Bone Marrow Transplantation (2007) 40, 1157–1164 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt 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 anti- bodies 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