M Hughes and R L Soutar
Department of Haematology Western Infirmary Glasgow
Corresponding author: Dr Marie Hughes: E-mail: rls4m@clinmed.gla.ac.uk
SMJ 2005 50(2): 47-50
Myeloma is a plasma cell tumour that predominantly affects those over 40 years of age. The incidence in the United Kingdom is 40 per million people per annum with approximately 200 cases diagnosed each year in Scotland. For the majority of patients the condition remains incurable. An overview of myeloma was published in 1998 1 however in the past few years important advances in therapy and supportive care have improved both the quality of life and life expectancy for those affected. This article outlines these advances.
Recent advances in diagnosis and prognostic markers
Patients may present to many specialities with skeletal, renal, infective, neurological, hypercalcaemic or anaemic complications. Although strict diagnostic criteria have been laid down,2 in clinical practice the diagnosis often still rests on the presence of two of the following three criteria:
1. Lytic bone lesions
2. The presence of a serum and/or urinary monoclonal immunoglobulin
3. Excess numbers of plasma cells in the bone marrow (generally >10%).
The ability to now quantify serum free light chains in addition to assessing serum and urine monoclonal protein has provided a new means of monitoring light chain only and non-secretory myeloma and also allows the response to treatment to be assessed more rapidly. Although not routinely indicated in assessment CT, MRI and FDG PET scanning are helpful in imaging extramedullary disease and evaluating symptomatic areas where radiographs are negative due to their higher sensitivity in detecting lytic lesions. Certain patterns of marrow involvement on MRI may have prognostic significance.3 PET imaging seems able to identify areas of residual myeloma after therapy and this may be of prognostic importance.4
Traditionally, myeloma has been staged according to the paraprotein level, degree of anaemia, extent of bone disease and presence of hypercalcaemia — so called “Durie-Salmon staging” introduced in 1975.5 More modern criteria are now in place to assess an individual’s prognosis. An international prognostic index based on serum levels of B2- microglobulin and albumin has recently been proposed with the benefit of using readily available information.6 Interphase cytogenetics using fluorescent in situ hybridisation (FISH) analysis has allowed identification of genetic abnormalities. Complete or partial deletion of chromosome 13 is a powerful adverse prognostic factor as well as certain balanced translocations (t4;14, t14;16).7,8
Autologous transplantation
Prior to the introduction of alkylating agents in the 1960s the median survival of myeloma patients was less than one year.1 The introduction of melphalan improved median survival to two years.9 Subsequent trials with combination chemotherapy improved response rates but failed to identify any agents that provided better overall survival than melphalan.10 In 1996 the French Myeloma Intergroup published the results of the first randomised, controlled trial of “high dose” therapy in myeloma (IFM 90)11 using doses of chemotherapy that required haematopoietic stem cell support to overcome the profound myeloablative effects of treatment. In this seminal paper 200 patients, aged less than 65 years, and analysed on an intention to treat basis, were randomised to either autologous bone marrow transplantation (ABMT) following myeloablative doses of melphalan, or combination chemotherapy alone. ABMT was superior in terms of complete remission rate (22 vs. 5%, p<0.001), five year event free survival (28 vs. 10%, p=0.01) and five year overall survival (52 vs. 12%, p=0.03). These results were recently confirmed in a large MRC trial that recruited 407 patients.12 In this trial, as compared with standard therapy, intensive treatment with ABMT increased median survival by almost one year (54 months vs. 42 months).
Transplant centres have now moved to using peripheral blood stem cells (PBSC), collected by apheresis, in preference to bone marrow stem cells for haemopoietic support in autologous transplants. Engraftment is faster with PBSC equating to lower infective risks for the patient and has reduced the complexity of autologous transplant procedures. Collection of PBSC has also made multiple autologous procedures technically possible and tandem autologous stem cell transplants (ASCT) have been the subject of several recent studies. A French trial (IFM 93) recently reported the results of double versus single autologous transplantation in 399 patients with myeloma under the age of 60 years.13 Improved event free and overall survival in the double transplant arm, with seven-year overall survival 42% versus 21% in the single transplant arm, was demonstrated. Tandem ASCT appeared particularly effective in patients who had not received a good partial response after first transplant. Other trials, however, have reported conflicting results with regard to event free and overall survival and at present tandem transplants remain an investigational procedure whilst these trials mature.14
Allogeneic transplantation
Despite the beneficial effect of ASCT there is no evidence of a plateau in the survival curve after ASCT and patients continue to relapse. There are, however, reports in the literature of long term survival (greater than 15 years) in patients who have received allogeneic transplants, usually from a HLA matched sibling. Unfortunately, allogeneic transplantation in patients with myeloma has historically been associated with a very high transplant related mortality (41-48%). In the past 10 years this fallen to <30% with improved supportive care, careful patient selection and transplantation earlier in the course of the disease.15 Five-year overall survival and progression free survival after allogeneic transplant has been reported as 60% and 39% respectively, with one third of these patients also being in persistent molecular remission with a very low risk of relapse.16 Allogeneic transplantation, however, is only available to younger patients (<50 years) with an HLA matched sibling donor. Conventional matched unrelated donor transplants (MUDs) continue to have a high transplant related mortality and at present are not recommended.
The therapeutic benefit of allogeneic transplantation is largely related to an associated immune-mediated graft versus malignancy effect, an effect first demonstrated in chronic myeloid leukaemia. A “graft versus myeloma” effect by donor lymphocytes is now also well recognised and indeed patients who have residual disease or relapse after allogeneic transplantation may enter remission by infusion of additional donor lymphocytes.17 Non-myeloablative allogeneic transplants, or “reduced intensity” transplant regimens utilise the recognised “graft versus myeloma” effect of donor lymphocytes while reducing the toxicity of conditioning. Conditioning treatment is not primarily used for treatment of the disease but for ensuring that engraftment can occur. Nonmyeloablative transplants are better tolerated than standard transplants because of reduced extramedullary toxicity and myelosuppression, and have reduced transplant related mortality (15%).18 This has widened the availability of allogeneic transplantation to older patients (up to 65 years) and those with co-morbidities. Non-myeloablative MUD transplants are also better tolerated providing an option for certain patients without a sibling donor. Although studies using non-myeloablative transplantation have shown response rates of 81%, with 52% achieving complete remission,18 toxicity from graft versus host disease remains problematic. The role of non-myeloablative allogeneic transplantation following autologous transplantation as consolidation therapy is being explored in patients under 65 years in the current MRC Myeloma IX trial.
Thalidomide
Patients with myeloma have prominent marrow vascularisation. Thalidomide is known to have antiangiogenic effects and this led to the introduction of its use in myeloma in the late 1990s.19 In 1999 a Phase II study in a group of heavily pre-treated, refractory myeloma patients reported partial response rates of 30% and two-year survival rates of 69% amongst the responders.20 These dramatic results, confirmed by others, mean that thalidomide is now extensively used in the treatment of myeloma and is being studied in combination with other agents. The addition of high dose dexamethasone to thalidomide may produce a response in patients who have failed to respond to either drug alone. In addition, dexamethasone and thalidomide are now being used in some centres as initial therapy in myeloma with reports of very high response rates (70-80%).
Trials, including MRC Myeloma IX, are currently evaluating the role of thalidomide in combination with other agents in initial therapy and are also studying the potential role of thalidomide as maintenance therapy after stem cell transplantation to prevent/delay relapse. Although thalidomide virtually lacks myelosuppressive effects it has other significant side effects including peripheral neuropathy, constipation, somnolence and thromboembolism. Peripheral neuropathy is the major treatment limiting toxicity. Milder neuropathy may be reversible with discontinuation of therapy but this may not occur with more advanced neuropathy. The risk of teratogeneicity remains a constant fear and careful patient counselling with detailed written advice must be given prior to therapy.
Thalidomide analogues
Two classes of drugs have been synthesised from thalidomide. The first class includes selective cytokine inhibitory drugs (SelCIDs) that are inhibitors of TNF alpha. The second class of analogues are the immunomodulatory drugs (ImiDs) that not only inhibit TNF alpha secretion but also stimulate T cell proliferation. Lenolidomid (Revlimid) is an ImiD that exhibits virtually no sedative and only occasional neurotoxic side effects. Unlike thalidomide, however, this drug is myelosuppressive. Responses to Lenolidomid have been reported in one third of patients with advanced and refractory myeloma.21 Clinical trials are now in place to evaluate the effect of Lenolidomid alone, and in combination with other agents.
Bortezomib
Bortezomib (Velcade) is a new class of drug that acts by inhibiting the proteosome. Bortezomib has been shown to be active in refractory myeloma. In a phase III study of 202 patients who had failed at least two lines of therapy, and whose disease was progressing, complete remission was seen in 19 patients (10%) with an overall response rate of 35%. 22 Responses were durable with median duration of response of 12 months. Principle side effects are neuropathy and thrombocytopenia. Bortezomib has recently been licensed for use in the UK and even more recently been given approval by the Scottish Medicines Consortium (SMC). However, although the drug represents a significant treatment advance it has to be given intravenously and comes with significant cost issues (approximately £14k per treatment course).
Future interests
From no new agents in the early 1990s there are now so many being developed that proper evaluation of them may prove difficult. Arsenic trioxide can induce apoptosis in drug resistant myeloma cell lines. A phase II trial of arsenic trioxide in 24 relapsed or refractory patients reported an objective response in 43% of patients and trials of arsenic in combination with other therapies are underway.23 Other new agents include farnesyl transferase inhibitors (FTIs),24 tyrosine kinase inhibitors, and immune therapy with myeloma vaccines or dendritic cells.
Bisphosphonates
Bone pain, hypercalcaemia and pathological fracture are a major cause of morbidity and mortality in patients with myeloma. Bisphosphonates act by inhibiting osteoclast mediated bone resorption and in addition may also have a direct anti-tumour effect on myeloma cells.25 Randomised controlled trials have shown the bisphosphonates clodronate, pamidronate and zoledronic acid to be efficacious in reducing hypercalcaemic events, vertebral fracture and pain.26-28 The MRC myeloma IX trial is currently comparing oral clodronate with intravenous zoledronic acid. Current recommendations from the British Committee for Standards in Haematology are that a bisphosphonate that has been shown to be active in myeloma should be administered long term to all patients with myeloma who require treatment.29
Vertebroplasty and kyphoplasty
Despite the introduction of bisphosphonates established bone disease and vertebral body deformity remain important and difficult management issues. Vertebroplasty and kyphoplasty are both minimally invasive techniques that result in quick, effective pain relief and have low complication rates.30 Percutaneous vertebroplasty involves the injection of bone cement into the vertebral body but does not expand the collapsed vertebra. (Fig 1) Kyphoplasty is performed through a cannula inserted into the vertebral body that acts as a corridor for the insertion of an inflatable bone tamp. The tamp reduces the compression fracture and restores the vertebral body towards normal height. The cavity is then filled with bone cement.
The analgesic effect is rapid and thought to be due to a combination of stabilisation of the bone and likely local chemical or thermal effects from the cement on nerve endings in the surrounding tissue. The procedures are performed by interventional radiologists and have been shown to have positive impacts on patient’s lives.31
Erythropoietin
Anaemia affects approximately two-thirds of myeloma patients. Erythropoietin (EPO) has been used extensively in myeloma both in patients without and with renal impairment. High quality trials have now clearly demonstrated the efficacy of EPO in improving haemoglobin, decreasing transfusion requirements and improving quality of life with response rates of up to 60% in patients with myeloma.32 The BCSH guideline states that a therapeutic trial of EPO should be considered in patients with symptomatic anaemia.29 This approach is in line with the UK NHS executive circular on “Better Blood Transfusion” that aims to reduce unnecessary red cell transfusion. To date, however, there have been no cost-benefit analyses comparing the use of erythropoietin with red cell transfusion in patients with myeloma and cost constraints currently limit the widespread application of EPO therapy.
Myeloma and renal impairment
Approximately 50% of patients with myeloma will develop renal impairment during the course of their disease. Those whose renal function fails to improve with conservative measures should be considered for renal replacement therapy. The MRC “MERIT” study is currently recruiting patients with newly diagnosed myeloma and acute renal failure to assess whether the addition of plasma exchange (to remove the paraprotein) in addition to chemotherapy increases the likelihood of renal function recovery.
Patient information and support
For a disease where the majority of patients will not be cured the provision of information and support for patients and their carers is extremely important. The IMF (UK) is a UK based charity that produces useful written material on myeloma, provides patient/carer support and runs patient and family seminars including advice on socio-economic problems resulting from their condition. Cancer BACKUP and the Leukaemia Research Fund also provide written information on myeloma. There is ongoing co-ordination between haematologists to ensure consistent and optimal care of patients with myeloma through the UK Myeloma Forum. Since the original review published in this journal in 1998 the BCSH guideline for the diagnosis and management of patients with myeloma has been published 29 and an updated UK/ Nordic version is imminent.
For young patients with myeloma prognosis is finally improving with high dose chemotherapy and stem cell transplantation. Unfortunately, myeloma remains essentially incurable apart for the small percentage of fit patients with HLA compatible siblings where allogeneic transplantation may offer cure. For elderly patients, or those with additional co-morbidities unfit for autologous transplantation, overall survival has probably remained unchanged from the 1960s although supportive measures have lessened morbidity and newer agents are being introduced that will likely impact on survival. The extent of the impact of these treatments awaits full assessment in randomised trials. The emerging issues of cost and drug selection will be increasingly debated. After decades of little progress this has become an exciting time for clinical and fundamental research in myeloma, as well as an encouragement for the patient with myeloma and those who care for them.
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