Guidelines for the diagnosis and management of Myeloma within AngCN

Guidelines for the diagnosis and management of Myeloma within AngCN Ref: AngCN-SSG-Ha5 Cancer Standards Measure: N/A Page 1 of 11 Approved and Published: March 2013

1 Introduction These brief guidelines are a summary representation of the current management of multiple myeloma in the Anglia Cancer Network region (AngCN). Included is guidance to General Practitioners with regards to what constitutes a diagnosis of multiple myeloma. The guidance of investigations and therapies does not replace the published UK Myeloma Forum and Nordic study group guidelines rather, it condenses them. Clinicians are however reminded to refer to these National guidelines for a more complete overview. 2 Pathology of multiple myeloma Multiple myeloma is a malignant disease of plasma cells. The incidence increases with advancing age and it is invariably incurable. Clinical presentations relate to bone marrow failure, bone destruction or damage from proteins released from the myeloma cells. Around 1% per annum of patients given a diagnosis of MGUS will progress to multiple myeloma. Most patients with myeloma are diagnosed without prior knowledge or evidence of a paraprotein. 3 Clinical Presentation Patients with multiple myeloma may present with a combination of any of the following: Symptoms of bone disease Impaired renal function Anaemia or less frequently leucopoenia or thrombocytopenia Hypercalcaemia Recurrent or persistent bacterial infections Hyperviscosity Spinal cord compression Features suggestive of amyloidosis Incidental finding of significant Paraprotein, raised ESR or plasma viscosity 4 GP referral guidelines 4.1 Paraproteinaemias Not all patients with a paraprotein need to be investigated by the haematology department. 4.2 MGUS Isolated paraproteinaemia in the absence of features of myeloma is termed MGUS or monoclonal gammopathy of uncertain significance. It is increasingly common with age: incidence 2% of age>50 years, 3% of >70 years. If patients are found to have MGUS they can usually be managed entirely by the GP or discussed with a haematologist and followed by the GP. The risk of progression to myeloma or a lymphoproliferative disorder is about 1% per annum. Serum free light chains may be useful for prognostic stratification a) Isolated low-level paraprotein Those with an isolated low level paraprotein (IgG less than 15g/l or IgA <10g/l) found on routine testing and who have no significant symptoms including those suggestive of bone disease and no anaemia, hypercalcaemia or renal impairment can be investigated by their GP. Investigations should include a FBC, U+E, creatinine and calcium. If the paraprotein is stable on 3 occasions, annual monitoring of clinical state and bloods is usually adequate. Page 2 of 11 Approved and Published: March 2013

b) Persistent isolated moderate level paraproteinaemia National Guidance suggests that patients who have a significant persistent isolated paraproteinaemia should be referred by letter to haematology if: IgG paraprotein is greater than 15 g/l or IgA/M paraprotein is greater than 10g/l. 4.3 Myeloma Symptomatic patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate admission to hospital. 5 Diagnostic Criteria and Differential Diagnosis The diagnosis of myeloma is usually confirmed by demonstration of: a monoclonal protein (M-protein/paraprotein) in the serum or urine together with an increased number of plasma cells in the bone marrow and/or lytic lesions on X-ray (Greipp, 1992). Other conditions in which an M-protein may be present include: Monoclonal Gammopathy of Undetermined Significance (MGUS) AL amyloidosis Solitary plasmacytoma (skeletal or extra-medullary) B-cell non-hodgkin's lymphoma (including Waldenstrom's macroglobulinaemia) Chronic lymphocytic leukaemia Diagnostic Criteria for MGUS, Asymptomatic Myeloma and Symptomatic Myeloma (International Myeloma Working Group, 2003) * AL amyloid and the IgM paraprotein-related neurological syndromes would be instances of monoclonal gammopathy associated with specific syndromes ** No specific level required for diagnosis. A small percentage of patients have no detectable M-protein in serum or urine but do have myeloma-related organ impairment (ROTI) and increased bone marrow plasma cells (non-secretory myeloma) *** Patients without symptoms but with significant myeloma-related organ damage are grouped with symptomatic myeloma because of the need for treatment. Page 3 of 11 Approved and Published: March 2013

5.1 Investigation of Suspected Myeloma Initial investigations: FBC, viscosity +/- ESR U&E, creatinine, albumin, calcium, bone biochemistry and uric acid Electrophoresis of serum +/- concentrated urine (BJP) Paraprotein estimation X-ray of symptomatic areas or skeletal survey if lytic lesions found or myeloma likely NB not required to make diagnosis of MGUS Consider bone marrow aspirate and trephine (including mmunophenotyping or immunohistochemistry) if paraprotein IgA/ IgM >10g/l or IgG/ >15 or above tests abnormal Immunofixation of serum and urine Skeletal survey. Albumin, β2microglobulin, +/- 24 hr urine light chain quantification if light chain myeloma Serum free light chain ratio if non secretory or light chain myeloma Paraprotein <30g/l Above investigations normal (BM plasma cells <10% - if performed) Paraprotein >30 g/l or plasma cells >10% in bone marrow No evidence of bone disease or other end organ damage* Evidence of bone disease or other end organ damage* and evidence of clonality *Myeloma-related organ or tissue impairment see below MGUS Asymptomatic myeloma Symptomatic myeloma Arrange to repeat initial blood tests at 3 and 6 months usually via GP. If stable annual monitoring thereafter Patients who are elderly or with low level paraprotein can be investigated by their GP and do not need to be referred to clinic. Follow up in clinic every 3-4 months or as clinically indicated. Restage with BM/skeletal survey if evidence of progression Requires treatment see below Page 4 of 11 Approved and Published: March 2013

6 Myeloma-related organ or tissue impairment (ROTI)* Clinical effects due to myeloma Increased calcium levels Renal insufficiency Anaemia Bone lesions Other Corrected serum calcium >0 25 mmol/l above the upper limit of normal or >2 75 mmol/l Attributable to myeloma Haemoglobin 2 g/dl below the lower limit of normal or haemoglobin <10 g/dl Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (more than two episodes in 12 months) *Where there is uncertainty as to whether or not organ or tissue impairment is attributable to myeloma the percentage bone marrow plasma cells should be >30%. 7 Prognosis in myeloma The international staging system is shown below: 7.1 International Staging System Stage Criteria Median survival (months) I Serum β 2 microglobulin <3 5 mg/l and serum 62 albumin >35 g/l II Neither I nor III* 45 III Serum β 2 microglobulin >5 5 mg/l 29 *There are two sub-categories for stage II: serum β 2 microglobulin <3 5 mg/l, but serum albumin <35 g/l, or serum β 2 microglobulin 3 5 5 5 mg/l irrespective of the serum albumin level. 8 Indications for therapy Chemotherapy is indicated for the management of symptomatic myeloma and asymptomatic myeloma with myeloma-related organ damage. Early intervention in other asymptomatic myeloma has shown no benefit. Care should be delivered by the multidisciplinary team. 9 Therapy 9.1 Supportive care All patients should receive supportive care which includes: Prevention of renal failure Encourage fluids (ideally 2-3 l per day if tolerated) Avoid drugs such as NSAIDS Page 5 of 11 Approved and Published: March 2013

Pain control Systemic analgesia (using WHO treatment ladder) Local analgesic approaches as required including: Radiotherapy (adjuvant pain relief) Stabilization of long bone Vertebroplasty/kyphoplasty Infections Early treatment Advise patients to have the influenza vaccine pneumovax & HIB each year Those with hypogammaglobulinaemia and severe recurrent infections may benefit from monthly immunoglobulin infusions see National guidance Prevention of bone disease / skeletal related event In all patients with symptomatic myeloma: initially intravenous bisphosphonates (Zoledronate / Pamidronate) There is evidence that Zoledronate may prolong progression free survival and overall survival. Consider checking vitamin D and calcium levels or replacing calcium and vitamin D supplementation with Zoledronate. Offer trial if appropriate and available Treatment should continue for 2 years. Treatment beyond 2 years should be at the treating haematologist s discretion, considering the disease status and extent of bone disease in the individual patient. It is reasonable to discontinue if achieve a CR or very good PR with no active bone disease.if treatment is continued beyond 2 years and the patient is receiving an intravenous bisphosphonate consider switching from IV to oral sodium clodronate. Bisphosphonate should be restarted at disease progression. Caution is required with all bisphosphonates in patients with moderate to severe renal failure refer to manifacturer s guidance. Zoledronic acid should not be used in patients with creatinine clearance of less than 30 ml/min, Pamidronate is also not recommended but may be used in patients with creatinine clearances of less than 30ml/min in the event of severe or lifethreatening hypercalcaemia (using a reduced dose and longer infusion times). Advise dental check up pre bisphosphonate therapy if possible and regular dental check ups throughout with the avoidance of invasive dental procedures if possible. Anaemia May be managed with transfusions or erythropoietin. All patients will managed as part of a multidisciplinary team comprising input from haematology, pathology, clinical biochemistry and immunology, specialist haematology nurses, palliative care team, radiotherapists, renal medicine, orthopedic surgery, neurosurgery, chemotherapy pharmacy, physiotherapy, dietician and rehabilitation. 9.2 First line Cyto-reductive therapy: All patients will be offered clinical trials where appropriate and available. For those not in trial: a) Patients who are candidates for high dose therapy High dose chemotherapy and autologous stem cell transplantation should be part of the primary treatment in patients up to the age of 65 who have an adequate performance status and absence of co morbidities. Page 6 of 11 Approved and Published: March 2013

Patients over the age of 65 may also be considered if fit without significant co morbidities. Allogeneic stem cell transplant is only recommended as part of a clinical trial Therapy: CTD (Cyclophosphamide, Thalidomide and Dexamethasone) or equivalent novel agent containing regime. Patients with renal failure consider Cyclophosphamide dose reduction as per guidelines Give thromboprophylaxis, usually low molecular weight Heparin or therapeutic Warfarin. Aspirin may be considered (75 150 mg) if no other VTE risk factors present. Treat to maximum response, usually minimum of 4 courses, and then aim for autologous PBSCT. Refer eligible patients to the stem cell transplant unit around third course. PBSCT conditioning should be with Melphalan at a dose of 200mg/m 2 but the dose should be reduced in the setting of significant renal failure, age over 65 or other clinical concerns. b) Patients who are not candidates for high dose therapy (NICE TAG 228, July 2011) 1.Thalidomide based regime for example CTDa or MPT or equivalent In renal failure avoid or dose reduce Melphalan and consider Cyclophosphamide Use steroids with caution in patients with diabetes. 2. For those with contraindications to or who are intolerant of thalidomide Bortezomib in combination with an alkylating agent and a corticosteroid for example melphalan, prednisolone and bortezomib or cyclophosphamide bortezomib and dexamethasone). c) Myeloma and renal failure In patients presenting in renal failure, a bortezomib containing regime should be commenced as early as possible to maximise chances of salvaging renal function. d) Maintenance therapy Consideration should be given to maintenance thalidomide after initial induction therapy. The greatest benefit is likely to be seen in those who have not achieved a VGPR or better. For treatment response criteria, see appendix 1 9.3 Refractory and Relapsed Disease For relapse definition see appendix 1 Continue best supportive care, restart IV bisphosphonates All patients will be offered clinical trials where appropriate and available a) 2nd line therapy: Bortezomib containing regime, for example Bortezomib and Dexamethasone received if IMID containing regime as 1 st line. Page 7 of 11 Approved and Published: March 2013

The role of 2 nd autograft should be considered for those that have progressed greater than 12 months post 1 st autograft following reinduction therapy. Allograft as part of a clinical trial. b) 3rd line or later progression Continue best supportive care. All patients will be offered clinical trials where appropriate and available Treat ment: Lenalidomide based regimes. Note lenalidomide dose reductions in renal failure Give thromboprophylaxis with lenalidomide based regimes: usually low molecular weight Heparin or therapeutic Warfarin. Aspirin may be considered (75 150 mg) if no other VTE risk factors present. Dexamathasone alone or in combination with alkylating agents e.g. Cyclophosphamide, melphalan, thalidomide or Bendamustine or other new agents. Bortezomib based regimes are appropriate for those patients who have previously responded to bortezomib and have a treatment free interval of 12 months or greater. 10 Treatment of Hypercalcaemia Local/AngCN guidelines In mild hypercalcaemia (corrected calcium 2.6 2.9mmol/l) rehydrate with oral fluids In moderate-severe hypercalcaemia (corrected calcium >2.9 mmol/l) rehydrate with iv fluids and give frusemide. If not already on a bisphosphonate, start intravenously immediately If on a bisphosphonate consider changing to a more potent bisphosphonate or increase the dose Consider additional therapy such as corticosteroids or i.m. calcitonin in refractory patients. 11 Management of Spinal Cord Compression See AngCN MSCC Service Description (AngCN-CCG-AO10) and patient information leaflet (APIN11) for those at risk of cord compression. In myeloma, in particular: Urgent MRI of spine Commence Dexamethasone 20 40mg daily for 4 days Urgent local radiotherapy Surgery not indicated unless spinal instability or bone compression. 12 Management of Hyperviscosity This may develop in patients with a high paraprotein especially if IgA or IgG3. If symptomatic, refer for urgent plasma exchange. Page 8 of 11 Approved and Published: March 2013

13 Management of Renal Failure The pathogenesis of renal failure in myeloma is usually multifactorial, commonly due to nephrotoxic drugs (in particular NSAIDs), dehydration, infection, hypercalcaemia light chain deposition, hyperuricaemia. Less commonly factors such as plasma cell infiltration and amyloid. Management includes prompt reversal of the above features stop nephrotoxic drugs vigorous rehydration (3 litres per day) treatment of infection reversal of hypercalcaemia Seek nephrology advice if no improvement within 48 hours. Dialysis may be appropriate If the underlying myeloma requires therapy, there should be early initiation of high dose Dexamethasone (40mg daily x 4 days) unless otherwise contraindicated. For those newly diagnosed patients, bortezomib should also be started. The role of plasma exchange is unclear. but physical methods of removing free light chains (plasma exchange or large pore haemodialysis) can be considered within the context of a clinical trial. 14 References and National Guidelines UK myeloma forum (UKMF) and Nordic myeloma study group (NMSG: Guidelines for the investigation of newly detected M proteins and the management of monoclonal gammopathy of uncertain significance (MGUS) Bird J et al. British Journal of Haematology, 2009,147, (22-42) BCSH and UKMF Guidelines on the diagnosis and management of multiple myeloma, 2010 www.bschguidelines.com BCSH and UKMF Guidelines for supportive care in myeloma. 2010 www.bschguidelines.com BCSH and UKMF Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytomas. 2009 update www.bschguidelines.com D Sa S, Abildgaard N, Tighe J, Shaw P, Hall-Craggs M Guidelines on the use of Imaging in the management of myeloma British Journal of Haematology 2007;137, 49-63 NICE Guidance 2007 : Bortezomib monotherapy for relapsed multiple myeloma (TA129) NICE guidance 2009: Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. (TA 171) NICE guidance 2011 Bortezomib and thalidomide for the first line treatment of multiple myeloma (TAG 228) Page 9 of 11 Approved and Published: March 2013

15 Patient support International Myeloma Foundation (UK) - www.ukmf.org.uk Macmillan Cancer Support www.macmillan.org.uk Anglia cancer network patient information leaflet - Patient Information on MSCC Signs and Symptoms APIN11 16 Monitoring the Effectiveness of the Process a) Process for Monitoring compliance and Effectiveness - Review of compliance as determined by audit. Any non compliance to be presented by PQ Manager to the AngCN Business Meeting on an annual basis the minutes of this meeting are retained for a minimum of five years. b) Standards/Key Performance Indicators This process forms part of a quality system working to, but not accredited to, International Standard BS EN ISO 9001:2008. The effectiveness of the process will be monitored in accordance with the methods given in the quality manual, AngCN-QM Equality and Diversity Statement This document complies with the Suffolk PCT Equality and Diversity statement an EqIA assessment is available on request to Anglia Cancer Network PQ Manager, Gibson Centre, Exning Road, Newmarket, CB8 7JG. Disclaimer It is your responsibility to check against the electronic library that this printed out copy is the most recent issue of this document. Please notify any changes required to the Anglia Cancer Network Quality Assurance Manager Document management Document ratification and history Approved by: Haematology SSG Date approved: March 2013 Date placed on electronic library: March 2013 Review period: 2 years (or earlier in the light of new evidence) Authors: Dr Jenny Craig, Consultant Haematologist Document Owner: Anglia Cancer Network, Tel: 01638 558580; www.angcn.nhs.uk Version number as approved and published: 3 Unique identifier no.: AngCN-SSG-Ha5 Page 10 of 11 Approved and Published: March 2013

Appendix 1 Response subcategory Stringent complete response (scr) Response criteria Response criteria CR as defined below plus Normal SFLC ratio Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence Complete response (CR) Very good partial response (VGPR) Partial response (PR) Stable disease (SD) Negative immunofixation in serum and urine Disappearance of any soft tissue plasmacytomas <5% bone marrow plasma cells Serum and/or urine M protein detectable by immunofixation but not on electrophoresis or >90% reduction in serum M protein and urine M protein level <100mg/24hr >50% reduction of serum M protein and reduction in 24hr urinary M protein by >90% or to <200mg/24hr If the serum and urine M-protein are unmeasurable a >50% decrease in the difference between involved and uninvolved SFLC levels required. If SFLC assay is also uninformative PR is defined by >50% reduction in bone marrow plasma cells Not meeting criteria for CR, VGPR, PR or progressive disease RELAPSE DEFINITION Relapse subcategory Relapse criteria Progressive disease (PD) Requires at least one of the following >25% increase in serum M protein in 3 months (absolute increase must be >5g/l) >25% increase in urine M protein in 3 months (absolute increase must be >200mg/24hr) >25% increase in the difference between involved and uninvolved SFLC levels (applicable only to patients without measurable serum and urine M protein. Absolute increase must be >10mg/dl >25% increase in bone marrow plasma cell percentage (absolute percentage must be >10%) Development of new bone lesions or soft tissue plasmacytoma Development of hypercalcaemia Clinical relapse Requires at least one of the following Development of new bone lesions or soft tissue plasmacytoma Increase in size of existing plasmacytomas or bone lesions Any of the following attributable to myeloma: Development of hypercalcaemia Development of anaemia (drop in Hb of >2g/dl) Rise in serum creatinine Relapse from CR Requires at least one of the following Reappearance of serum or urine M protein by immunofixation or electrophoresis Development of >5% plasma cells in the bone marrow Appearance of any other sign of progression Page 11 of 11 Approved and Published: March 2013