Future Challenges

REVIEW Future challenges

B Sirohi1 and R Powles2

1Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, UK and 2Leukaemia and Myeloma Unit, Parkside Cancer Centre, Royal Marsden Hospital, Wimbledon, UK

Treatment for patients with myeloma has changed At the American Society of Haematology (ASH) meeting unrecognisably over the last two decades and now includes in December 2006, 7% of the presentations were concern- a sequence of treatments including chemotherapy, biolo- ing myeloma, which was the biggest single disease entity gical targeted therapy with or without consideration for represented and most of this related to treatment. As a high-dose therapy (autologous and allogeneic stem cell consequence, ASH has formed a new ad hoc Plasma Cell transplantation for younger and fit patients). As patients Biology Scientific Committee. But this means for physicians can now expect a doubling of median survival and a 20– in the clinic, there are confusing messages to decide exactly 30% chance of surviving longer than 10 years, the focus of how such new treatments are used in combinations, and treatment is shifting to long-term quality of life. This how they fit in to the previously accepted state-of-the-art article focuses on future challenges facing clinicians therapies of infusional chemotherapy (VAD/VAMP), high- treating myeloma and how best we may optimize our dose autologous stem cell transplantation and for some, resources. maintenance interferon.1–5 Most of all, it is not at all clear Bone Marrow Transplantation (2007) 40, 1157–1164; what now is the optimum treatment for relapse, and it is doi:10.1038/sj.bmt.1705865; published online 1 October 2007 not possible to inform a new patient what their extended Keywords: myeloma; quality of life; long-term survival sequenced treatment plan will be. Three areas for further progress need prioritized atten- tion, namely:

Introduction (1) tailoring of sequential targeted treatment for an individual patient, It is an exciting time for those currently working in (2) optimization of limited financial resources to best myeloma. With skilled sequential use of various treatments, deliver treatment plans it is possible to attain an ever increasingly proportion of (3) how we maximize the QoL for an individual patient. patients with normal quality of life (QoL), living longer than 10–20 years, and for older patients this translates into ‘operational cure’.1–3 The ability of the pharmaceutical companies and regulators to fast-track development and Tailoring of sequential targeted treatment for an individual approval of newer drugs, and the trend for worldwide patient collaboration coupled with patient support agencies like the Multiple Myeloma Research Foundation (MMRF) and Difficulty in initial diagnosis and molecular methodology International Myeloma Foundation (IMF) means that Early and accurate diagnosis is critical to the successful more clinical trials delivering new tangible treatments are treatment of new myeloma patients, but it is difficult to available for patients with myeloma. Substantial advances diagnose early because symptoms such as fatigue, weight have been made in our understanding of the biology of loss and compromised immune systems are often confused myeloma leading to the availability in the last 4 years of with other illnesses and specific tests relating to myeloma three new approved targeted therapies that are now in are not routinely done in the general practitioners surgery. common usage, namely thalidomide, lenalidomide and As a result, patients are often misdiagnosed and/or bortezomib. These are being used not only in a salvage diagnosed after preventable end-organ damage has oc- setting but also as upfront treatments in numerous trials curred. This makes a huge difference to long term QoL. It and for non-trial patients in the clinic. might be timely that general physicians are educated to routinely screen for testing for paraprotein as part of the general work-up for all patients and this could be driven through the patient support groups. Correspondence: Professor R Powles, Leukaemia and Myeloma Unit, With increasing use of MRI, PET, SAP scans and light Parkside Cancer Centre, Royal Marsden Hospital, Surrey 49 Parkside, Wimbledon SW19 5NB, London, UK. chain assays, we are able to diagnose and stage patients E-mail: [email protected] accurately, but an understanding of the significance of Received and accepted 28 August 2007; published online 1 October 2007 which relevant genes are involved needs to be further Targeted therapies for myeloma B Sirohi and R Powles 1158 developed to improve prognostic sub-classification. This is an expected normal lifespan of 10–20 years, the best way important because myeloma is still regarded rightly as the may be to start with a combination such as cyclopho- disease of older people and absolute numbers diagnosed sphamide, thalidomide and dexamethasone (CTD) or and treated are increasing exponentially as life expectancy melphalan, prednisolone and thalidomide (MPT) to max- goes up and myeloma patients survive longer. A clear imum response,21,22 and after relapse to sequence treatment strategy of prolonged survival for these patients without packages that each time contains only one new class of harm is the correct vision. The issues therefore are the early drug, for example, switching from CTD to cyclopho- accurate diagnosis with multivariate indicators of when to sphamide, lenalidomide and dexamethasone. This strategy treat and when not to treat (including unmaintained leaves in hand other classes of drugs such as proteasome remission), and this will lead to an increasing proportion inhibitors for the future, but depends upon drugs such as of older patients with a normal lifespan with good QoL dexamethasone always being synergic with new previously (‘operational cure’).2,3 unseen drugs. If bortezomib is combined with lenalido- Recent methodology developments for individualized mide, it uses two effective classes of drugs at once (maybe treatment strategies are the use of microfluidic chips in the without consensual benefit) and possibly reduces future application of PCR, electrophoresis sizing, cytometry, and options. gene-sequence detection. The signature sequence of the However with so many treatment options and with at heavy-chain immunoglobulin VDJ sequence in myeloma is least two new options each year there are countless possible a clonotypic marker of the malignancy. An on-chip trial permutations and combinations that could be under- microfluidic analysis of the myeloma clonotypic sequence, taken. We therefore need to prioritize which are the most combining PCR cycling on the chip and electrophoretic important studies to undertake that define the best separation to distinguish polyclonal products of the normal sequence for therapy, and it maybe that smaller well- population from the monoclonal ‘spike’ produced by the designed studies answering specific questions that are not malignant clone has also been developed.6–8 These powered to give us a plethora of answers but simply take us approaches will allow analysis of unique properties of each on to the next question will be the way that we do this best. malignant clone, detection of minimal residual disease and Risk stratification approach to treatment relating to possibly a rapid analysis of therapeutic response. biochemical and genetic criteria or whether a ‘patient is a However, these advancements in the field of molecular transplant candidate or not’ has been advocated by various profiling have increased the importance of obtaining pre- groups and maybe the way forward in individualizing treatment tissue samples and subsequent samples over time treatments, but has yet to confirmed within a prospective that link to accessible databases of what happened to these trials setting with mature follow-up data.23–25 patients clinically. Patients must be educated about the importance of providing samples. All oncologists and New drugs surgeons, including those at cancer centres and those at Various new classes of drugs currently in clinical trials community practices, where most patients are evaluated, include immunomodulatory drugs, proteasome inhibitors, must be educated and motivated to obtain, analyse and arsenic trioxide, interleukein-1 receptor antagonists, cyclic distribute tissue samples to ensure accurate diagnosis and depsipeptides, farnesyltransferase inhibitors, p38 mitogen- to enhance future research. The IMF ‘Bank on a cure’ activated protein kinase inhibitor, modifiers of histone programme is leading the way in this (www.myeloma.org). acetylation, heat shock protein inhibitors including KOS- 953, direct AKT-targeting agents and monoclonal antibodies as well as passive and active immunotherapeutics Designing trials for a sequence of treatment options from (either given alone or in combination with established diagnosis to death: the patient pathway therapies).26–37 The Table 1 shows some of these drugs As the result of countless trials and studies, coupled with within phase I/II studies. what happens in the ‘real-world clinic’ outside of the The role of these new agents in relation to stem cell context of trials, treatment packages have evolved that are transplantation and their impact on the timing of being used frequently in the clinic. Examples are oral transplantation (upfront versus at relapse) needs optimiz- melphalan–prednisolone combinations from 1960s, the ing and it is this that has prompted us to produce this infusional VAD/CVAMP of the 1980s, and thalidomide/ special issue now. A better understanding of the mechanism dexamethasone ( þ alkylating agent) in the 1990s. More of action of these drugs will likely provide additional recently, there is now lenalidomide/dexamethasone targets and insights into other potentially useful new ( þ alkylating agent) and the bortezomib/dexamethasone agents. We also need to determine predictors of response ( þ Doxil) combinations.1,3,9–17 All of these interdigitate to these agents based on pharmacogenomics and such with high-dose melphalan, autografting, full allografting, studies are ongoing. Treatments with drugs like thalido- reduced intensity conditioning allografting and interfer- mide and lenalidomide although effective are not curative, on.1,4,5,18–20 New treatment packages do not necessarily and clearly more active agents are needed if, for younger make the old treatment obsolete, however they do pose the patients, the same results are to be attained as in leukaemia. question: ‘where do they fit in a 10–20 year sequence plan’? Thus there are at least 10 packages of treatment that can at present be given (and more new ones each year) and New drugs targeting bone some general principles are evolving in the clinics on how In myeloma bone disease, research until recently has been we sequence these treatments. For the older patients, with directed exclusively to the destructive powers of ‘switched

Bone Marrow Transplantation Targeted therapies for myeloma B Sirohi and R Powles 1159 Table 1 Some of the drugs (alone or in combination) currently other cancers. Potential advantages of denosumab over the undergoing phase I/II testing in myeloma patients bisphosphonates is that it is completely cleared over a Drugs Main target Phase NCT number relatively short period of time, hence the effects on bone are not long lasting, this could be the first anti-bone-resorbing Bevacizumab Angiogenesis II NCT00410605 agent to stop erosions and osteolysis.42–44 To date, the I NCT00428545 clinical experience with denosumab shows that it can CCI-779 m-TOR I NCT00398515 (Temsirolimus) effectively inhibit bone resorption with minimal side effects. NCT00483262 Atiprimod STAT3 activation I NCT00086216 I NCT00491972 Pegylated interferon-a CNTO-328 IL-6 II NCT00402181 Data on maintenance treatment with interferon-a currently II NCT00401843 do not support its use since cost-effectiveness ratios are Sunitinib Multi-receptor II NCT00514137 45 tyrosine kinase generally beyond acceptability. This results from margin- Sorafenib Multi-receptor II NCT00253578 al improvements in progression-free survival without tyrosine kinase proven benefit on overall survival and an unfavourable I NCT00474929 impact of treatment on QoL.4,45 Use of pegylated Perifosine Akt II NCT00375791 interferon which has better patient compliance and better I NCT00401011 I NCT00415064 tolerability than interferon should be the basis for a new BB-10901 CD56 I NCT00346255 generation of trials with dose escalation to determine if HCD122 CD40 I NCT00231166 there is a role for this form of treatment in the now long Cetuximab EGFR II NCT00368121 patient treatment pathway.46 It gives the opportunity to HuLuc63 Monoclonal IgG1 I NCT00429741 I NCT00425347 interdigitate this novel drug between other conventional ATN224 Angiogenesis I NCT00352742 treatment packages and may lead to larger overall gains in PTK787 Angiogenesis II NCT00240162 survival, and possibly added effects relating to generalized Aplidin Rac1-JNK II NCT00229203 immune stimulation. In our experience, some patients have Carfilzomib or PR Proteasome II NCT00511238 received interferon-a for longer than 10 years with good 171 I NCT00150462 tolerability. NPI-0052 Proteasome I NCT00461045 Tanespimycin Hsp90 II NCT00514371 IPI 504 Hsp90 I NCT00113204 Immune strategies Vorinostat Histone deacetylase I NCT00111813 We have not in this special issue included a chapter on LBH589 Histone deacetylase II NCT00445068 cellular immunotherapy. This is because at the moment it is PXD101 Histone deacetylase II Ref 30 SCIO 469 p38a MAPK II Ref 29 purely experimental, logistically difficult, very expensive Mapatumumab TRAIL-R1 II NCT00315757 and impossible to standardize. However, this does not diminish its importance. Abbreviation: IL-6, interleukein-6. It is becoming clear that the human immune response is the result of highly complex continuously evolving interac- tions between cells of the adaptive and innate arms of the immune system, the internal and external environments, on’ osteoclasts. All treatment has been directed this way. and normal and abnormal plasma cells. Immune-based We now are aware that the insidious ‘switched off’ strategies currently being evaluated are vaccination, includ- osteoblast with its consequential osteopenia is equally ing the creation of fusion cells from myeloma cells, or important. proteins and dendritic cells, donor lymphocyte infusions, tumor-specific T cells.47–49 It is also speculated that 1. Bortezomib. Early phase I and II data demonstrate immunomodulatory drugs such as lenalidomide may be remarkable activity of bortezomib in combination with useful in increasing the immune response to vaccines. We anthracyclines, melphalan, cyclophosphamide and thalido- predict a huge growth in research in this area, with tangible mide.38,39 Studies are also ongoing to assess the role of returns in treatment options within a decade. Cost will be a bortezomib on bone metabolism (NCT00128921) as there is very serious limitation to wide usage. evidence to suggest that bortezomib may increase osteoblast activity.40 This is the only targeted therapy in use at present that is directed towards the osteoblast rather than Optimization of limited financial resources to best deliver the osteoclast. This should now be the basis of intense treatment plans research for other agents. Cancer is becoming, for many patients, a chronic condi- 2. Anti-receptor activator of nuclear factor-kB ligand tion—incurable, but treatable, with long survival. We can therapy. Denosumab (formerly known as AMG 162) is expect for the near future a rapidly growing number of new a fully human monoclonal antibody directed against treatment options, some very costly. How society deter- RANK.41 Current phase III trials (for example, mines its priorities for cancer care in relation to other major NCT00330759) are seeking approval for the use of health demands and for health care versus other public denosumab in patients with multiple myeloma and various expenditure is a very complex issue, but there is a growing

Bone Marrow Transplantation Targeted therapies for myeloma B Sirohi and R Powles 1160 requirement that these processes should be transparent, conclusions on cost-effectiveness. In a joint study from the rational and widely discussed by all stakeholders. EORTC and MRC, the impact of treating institutions on survival of patients with poor prognosis non-seminomatous germ cell cancer treated within randomized clinical trials Health care cost delivery was studied. They reported that overall survival for patients Introduction of these new and mostly expensive treatments treated in 26 institutions who entered fewer than five poses major problems worldwide for health care systems patients into the trial was significantly lower than in the 23 with finite resources. Reliable assessment of efficacy and institutions where more than five patients were entered. The cost effectiveness of new treatments is a priority especially received dose intensity of chemotherapy was significantly in comparison to standard treatments. lower in the low accruing centres.50 This suggests that In the United Kingdom, The National Institute of outcome for patients treated in low accruing institutions is Clinical Excellence (NICE) was launched in April 1999 worse, based on a greater tendency to reduce dose of and covers England and Wales (www.nice.org.uk), its role chemotherapy, and that reliable conclusions about effec- being to appraise new technologies and provide guidance to tiveness (and therefore cost-effectiveness) could not be NHS on clinical effectiveness and also develop guidelines made based on data from these centres. We saw a similar outlining best practice. It has been a leader, worldwide, in ‘centre effect’ in bone marrow transplants for acute myeloid how this can be done. However, there is regional inequality leukaemia, across Europe, so it is likely that myeloma in implementing NICE cancer care across United Kingdom behaves in a similar way.51 by local National Health Service (NHS) health care commissioners, increasing the development of a two-tiered system whereby patients with wealth or health insurance Outcomes research in myeloma have access to treatments that much of the rest of the world Outcomes in cancer are usually expressed in terms of considers standard. Also, NICE until recently has had overall survival and disease-free survival, and organizations challenges in keeping pace with the evolving field of such as the NICE have used survival data as a measure of myeloma, and United Kingdom still lags behind the United treatment success. There is now emerging an area of States/Europe in delivering the state-of-the-art care for research that is looking into a more global impact of all patients with myeloma. aspects of treatment benefit that can act as an end point for In a surprisingly new positive development, NICE has all parties involved in taking decisions about whether recommended that all suitable myeloma patients should be treatments have improved outcome. This includes the offered treatment with bortezomib. Patients showing a full health care workers and patients and also the health care or partial response to the drug should be kept on it and purchasers and facilitators such as NICE and society as a funded by the NHS. Patients showing a minimal or no whole. Factors that now make up part of outcome research response should be taken off the drug, and the drug costs besides survival and disease-free survival are also QoL refunded by the drug’s manufacturer. Hence, patients with assessment, often disease-specific, and the economic im- stable disease will have to stop the drug. The draft plications for the individuals involved.52 recommendations followed an evaluation of a refund To this end, a monograph was published in the Journal scheme put forward by the drug’s manufacturer. The final of the National Cancer Institute in which the aim was to decision on whether to put the refund scheme into practice provide a review and evaluation of peer reviewed literature rests with the manufacturer and the Department of Health. in cancer outcomes research.53 The US Agency of Health Some argue that something is better than nothing. Care Research and Quality and the NCI have defined outcome research as an understanding of the end results of Clinical versus cost effectiveness studies particular health care practices and intervention, of which a Assessment of cost-effectiveness is expensive and time key criterion is the ability to function.54 consuming. It is therefore essential that the decision to It is clear that our understanding of current myeloma undertake cost-effective studies is only undertaken when it outcomes is naive and a long way from the global is likely to influence the subsequent use of a therapy. description above. For example, health-related QoL Results from well-conducted randomized clinical trials measurements in routine clinical practice, as distinct from with high statistical power should be the major factor in its use in clinical trials, are currently rarely done. The decision-making about the widespread use of expensive new decision-making process for care of myeloma patients will agents. As clinicians caring for patients with myeloma, our require us to pursue descriptive studies that correlate the primary responsibility is to advocate treatments of proven publication of practice guidelines with the subsequent efficacy, either in terms of survival benefit or tolerability, changes in patterns of care. Following this, we will need irrespective of cost. Well-designed randomized clinical to identify which particular outcomes research findings trials of adequate sample size provide the best setting to change the decision-making process to further improve the compare new with established therapies. They should, global benefit for treatment of myeloma and in turn, this therefore, also provide the best context in which to assess will help design better ways of undertaking myeloma comparative costs. outcomes research. However, recent studies have demonstrated that results Outcome data from unselected patients are now expected in multicentre randomized trials can vary between centres, by purchasers and presented in this way, help qualify the especially when the number of patients entered at particular activity impact of advances made from research trials for centres is low, and that this may have significant effect on the treatment of population-based cancer problems.52

Bone Marrow Transplantation Targeted therapies for myeloma B Sirohi and R Powles 1161 How we maximize the quality of life for individual patients professional input. What influences ‘Hope and Trust’ by patients is very individually driven. Long-term survival in myeloma/‘operational cure’ The emergence of new drugs and trials in haematological Because the aim of treating non-trial patients over 60 years malignancies brings hope to patients; however, under- (the majority) is to not cure the disease, but control it with standing the advantages and accessibility of new and normal QoL for many years, it is likely that an increasing emerging treatments can be overwhelming. Although many proportion of the patients currently being treated outside of patients rely on their community oncologist for guidance, the context of research trials, are already living significantly the community oncologist may not be up-to-date on the longer than 10 years. We feel therefore that randomized latest approaches for myeloma. Easy access to up-to-date trials might need to be focused not only on changes in information about treatment options is critical to ensure median disease-free survival but also on increasing the that appropriate medical decisions are made. proportion of patients surviving longer than 10 years. This Random searching of the Internet is not appropriate, and group of patients who are operationally cured, and many of the patient support groups such as the IMF, MMRF and whom will die with their disease rather than of it, will best the UKMF seem to be competing with each other rather be rewarded if their QoL is maximized.2,3 than complimenting. It may be time all of these agencies Over the longer term, patients’ QoL must be optimized. met and put their resources together. The European As patients with myeloma face anaemia, recurrent infec- Myeloma Network (www.myeloma-europe.org) was in- tions and severe bone pain, their treatment plans require itiated in 2003 in order to allow scientists and physicians continual evaluation. Furthermore, many patients also face with interest in Multiple Myeloma and related disorders to the onset of second cancers or second and third chronic share their experience and develop co-operative studies, but conditions related to age; and the potential long-term at present it is not widely used by clinicians. health consequences of treatment, including heart disease and compromised immune systems. These challenges must be taken into the treatment programme in a positive way Bone disease/vertebroplasty: increasing awareness and not an excuse to simply palliate. Bone destruction at any site is the cause of significant morbidity in patients with myeloma.55 Patients can for example present with a pathological fracture of a long Patient dilemma bone, rib or the sternum, but easily the most upsetting and QoL issues also relate to avoiding unnecessary anxiety. potentially dangerous site is the spine. Besides the direct Once a diagnosis is confirmed, a proportion of myeloma clinical implications, a source of huge distress is the loss of patients are asked to ‘watch and wait’, putting off up to 10 cm in height because of vertebral collapse, which treatment until symptoms require intervention. These may continue to occur during the initial period after the patients must learn to live with chronic cancer and manage start of treatment, and therefore the speed of response may their lives accordingly. Other patients are diagnosed with be a factor in the final total loss of height. There therefore high-risk (based on various stratification systems) aggres- arises the possibility that for certain selected patients, rapid sive disease that requires immediate treatment. Both these response may be crucial to their long-term QoL. Again, we scenarios evoke extreme anxiety and frustration as patients need evidence-based methodology to define which specific strive to understand the complexities of their disease. At an treatment is best for an individual patient. This clearly IMF patient-family ‘interactive’ seminar organized at the needs to be linked to radiotherapy and vertebroplasty/ Royal College of Physicians, London in 2003, we examined balloon kyphoplasty, but at present there are no rando- how important Hope and Trust was for the patients and mized studies to define the place of radiotherapy in this their carers. We asked a total of 52 questions relating to context, and the possibility exists that radiotherapy could health care workers, the environment and the treatment for some patients lead to increased height loss if given early and its responses (www.myeloma.org). In no instance, was after diagnosis because it inhibits osteoblast activity but the response to a question unanimous and unambiguous in drugs like bortezomib which promotes osteoblast activity its answer, and thus the immediate take home message of laying down new bone early may reduce vertebral the meeting was that it is impossible to proscribe collapse.40 recommendations for all patients that will not often be Advances in minimally invasive surgical techniques, such inappropriate to a minority. For example, we asked as percutaneous vertebroplasty or balloon kyphoplasty, patients that had entered a trial and were randomized offer these patients’ less-invasive options for treating between treatment options—‘did this erode your Hope and vertebral collapse and restoring function.55 However, Trust’ and 9% said yes. Concerning the doctor, 87% felt undertaking randomized trials of vertebroplasty would be that if the doctor was upbeat and positive, this would a logistic and ethical nightmare, and would require increase Trust but 13% thought otherwise. Another prolonged follow-up to determine long-term significance. intriguing observation was that in the United Kingdom, The IMF is currently looking at current physician practice we found only 2% of patients recorded their consultation data, which at least gives us a feel for how this practice is with doctors in contrast to the United States where about evolving outside of the context of clinical trials. 50% patients would record the interview. Vertebroplasty has impacted significantly on patient’s Although support via Internet and patient helpline QoL along with the use of oral and i.v. bisphosphonates. through agencies such as the MMRF, IMF is available, Biophosphonates are considered cost effective and have clinicians generally handle this on an ad hoc basis with little become part of routine practice since they significantly

Bone Marrow Transplantation Targeted therapies for myeloma B Sirohi and R Powles 1162 improve QoL by preventing skeletal events.56 However, 3 Sirohi B, Kulkarni S, Powles R. Some early phase II trials in they are costly and no data are available to assess correctly previously untreated multiple myeloma: the royal Marsden the cost per quality adjusted life years (QALY) associated experience. Semin Hematol 2001; 38: 209–218. with these treatments. There is no evidence to support the 4 Powles R, Raje N, Horton C, Mehta J, Singhal S, Hickish T choice of either pamidronate or zoledronic acid based on et al. 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