failure who were dialysisdependent with biopsyproven cast nephropathy; treatment included chemotherapy & HCO-HD 4 Patients with MM & renal failure who were dialysisdependent; treatment included chemotherapy & HCO-HD 67 Patients with MM & renal failure who were dialysisdependent; treatment included chemotherapy & HCO-HD Change in FLC concentrations & dialysis independence; length of follow-up not reported Change in FLC concentrations & dialysis independence; follow-up till death or Aug Change in FLC concentrations & dialysis independence; Follow-up median 26 months (range months) Change in FLC concentrations & dialysis independence; length of follow-up not reported NR The authors declared no COI The authors declared no COI Study funded by manufacturer 7 of 8 authors received manufacturer support Table notes: COI=conflict of interest; FLC=free light chains; HCO-HD=high cut-off haemodialysis; MM=multiple myeloma; NR=not reported Theralite for renal failure in patients with multiple myeloma update: November

6 Marn-Pernat et al (conference abstract) Researchers in Slovenia reported on 22 patients with MM and renal failure who were dialysis-dependent and had FLC concentrations of more than 500 mg/l (91% had new MM presentation). In addition to chemotherapy, patients received Theralite HCO-HD every one to two days (2 to 24 sessions per patient). The researchers added regional citrate anticoagulation to minimise bleeding risk and decrease the adherence of blood constituents to the membrane, aiming for better dialyser performance. Length of patient follow-up was not reported. Safety No serious side effects were documented. Seven of 22 patients died (32%), however, this was reportedly not due to the use of Theralite (no additional details were provided). Efficacy Of the 15 patients who survived (length of follow-up unspecified), 10 patients (67%) became dialysis-independent. FLC concentration was reduced by 84 per cent. The authors noted that their use of regional citrate anticoagulation appeared to be effective and safe. Tan et al A retrospective chart review of patients at three Auckland hospitals was conducted to investigate whether those with myeloma cast nephropathy and renal failure had benefitted from the use of HCO-HD therapy. The six patients identified had a mean age of 66 years (range 61 to 74 years). Five were newly diagnosed with MM while one had plasma cell leukaemia. The median time from diagnosis to the start of chemotherapy and HCO-HD was 3.5 days (range 2 to 18) and 8.5 days (range 4 to 12), respectively. The median number of HCO-HD sessions was 8.5. The devices used were not reported, but it appears that three patients had haemodialysis using Theralite while the other three may have had Gambro s HCO 1100 (one patient as a single HCO 1100 device and the other two patients as a series of two HCO 1100 devices).all patients received the same chemotherapy regimen (cyclophosphamide, high-dose dexamethasone and bortezomib). Follow-up occurred until patient death or until August 2013 (median 7.5 months, range 4 to 61 months). Safety No significant adverse events were reported. At the end of the follow-up period three patients were surviving. Three patients had died one (a responder) of cancer at seven months, one (a non-responder) of cardiac disease at 60 months, and the third (a nonresponder) of MM and end-stage renal disease at eight months. Theralite for renal failure in patients with multiple myeloma update: November

7 Efficacy At six weeks post-treatment, FLC levels had decreased substantially in four patients (80% to 99% reduction), partially in one patient (37% reduction), and had increased (52%) in the remaining patient. Three of the six patients were alive at the end of the follow-up period (4, 6 and 32 months). Two were dialysis-independent (beginning at 3 and 27 days) and one required peritoneal dialysis. These three patients displayed the largest reductions in FLC levels. The researchers compared their 50 per cent success rate to the 71 per cent success rate in the case series of 19 patients reported in 2009 by Hutchison et al (2009b). In the Australian series however, patient FLC levels prior to treatment were 4.5 times higher. In conclusion, Tan et al noted that the added benefit of HCO-HD to current anti-myeloma therapies requires further evaluation before it can be adopted. (p. 434) Hutchison et al This international study was briefly reported in abstract form in the original 2012 Technology Brief 7 but has since been published. Sixteen centres in Australia and Europe (Austria, Denmark, Finland, Germany, Spain, Sweden, Switzerland and the United Kingdom [UK]) using high cut-off haemodialysis (HCO-HD) were invited to contribute anonymised information to an international patient database. HCO-HD was delivered using the Theralite device and/or, in a few cases, a related Gambro product called HCO The 67 included patients were treated at centres known to use HCO-HD for renal failure in MM. Thirteen centres entered data on one to three patients, and three centres (two in Germany and one in the UK) entered data on at least four patients each (unknown whether they were consecutive). Length of patient follow-up was not reported. The median time from diagnosis of renal failure to initiation of HCO-HD was five days (range 1 to 360 days). Patients received a median of 12 HCO-HD sessions (range 3 to 45 sessions). All but two of the 67 patients had an extended dialysis schedule longer than four hours and 48 per cent had sessions longer than six hours. Of the 67 patients (mean age 67 years), 75 per cent had a new diagnosis of MM and 25 per cent had relapsing or refractory disease. All but one received concurrent chemotherapy. The main outcome of dialysis independence was based on the clinical parameters of urine output and biochemical kidney function as assessed by the supervising nephrologist. Safety Hypotension, fever with negative culture, reversible muscle weakness, and thrombosis of central venous catheter, were reported in four patients (6%) from the small enrolment centres. No additional details on adverse events were provided. Theralite for renal failure in patients with multiple myeloma update: November

8 Efficacy In total, 42 patients (63%) became dialysis-independent. Factors that predicted independence were the degree of FLC protein reduction at day 12 (p=0.002) and day 21 (p=0.005), and the time to initiating HCO-HD after presentation (p=0.006). Patients who became dialysis independent had a median initial delay from diagnosis of renal failure to initiation of HCO-HD of 3.5 days. Those who did not become dialysis independent had a seven-day delay (p=0.005). Patients in the high enrolment centres (>3 patients) were more likely to become dialysis independent (71%), compared with those in low enrolment centres (1 to 3 patients) (42%) (p=0.03). This difference was attributed to more rapid initiation of HCO-HD therapy at the high enrolment centres. It is unclear whether dialysis independence was maintained as the length of follow-up was not reported. Khalafallah et al A small case series from a single institution in Tasmania, Australia, reported on the treatment of four patients (mean age 60 years; two males) with MM and renal failure who were dialysis dependent and had high FLC levels. Treatment included chemotherapy plus HCO-HD for 10 to 29 sessions over 16 to 57 days (and ongoing in one patient). Median follow-up was 26 months (range, 13 to 36 months). Safety No safety concerns were noted beyond those associated with conventional haemodialysis. Efficacy At follow-up, three of the four patients (75%) were dialysis-independent. These three were newly diagnosed with MM, whereas the non-responder had relapsing MM. The serum FLC concentration decreased dramatically in the three responders but increased in the non-responder. The researchers hypothesised that early treatment provided a greater likelihood of a patient becoming dialysis-independent. Economic evaluation No new economic information was located. Theralite for renal failure in patients with multiple myeloma update: November

9 2014 Ongoing research Searches of ClinicalTrials.gov and the Australian and New Zealand Clinical Trials Register located two ongoing randomised studies of Theralite (Table 2) Table 2: Trial Number Location Ongoing studies on Theralite for renal failure in patients with MM Design Interventions Status N Patients Estimated completion date ISRCTN EuLITE Denmark, Germany, UK Randomis ed controlled trial, multicentr e HCO-HD plus chemotherapy; standard HD plus chemotherapy Recruiti ng 90 Adults with symptomatic, newly diagnosed MM with acute renal failure who are dialysis dependent End date for recruitment postponed several times currently December 2014 NCT France Randomis ed controlled trial, multicentr e Four arms: - one pair of arms for different chemotherapy regimens - one pair of arms for Theralite plus chemotherapy vs. conventional high-flux dialyser plus chemotherapy Recruiti ng 284 Adults with MM and myeloma cast nephropathy and chronic renal failure who are dialysis dependent Estimated end date June 2015 Table notes: FLC=free light chain; HCO-HD=high cut-off haemodialysis; HD=haemodialysis; MM=multiple myeloma; UK=United Kingdom Detail about the two ongoing studies: ISRCTN is a manufacturer-funded, European study that started in The primary outcome measure is haemodialysis independence at three months. NCT is a government-funded French study ( Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy (MYRE) that started in The study has four arms: One pair of study arms assesses different chemotherapy regimens in patients with MM and renal failure related to myeloma cast nephropathy who are not dialysis dependent. One pair of study arms assesses chemotherapy plus either Theralite or a conventional high-flux dialyser (controls) in patients who are dialysis dependent. The primary outcome measure is haemodialysis independence at three months Other issues The Theralite device has not yet been approved by the United States Food and Drug Administration. Theralite for renal failure in patients with multiple myeloma update: November

10 The status of device marketing is unclear. Theralite was marketed by Gambro AB until Gambro s acquisition by Baxter International Inc. in , 9 Commercial information about Theralite is scanty and appears to be limited to the Gambro website Summary of findings The original HealthPACT Technology Brief (April 2012) was able to present only a small case series (n=19) 7 in which 68 per cent of patients achieved dialysis independence at a median follow-up of 360 days (range 150 to 630). In this Update, two slightly larger case series (n=67 and n=22) plus two small case series are presented. Dialysis independence was achieved in 50 to 75 per cent of patients, but the length of follow-up was unclear in two of the four studies. The safety of the device was not comprehensively reported. The status of device marketing and use is unclear because Gambro AB, the original marketer, was purchased by Baxter International Inc. in mid However, clinical trial registries report two ongoing randomised controlled trials of Theralite (one in Denmark, Germany and the UK, and the other in France) with recruitment end-dates of December 2014 and June 2015, respectively HealthPACT assessment The use of the Theralite filter for the treatment of renal failure in patients with multiple myeloma would depend on the palliative care approach of individual treatment centres and, to some extent, patient choice. In addition, the filters are considered to be an expensive treatment option, which may influence purchasing decision-making and limit diffusion of the technology. The current evidence-base is limited in that case series can only inform on the safety of the technology, rather than its effectiveness. As two randomised controlled trials are currently underway and it would be useful to incorporate the results of these studies into this brief when published to enable individual jurisdictions to make an informed decision in respect to the clinical use of the Theralite filter Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT website. Total number of studies: 4 Total number of Level IV studies: 4 Theralite for renal failure in patients with multiple myeloma update: November

11 2014 References 1. Borrego-Hinojosa, J., Perez-del Barrio, M. P. et al (2013). 'Treatment by long haemodialysis sessions with high cut-off filters in myeloma cast nephropathy: our experience'. Nefrologia, 33 (4), Hutchison, C. A., Heyne, N. et al (2012). 'Immunoglobulin free light chain levels and recovery from myeloma kidney on treatment with chemotherapy and high cut-off haemodialysis'. Nephrol Dial Transplant, 27 (10), Khalafallah, A. A., Loi, S. W. et al (2013). 'Early application of high cut-off haemodialysis for de-novo myeloma nephropathy is associated with long-term dialysis-independency and renal recovery'. MediterrJ Hematol Infect Dis, 5 (1). 4. Marn-Pernat, A., Benedik, M. et al (2014). 'High cut-off (theralite) citrate hemodiafiltration for treating acute kidney injury in multiple myeloma patients'. Nephrol Dial Transplant, 29, iii Martin-Reyes, G., Toledo-Rojas, R. et al (2012). 'Haemodialysis using high cut-off dialysers for treating acute renal failure in multiple myeloma'. Nefrologia, 32 (1), Tan, J., Lam-Po-Tang, M. et al (2014). 'Extended high cut-off haemodialysis for myeloma cast nephropathy in Auckland, '. Nephrology, 19 (7), Hutchison, C., Airia, P., Cook, M., Grima, D., (2009). Abstract # 1875: Improving outcomes in patients with renal failure secondary to multiple myeloma: Results from ChAR2M2, American Society of Hematology 51st Annual Meeting & Exposition, New Orleans, LA. Available from: ]. 8. Baxter (2014). Baxter completes Gambro acquisition. Available from: August 2014]. 9. Gambro (2013). The Gambro story. Available from: August 2014]. 10. Gambro, T. (2011). Theralite, Available from: Therapy/Theralite/[Accessed August 2014]. Theralite for renal failure in patients with multiple myeloma update: November

12 TECHNOLOGY BRIEF (APRIL 2012) Register ID Name of Technology Purpose and Target Group WP094 Theralite for treatment of renal failure in patients with multiple myeloma To remove serum free light chains in adult patients in renal failure due to multiple myeloma, thus aiming for dialysis independence and reduced morbidity and mortality Stage of Development in Australia Yet to emerge Established Experimental Established but changed indication or modification of technique Investigational Should be taken out of use Nearly established Australian Therapeutic Goods Administration Approval Yes ARTG number: No Not applicable International Utilisation COUNTRY LEVEL OF USE Trials underway Limited use or completed Australia Canada (assumed; regulatory approval granted) Europe c Germany Japan Slovenia United Kingdom Widely diffused Impact summary Gambro AB (Lund, Sweden) provides the Theralite High Cut-Off haemodialysis (HCO- HD) device with the aim of filtering free light chains (FLCs) from the serum of patients with multiple myeloma (MM) who are in severe renal failure. The technology would be made available through hospitals and dialysis centres as an alternative to traditional haemodialysis (HD) dialysers which have been found to be minimally effective. c According to Grima et al (2011) in a cost-effectiveness analysis, [This] technology is commercially available and currently used in regular clinical practice in Europe and other parts of the world. Theralite for renal failure in patients with multiple myeloma: February

13 Annually, about 1300 new cases of MM are diagnosed in Australia, and at least 10 percent of these patients will experience renal failure severe enough to require longterm HD. A single case series study (n=19) examined the impact of HCO-HD (plus chemotherapy). Thirteen patients (68%) completed the course of therapy and all 13 became dialysis-independent versus six patients who were unable to complete therapy as planned, only one of whom was able to regain renal function. A study update (67 patients, 16 dialysis centres, and 9 countries) reported that 63% of patients treated with HCO-HD became dialysis-independent versus the expected proportion of about 16 percent. A cost effectiveness analysis (CEA) used a lifetime decision tree model that followed patients from initial presentation for HD to death. A health system perspective was taken. The model predicted an average survival of 34 months for HCO-HD versus 20 months for standard HD; quality-adjusted life years (QALYs) were 22 months for HCO-HD versus 13 months for HD; and the expected costs of treatment were lower for HCO-HD, making it the dominant economic strategy. Background Plasma cells are an important part of the immune system, and produce immunoglobulins that help to fight infections and disease. MM d is a progressive cancer of the plasma cells, characterised by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact immunoglobulins (IgG, IgA, IgD or IgE) or free light chains (FLCs) (Gambro 2010). In healthy people, FLCs are rapidly removed from the circulation by renal clearance but in patients with MM, serum concentrations of FLCs may be several thousand times higher than normal. These high concentrations of FLCs cannot be effectively cleared by the kidney. They co-precipitate with local proteins to form waxy casts, block the flow of urine, cause interstitial inflammation, and result in cast nephropathy or myeloma kidney (Hutchison et al 2009). Up to 50 per cent of patients with MM have renal impairment at presentation, and 10 to 20 per cent become dependent on dialysis, most requiring dialysis long-term. Unfortunately, traditional HD is minimally effective, as FLCs are too large to move through the pores of standard dialysis membranes. Therefore, the management options for the severe renal failure experienced by 10 to 20 per cent of patients with MM are limited. Researchers from the University of Birmingham tested seven types of dialysers in vitro and found the Gambro HCO1100 to be superior. Model calculations suggested that the d Common clinical manifestations of MM are hypocalcaemia, anaemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulins (Gambro 2010). Theralite for renal failure in patients with multiple myeloma: February

14 device might remove 90 percent of FLCs over 3-weeks, so the device was then evaluated in eight patients (in combination with chemotherapy); serum FLCs dropped by 35 to 70 per cent within two hours (Hutchison et al 2007). The Gambro device uses a unique membrane technology to target FLCs and other plasma components with a molecular weight of up to 45 kda, while ensuring effective retention of larger proteins with molecular weights greater than 60 kda such as clotting factors and immunoglobulins. The device is used with a HD machine, and one new device per treatment session is required (Gambro 2011). Clinical Need and Burden of Disease Australian Institute of Health and Welfare (AIHW) data reported 1312 new cases of MM in 2008 (772 men and 540 women) (AIHW 2011). Patient numbers have been steadily increasing as the country s population grows, although the rate of myeloma as a proportion of all cancers has remained stable at about 1.2 percent. The incidence of the disorder rises with age and in 2008 peak age was years in both sexes. Of patients with newly diagnosed MM, 10 to 20 percent have dialysis-dependent acute renal failure caused by FLCs; of these, 80 to 90 percent require long-term renal replacement therapy. Early treatment using plasma exchange reduces serum FLC concentrations; however, randomised controlled trials (RCTs) have shown no evidence of renal recovery, attributed to low procedure efficiency (Hutchison et al 2007). Most patients remain on long-term dialysis, with a greatly increased morbidity and mortality compared with patients who remain dialysis-independent (Hutchison et al 2008a). Diffusion of technology Australia Theralite has been approved for use in Australia and is listed on the Australian Register of Therapeutic Goods (ARTG number ). Theralite is in limited clinical use in Australia. In Victoria, a two-year study of HCO-HD for the management of acute kidney injury from myeloma cast nephropathy was funded through a Victorian State Government New Technology grant (Ramessur et al 2011). It is likely that this study is part of the larger Chart Audit of Renal Recovery in Multiple Myeloma (CHAR 2 M 2 ) Study (Hutchison et al 2009b; Bridoux et al 2011, page 27), the results of which are discussed in this brief. Clinical expert opinion suggests that currently, the cost of this technology does preclude it from being widely implemented in many centres in Australia. Canada and the United States (USA) In Canada, Gambro s Theralite high cut-off dialyser was approved for marketing as a Class III device in November 2009 (Licence #81336) (Health Canada 2011). The device Theralite for renal failure in patients with multiple myeloma: February

15 has not received 510(k) approval from the USA Food and Drug Administration (FDA 2011), although the FDA granted a Humanitarian Use Device (HUD) designation to the Theralite membrane for the treatment of myeloma kidney in patients with MM(Gambro 2010). According to the manufacturer, this is the first step toward obtaining marketing approval in the USA (Gambro 2010). Europe Theralite HCO-HD technology has been commercially available since 2007 in Europe, according to the device manufacturer (Gambro 2010). Essentially all patient-related research to date has been conducted in the United Kingdom (UK) and an RCT in several countries including the UK and Germany is currently recruiting patients (planned enrolment is 90). A multicentre French RCT is also currently recruiting patients. According to Grima et al (2011) in a cost-effectiveness analysis, [This] technology is commercially available and currently used in regular clinical practice in Europe and other parts of the world. According to the manufacturer, Germany and Austria currently have forms of reimbursement in place for this technology, and in Switzerland a decision regarding full reimbursement is expected to be made shortly. Comparators To remove the over-abundance of FLCs from serum, the historical approach has been plasma exchange; however, its efficacy has not been established (Hutchison et al 2008b). FLCs are present in similar concentrations in serum, the extravascular compartment, and tissue oedema fluid, with the intravascular compartment containing only 15 to 20 percent of the total. Plasma exchange therefore has minimal impact (Hutchison et al 2007). In addition, standard dialysers are also ineffective when used to remove FLCs because their pores are too small to allow FLCs to pass through (Hutchison et al 2007; Gambro 2009). Safety and Effectiveness Issues Study description Only one small study was located (Hutchison et al 2009a), with patient overlap occurring with previous studies by the same authors (Hutchison et al 2007, Hutchison et al 2008a). This single-centre, prospective, case series pilot study (level IV intervention evidence) was undertaken between April 2006 and May 2008 in Birmingham, UK. The objectives of the study were: (a) to determine whether chemotherapy in combination with FLC removal by HCO-HD resulted in sustained reductions in serum FLC concentrations, and (b) to relate changes in serum FLC levels to renal recovery. Included in this study were 19 patients with MM and dialysis-dependent renal failure (egfr<15 ml/min/1.73 m 2 ) who demonstrated cast nephropathy on renal biopsy. Mean patient age was 60 years (range years) and 74 percent of patients were male. Treatment combined standard chemotherapy plus FLC removal using two Gambro HCO Theralite for renal failure in patients with multiple myeloma: February

16 1100 dialysers in series (Table 1). The dialysis schedule started intensively, tapered to six hours 3 times a week, and continued until the patient was independent of dialysis. Table 1 Overview of Hutchison et al (2009a enrolment) Study Type & Level of Evidence (See Appendix) Patient Enrolment Exclusion Criteria Treatment Protocol Prospective, observation al, open label, pilot study, level IV evidence n=19 adults w/ MM and dialysisdependent renal failure who demonstrated cast nephropathy on renal biopsy; 16 had de novo MM & 3 had relapsing disease 3 patients of 22 initially assessed were excluded due to relapsing disease not suitable for new therapies (2) and dementia (1) FLC: free light chain; HCO-HD: high cut-off haemodialysis; MM: multiple myeloma Effectiveness Standard chemotherapy + HCO-HD: Chemotherapy regimen: o De novo MM: high dose dexamethasone + cyclophosphamide, thalidomide & / or vincristine/doxorubicin o Relapsing MM: high dose dexamethasone + doxorubicin + bortezomib HCO-HD: FLC removal via 2 Gambro HCO1100 dialysers in series; schedule was 8 hours/day x 5 days, 8 hours alternate days x 12 days, then 6 hours 3 times/week, continued until patient was independent of dialysis Thirteen of 19 patients (68%) completed 6-weeks of uninterrupted therapy and all sustained early reductions in FLC concentrations, with a median reduction of 85 per cent (range 50-97%). The remaining six patients (32%) had chemotherapy interrupted, primarily due to infection, and none had sustained FLC reductions. Two of these six patients were able to restart chemotherapy within 6 weeks and two after 6 weeks. The remaining two patients died (one each of fungal pneumonia and intracranial haemorrhage). All 13 patients with early FLC reduction became independent of dialysis at a median of 24 days (range 8-58 days). Three months after the start of treatment, these 13 patients had a median estimated GFR of 40 ml/min (range ml/min). Of the six patients with interrupted courses of chemotherapy, two died of their disease and only one of the remaining four was able to become independent of dialysis (at 105 days). Kaplan-Meier survival analysis showed that early interruption of chemotherapy was associated with significantly worse outcomes (P<0.002). The median survival for these patients was 53 days (range days), compared with patients who completed chemotherapy who were alive at a median follow-up of 360 days (range days; P<0.02). Safety The authors reported that HD using the Gambro device was well tolerated by all patients, with no unexpected adverse events (AEs) related to the procedure. Specifically, Theralite for renal failure in patients with multiple myeloma: February

17 no non-infective complications related to venous access or anticoagulation were reported. However, infections were not uncommon, with five patients required to interrupt chemotherapy due to line sepsis (3), pneumonia (1) and neutropenic sepsis (1). Another patient was required to interrupt chemotherapy due to dermatitis. Three of the 13 patients who did not require interruption of chemotherapy experienced infections during their treatment course (two urinary tract infections and one line-related infection). Updated study information The most recent available data on HCO-HD comes from the Chart Audit of Renal Recovery in Multiple Myeloma (CHAR 2 M 2 ) Study (Hutchison et al 2009b; Bridoux et al 2011, page 27). A 2011 conference abstract and a separate presentation state that, across 16 dialysis centres in Europe and Australia, 63 per cent of 67 patients treated with HCO-HD became dialysis independent after 12 sessions. e The rate of dialysis independence was higher (64% versus 56%, P=0.04) in the 76% of patients with de novo MM versus the 24% with relapsing MM. Dialysis related AEs were reported in six per cent of patients (no detail was provided). Cost Impact The cost of each Gambro HCO1100 dialyser in Australia, provided by the Sponsor (Gambro Pty Ltd), is $1,470. One new dialyser is used for each treatment session. Patients undergo a series of treatments, and based on the results from the Chart Audit of Renal Recovery in Multiple Myeloma (CHAR 2 M 2 ) Study, approximately 12 sessions are required in order for patients to become dialysis independent. As mentioned earlier, clinical expert opinion suggests that currently, the cost of this technology does preclude it from being widely implemented in many centres in Australia; however, it is important to balance this with the long-term cost of HD, as well as the lack of available management options for MM patients with severe renal failure. A manufacturer-funded f CEA compared HCO-HD to standard HD in the management of myeloma kidney (Grima et al 2011). g The CEA used a lifetime decision tree model that followed patients from treatment of the initial presentation for HD to death. Clinical data came from Hutchinson et al publications and expert opinion, costs were based on those in the UK, and a UK National Health Service perspective was employed (i.e. this study only considered costs directly borne by the health service). Costs and outcomes beyond the first year were discounted at a rate of 3.5 per cent. e In contrast, renal recovery in patients on haemodialysis ranges from 4% to 24% (mean across studies 16%) (Grima et al 2011). f The authors had independent control over model structure, data inputs, interpretation, and manuscript development; however, the manufacturer provided comment on the analysis and manuscript. g The key clinical expert in this area (C. A. Hutchinson) was also an author. Theralite for renal failure in patients with multiple myeloma: February

18 Grima s model predicted an average survival of about 34 months for patients in the HCO- HD group versus 20 months for patients on standard HD. QALY calculation was about 22 months for HCO-HD versus 13 months for HD. Expected costs of treatment were lower for HCO-HD at about 25,000 versus 31,000 per patient for HD (due to avoidance of long-term HD in the former group). Cost-effectiveness ratios were not calculated as HCO-HD was more effective and less costly, i.e. dominant over standard HD. Sensitivity analysis showed that HCO-HD remained the dominant strategy (lower cost and greater QALYs) in all sensitivity analyses except when the percentage of patients who recovered after standard HD increased from the base case of16 percent 3 to 37 percent. The authors concluded that Overall, the analysis found that treatment of myeloma kidney using an extended schedule of HCO-HD may substantially improve renal recovery compared to standard HD, resulting in greater life expectancy and cost savings due to avoided chronic dialysis. The limitations of the study include those common to rare diseases including small study sizes and limited natural history data. Ethical, Cultural or Religious Considerations No issues were identified from the retrieved material. Other Issues Upcoming clinical trials The European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy (EuLITE) (NCT ) is a trial that will be led by the University Hospital, Birmingham, United Kingdom with collaborators, Gambro Renal Products, Inc and Ortho Biotech, Inc. The multi-site (Germany and United Kingdom), parallel assignment, open label, efficacy study is currently recruiting adult participants (n=90) who will be centrally randomised to: o o Trial chemotherapy (bortezomib, doxorubicin and dexamethasone) and FLC removal haemodialysis (two Gambro HCO1100 dialysers in series over an intensive treatment schedule); OR Trial chemotherapy and standard high flux haemodialysis. The primary outcome is independence from dialysis at 3 months. Secondary outcomes include duration of dialysis, serum FLC concentrations, myeloma response, and survival. A study protocol has been published (Hutchinson et al 2008b; ClinicalTrials.gov 2010). In addition, there is another RCT that is currently ongoing across 50 centres in France, which is being sponsored by the French government. This RCT, known as MYRE or PHRC, has the same aims as the EuLITE study. Conflict of interest of study authors Theralite for renal failure in patients with multiple myeloma: February

19 Until recently, only one research team has been involved in studies of this technology, i.e. Hutchinson et al from the University of Birmingham in the UK, and research has been funded by the device manufacturer. The lead author and several colleagues have close relationships (employees or directors) with The Binding Site Ltd in Birmingham, a company developing immunodiagnostic assays, including those to detect FLCs in patients with MM ( The Binding Site is providing the immunoassays to measure FLCs free of charge for the planned RCT (Hutchinson et al 2008b). Summary of Findings MM is an uncommon cancer (1.2% of all cancers in Australia). Of patients with MM, 10 to 20 percent have severe renal failure requiring dialysis. Traditional HD has provided inadequate treatment, which has necessitated the development of HCO-HD (Theralite) technology. The only study currently available is very small (n=19) and of low rigour (level IV evidence), although its findings were dramatic with respect to renal recovery leading to independence from dialysis and survival. A CEA showed HCO-HD to be the dominant strategy over standard HD (i.e. lower cost and greater QALYs), although clinical data were mainly drawn from small observational studies performed by the same research team. HealthPACT Assessment: Based on limited clinical data, HCO-HD appears to be a safe and effective treatment for selected patients with MM and severe renal failure who currently have few treatment options. Two multi-centre RCTs are currently recruiting patients, and the results from these trials will provide valuable information about the utility of HCO-HD for patients with MM and severe renal failure. Therefore, HealthPACT wish to monitor the technology, which will be reviewed in 12 months time. Number of Studies included Total number of studies 1 Total number of intervention level IV studies 1 References Australian Institute of Health & Welfare (AIHW) (2011).Australian Cancer Incidence and Mortality (ACIM) books [Internet]. Available from: [Accessed January 5, 2012]. Bridoux F., Leung N., Hutchison, C. A. (2011). Myeloma cast nephropathy, Departments of Nephrology, Poitiers France; Mayo Clinic, Rochester, MN, USA; Birmingham, UK, Available from [Accessed January 7, 2011]. Clinialtrials.gov (2010).European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy (EuLITE) [Internet]. Available from: [Accessed January 8, 2012]. Theralite for renal failure in patients with multiple myeloma: February

20 Food & Drug Administration (2011).Search 510(k) database [Internet]. Available from: [Accessed January 5, 2012]. Gambro (2009).Renal rescue for myeloma patients [Internet]. Available from: eloma_low.pdf?epslanguage=en [Accessed January 7, 2012]. Gambro (2010).FDA grants HUD (Humanitarian Use Device) Designation to Gambro s Theralite [Internet]. Available from: News/FDA_Theralite/ [Accessed January 5, 2012]. Gambro (2011).Theralite high cut-off technologydata sheet [Internet]. Available from: Therapy/Theralite/?tab=documentTab#tabList [Accessed January 8, 2012]. Grima D. T., Airia P., Attard C., Hutchison C.A. (2011). Modelled cost-effectiveness of high cut-off haemodialysis compared to standard haemodialysis in the management of myeloma kidney, Curr Med Res Opin, 27(2), Health Canada (2011).Medical Devices Active Licence Listing [Internet]. Available from: January 5, 2012]. Hutchison C. A., Cockwell P. et al (2007). Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies, J Am SocNephrol, 18(3), Hutchison, C. A., Harding, S. et al (2008a). Serum free-light chain removal by high cutoffhemodialysis: optimizing removal and supportive care, Artif Organs.2008, 32(12), Hutchison, C. A., Cook, M. et al (2008b). European trial of free light chain removal by extended haemodialysis in cast nephropathy (EuLITE): A randomised control trial, Trials, 9, 55. Available from: [Accessed January 7, 2012]. Hutchison, C. A., Bradwell, A. R. et al (2009a). Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis, Clin J Am SocNephrol, 4(4), Available from: [Accessed January 7, 2012]. Hutchison, C., Airia, P., Cook, M., Grima, D. (2009b). Abstract # 1875: Improving outcomes in patients with renal failure secondary to multiple myeloma: Results from ChAR 2 M 2, American Society of Hematology 51 st Annual Meeting & Exposition, New Orleans, LA. Available from: [Accessed January 7, 2011]. Ramessur, S., Kerr, P. et al (2011). High Cut-Off extended-hours haemodialysis for the management of acute kidney injury from myeloma cast nephropathy: results from a prospective Victorian study, Nephrology, 16(Supplement 1), Search Criteria to be used Theralite OR Free light chain removal OR High cut-off haemodialysis OR HCO-HD; Renal failure OR Cast nephropathy OR Multiple myeloma OR Myeloma kidney Theralite for renal failure in patients with multiple myeloma: February