Advances in multiple myeloma

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1 Oncology 295 Advances in multiple myeloma Multiple myeloma is a malignant disease characterised by a clonal population of plasma cells in the bone marrow. The disease occurs in the elderly and results in lytic bone lesions, blood cytopenias and the production of monoclonal immunoglobulin heavy and light chains. Multiple myeloma is an incurable condition and therefore treatment is reserved for symptomatic patients or those with documented bone lesions. Prognosis has improved considerably in the last five years due to novel agents and improved supportive care. Dr Rebecca Maddams* Haematology Specialist Registrar Dr Rachel Hall Consultant Haematologist, Royal Bournemouth Hospital * rlmaddams@doctors.org.uk Multiple myeloma is a clonal disorder of plasma cells in the bone marrow. The average age of presentation is 70 years. Multiple myeloma has an incidence in the UK of four in 100,000 increasing to 30 in 100,000 in those aged 80 years or older. The malignant plasma cells accumulate in the bone marrow causing pancytopenia, lytic bone lesions (Figure 1), bone pain and hypercalcaemia. Myeloma cells secrete a monoclonal protein (IgG commonly), which causes renal impairment and more rarely hyperviscosity. Immunoparesis results in vulnerability to infections. Clinical presentation Symptoms include fatigue, pallor, weakness, ankle swelling, breathlessness and palpitations. Bone pain Caused by osteoclast activation by plasma cell-released cytokines including tumour necrosis factor (TNF) and nuclear factor kappa B (NFkB). Crush fractures of the vertebrae are common, and pathological fractures can occur in long bones spontaneously or after minimal trauma. Recurrent infection Pneumonia and other infections are common in multiple myeloma because of a reduction in the normal immunoglobulins (immunoparesis) and neutropenia due to bone marrow infiltration by the malignant plasma cells. Hypercalcaemia Symptoms include polydipsia, polyuria, constipation, nausea and mental disturbance. It occurs as a result of bone destruction by osteoclasts releasing calcium into the blood. Renal failure Symptoms include nausea, vomiting and oliguria. Renal failure in multiple myeloma is often multifactorial; causes are listed in box 1. Bleeding tendency T h i s i n c l u d e s b r u i s i n g, nosebleeds and gum bleeding. T h r o m b o c y t o p e n i a d u e to marrow infiltration is a l s o c o m m o n. A c q u i r e d coagulopathies can also occur. Hyperviscosity syndrome This is rare but seen occasionally in IgA multiple myeloma. Features include bleeding, headaches, visual disturbance, central and peripheral neuropathies and mental disturbance. Amyloid deposition Rarely, multiple myeloma patients can develop secondary amyloid. Features include diarrhoea, carpal tunnel syndrome or other peripheral neuropathies, macroglossia and cardiac and renal failure. Figure 1 : Lytic lesions of the skull June 2010 Midlife and Beyond GM

2 296 Oncology Box 1: Causes of renal failure in myeloma Dehydration Hypercalcaemia Hyperuricemia Analgesics (particularly NSAIDs) Infection Renal light chain deposition Renal amyloid deposition Investigations Suggested initial investigations are listed in box 2. If these tests are suggestive of a diagnosis of multiple myeloma, referral to a specialist haematology clinic is advised for further investigations including serum beta-2 microglobulin (B2M) and bone marrow examination. Several more specialist investigations may also be performed. Serum free light chain measurement This blood test detects free light chains in serum at lower levels than in urine and is therefore more sensitive for diagnosis and disease monitoring. It is particularly useful in the 10% of multiple myeloma patients previously labelled as nonsecretory. Magnetic resonance This can be useful in selected patients with multiple myeloma as standard radiology is known to miss 25% of abnormal lesions. In addition, magnetic resonance imaging (MRI) scans can detect an abnormal bone marrow pattern suggestive of multiple myeloma in cases of osteopenia. Bone marrow biopsy Inspection of the bone marrow aspirate is the diagnostic test for multiple myeloma. Features include an infiltrate of abnormal plasma cells which comprise >10% of nucleated cells counted. A bone marrow trephine can be useful in cases where the aspirate is hypocellular. Several more sophisticated tests available to perform on the sample include: Flow cytometry. This test uses plasma cell surface antigens (CD138, CD56) to detect the level of plasma cells present. Cytogenetic studies. It is now known that acquired cytogenetic changes are present in some multiple myeloma patients and have prognostic implications. These changes include hyperdiploidy, deletions of chromosome 13 and translocations involving chromosome 14 (point 14q32). 1 Diagnosis The diagnosis depends upon the presence of clinical features of multiple myeloma with: Monoclonal protein in the serum or urine Myeloma-related organ or tissue impairment (see box 4) 10% abnormal plasma cells in the bone marrow or biopsyproven plasmacytoma. 2 Staging and prognosis The International Staging System based on serum albumin and B2M indicates disease burden and prognosis (box 3). 3 Box 2: Initial screening tests for multiple myeloma Full blood count Erythrocyte sedimentation rate Urea, electrolytes and creatinine Calcium Serum immunoglobulins with protein electrophoresis for detection of M protein Urine sample for detection of free immunoglobulin light chains (BJP) Plain X-ray imaging of symptomatic bony sites or skeletal survey (Nb. radionuclide bone scanning is unhelpful in multiple myeloma due to the lytic nature of the bone lesions) Management Myeloma remains an incurable disease. It has a heterogeneous clinical presentation that requires a multi-disciplinary approach, including involvement of haematologists, renal p h y s i c i a n s, o r t h o p a e d i c s, palliative care, physiotherapists, occupational therapists and dieticians. There is no evidence that treating early myeloma (smouldering or asymptomatic) has an impact on overall survival. Management for early myeloma includes careful monitoring of monoclonal protein levels and the functioning of other organs. Chemotherapy is commenced in patients with symptomatic multiple myeloma and measurable end organ damage (see box 4).

3 Oncology 299 Supportive care Renal failure Renal impairment is present in 30% of patients at presentation. Prevention includes encouraging high fluid intake and avoiding nephrotoxic drugs, including aminoglycosides and NSAIDS. See box 5 for details of management. Pain Multiple myeloma patients commonly present with bone pain. Most can be controlled with oral analgesia. Lytic lesions can be treated with 8Gy single fraction radiotherapy. Long bone fractures may require orthopaedic intervention. Vertebral collapse can cause functional disability in addition to pain. Surgical solutions include vertebroplasty and kyphoplasty. Kyphoplasty is performed by inserting a balloon-like device through a catheter passed into the fractured vertebrae. The balloon is inflated. Cement is then injected into the cavity created by the balloon to correct the vertebral collapse. Although there are no published trials of kyphoplasty in multiple myeloma patients, case reports have demonstrated pain relief and improvement in function following the procedure. 4 is present in two thirds of multiple myeloma patients. Red cell transfusional support may be required. Transfusions should be used with caution in patients with high paraprotein to avoid increasing blood viscosity. The rising cost of red cell transfusions and the risks associated have prompted erythropoietin (EPO) Box 3: International prognostic index for multiple myeloma Stage Criteria Median survival (months) I Serum Β2M <3 5 mg/l 62 and serum albumin >35 g/l II Neither I or III* 45 III Serum Β2M >5 5 mg/l 29 * There are two sub-categories: serum Β2M <3 5 mg/l, but serum alb <35 g/l or serum Β2M mg/l irrespective of serum Alb. use. Many studies have shown efficacy of EPO in multiple myeloma, reducing the need for transfusions. 5 EPO is recommended in anaemic patients with multiple myeloma and chronic renal failure. 6 Bisphosphonates Strong evidence from randomised trials supports the use of longterm bisphosphonates in all patients with symptomatic multiple myeloma requiring treatment. A reduction in skeletal morbidity, improved quality of life and reduction in analgesic and radiotherapy requirements have been demonstrated. 7 They are also used acutely to reverse hypercalcaemia. Intravenous zoledronate and pamidronate and oral sodium clodronate are all effective in multiple myeloma. Disease-modifying treatment When commencing treatment for symptomatic disease, consider the patient s age, performance status and wishes. Box 4: CRAB End organ damage caused by myeloma Calcium levels increased Renal insufficiency Bone lesions Other Corrected serum Ca > 2.75mmol/l Attributable to myeloma Hb 2g/dl below lower limit of normal or <10g/dl Lytic lesions or osteoporosis with compression fractures Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (more than two episodes in 12 months) June 2010 Midlife and Beyond GM

4 300 Oncology Box 5: Initial management of renal failure in patients with multiple myeloma Rehydrate (central venous pressure measurements may be required) Stop all nephrotoxic drugs if possible Treat infection rapidly Correct hyperuricemia using drugs such as rasburicase or allopurinol Correct hypercalcaemia; seek advice on the dose of bisphosphonates Seek advice of a renal physician if no improvement after 48 hours, or earlier if severe renal failure/anuria Be careful using opiates for pain as they accumulate rapidly Treatment of patients with good performance status The standard treatment for those aged 70 years or less is combination chemotherapy for 4 6 months, which aims to produce a rapid reduction in bulk disease. Peripheral blood stem cells are then collected and re-infused after the patient has received high dose chemotherapy (HDT), usually with melphalan. This procedure is called Autologous Peripheral Blood Stem Cell Transplant (PBSCT). As first-line therapy, complete remission rates vary between 24% and 75%, with a median survival of 4 5 years. The national Medical Research C o u n c i l / N a t i o n a l C a n c e r Research Insitute trial MYELOMA IX, has recently finished recruiting patients. This trial compared combinations of induction chemotherapy used in this patient group. The C-VAD regimen (vincristine and doxarubicin as an infusion and oral dexamethasone and cyclophosphamide) was compared with oral CTD (cyclophosphamide, thalidomide and dexamethasone). Preliminary results have shown improved overall response rates (ORR) and complete remission (CR) rates with the CTD regimen (ORR 95.7% CTD vs 83% CVAD and CR 20% vs 11%). Thalidomide Thalidomide was prescribed during the late 1950s to treat morning sickness in pregnancy. Many children with severe limb malformities were born due to its anti-angiogenic effects. Thalidomide is thought to be effective in multiple myeloma through its anti-angiogenic and immunomodulatory properties which affect the bone marrow microenvironment and reduce myeloma cell survival. There is strong data to support the use of a thalidomide-based regimen (such as CTD) as initial multiple myeloma therapy. 8 In addition, thalidomide is used as consolidation/maintenance therapy after HDT and for relapsed/refractory multiple myeloma. Thalidomide can be used without dose modification in renal failure. Common sideeffects of thalidomide are peripheral neuropathy, sedation, constipation, rash, venous thromboembolic disease and myelosuppresion. Thrombo-prophylaxis should be considered in all patients receiving thalidomide due to an increased incidence of venous thromboembolism. Treatment of patients with less good performance status Patients over 70 years of age are less likely to tolerate intensive chemotherapy and the intent of treatment is to achieve a plateau phase of the multiple myeloma and a good quality of life. Melphalan Oral melphalan in low doses has been used for many years and is still considered the gold standard for elderly patients. Response is gradual and it may take several months to achieve a plateau phase. The plateau phase can last months before relapse, and the median survival is 2 4 years from diagnosis. Melphalan must be avoided in patients in whom HDT is being considered, as it is stem cell toxic. Steroids Dexamethasone can be used in pulses to treat myeloma. This is particularly useful in renal failure when other chemotherapy is contraindicated. Alternatives include prednisolone, usually used in combination with chemotherapy. Thalidomide combinations Recent trials have looked at thalidomide combinations in the elderly as first-line treatment. Cyrille et al compared melphalan and prednisolone (MP) with melphalan, prednisolone and thalidomide (MPT) in elderly patients >75 years. The median overall survival was 27 7 months for MP versus 45 3 months for MPT. 14 It is, however, especially

5 302 Oncology 302 important to consider the sideeffect profile of thalidomide in elderly multiple myeloma patients. Novel treatments Bortezomib (Velcade) Bortezomib has recently been licensed in Europe for second -line and third-line treatment of multiple myeloma. It is given intravenously on days 1, 4, 9 and 11 of a 21-day cycle. It inhibits the cell proteosome, which functions to maintain intracellular homeostasis. This inhibition results in apoptosis and cell death T h e S U M M I T t r i a l demonstrated an overall response rate of 35% and a complete response rate of 10% in relapsed multiple myeloma patients. The APEX trial showed an improvement in time to progression in the bortezomib arm (6 2 months vs 3 5 months for dexamethasone alone). The main side effects include painful peripheral neuropathy and myelosuppression. Lenalidomide Lenalidomide is a secondgeneration oral immunomodulatory thalidomide analogue that is licensed for use in combination with dexamethasone in relapsed or refractory multiple myeloma. It is administered orally on days 1 to 21 of a 28-day cycle. It appears to have fewer side-effects than thalidomide including less risk of constipation, peripheral neuropathy and somnolence. Side-effects include neutropenia and thrombocytopenia. An increased risk of venous thromboembolism is present and thromboprophylaxis should be considered on an individual patient basis. Because of its reduced side-effect profile, lenalidomide is generally well tolerated in the elderly. Conclusion In recent years, there has been a great advance in our understanding of the biology of myeloma, which can result in the clinical features of anaemia, bone disease, infection and renal failure. Several new treatments that have been developed including thalidomide, bortezomib and lenalidomide are improving the overall prognosis and quality of life for elderly patients with multiple myeloma. We have no conflict of interest References 1. Fonseca R, Greipp PR. Molecular cytogenetics of myeloma biology: clinical and prognostic implications. Hematology Journal 2003; 4(S1): Guidelines on the diagnosis and management of multiple myeloma Greipp PR, San Miguel J, Fonseca R, et al. Development of an international prognostic index (IPI) for myeloma: report of the international myeloma working group. Hematology Journal 2003; 4: S42 4. Lane JM, Hong R, Koob J, et al. Kyphoplasty enhances function and structural alignment in multiple myeloma. Clinics in Orthopedics 2004; 426: Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. British Journal of Haematology 2001; 113: Cameron JS. European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrology Dialysis and Transplantation 1999; 14( Suppl. 2), McCloskey EV, et al. A randomised trial of the effect of clodronate on skeletal morbidity in multiple myeloma. British Journal of Haematology 1998; 100: Morgan GJ, Davies FE, Owen RG, et al. Thalidomide combinations improve response rates; results from the MRC IX study.blood (ASH Annual Meeting Abstracts) : Abstract Rajkumar SV, Hayman SR, Gertz MA, et al.thalidomide plus dexamethasone and thalidomide alone as first line therapy for newly diagnosed myeloma (MM). Blood 2000; 96: 168A 10. Garcia- anz R. Gonzalez- Fraile MI, Hernandez JM, et al. The oral combination of thalidomide, cyclophophamide and dexamethasone is effective in relapsed/refractory multiple myeloma. Leukaemia 2004; 18: Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: Olojohungbe AB, et al Prednisolone added to the ABCM as treatment for multiple myeloma increases serological responses but not overall survival or the number of stable clinical responses. British Journal of Haematology 1996; 9: Facon T, Jean YM, Cyrille H, et al. Melphalan and prednisilone plus thalidomide versus melphalan plus prednisilone alone or reduced intensity autologous stem cell transplantation in elderly patients with multiple myeloma(ifm99-06): a randomised trial. Lancet 2007; 370: Hulin C, Facon T, Rodon P, Pegourie B, et al.melphalan-prednisilone- Thalidomide(MP-T) demonstrates a significant survival advantage in elderly patients >75 years old with multiple myeloma compared with Melphalan- Prednisilone(MP) in a randomised, double blind, placebo controlled trial, IFM 01/01.Blood (ASH annual meeting abstract) 110: 75