Exclude a coexisting haematopoietic neoplasm (SM-AHNMD), hypercellularity or dysmyelopoiesi s (prognostic value); exclude reactive non-clonal mast cell hyperplasia that may accompany several hematological disorders where mast cells lack atypia and are sprinkled throughout t he marrow rather than in aggregates.2 \200 Immunohistochemistry for tryptase, CD117 (KIT) and CD25 to demonstrate infi ltrate of tryptase +ve spindle-shaped mast cells. \200 If i solated infi ltrate only or multifocal small aggregates (<15 MCs) consider minor diagnostic criteria (Table 7.15). If subdiagnostic (n <3), repeat biopsy; if remains subdiagnostic in patient with high clini cal suspicion monitor closely. KIT-mutation analysis might help. Table 7.15 WHO diagnostic criteria for SM2 \200\2234 Major criteriona Multifocal, dense infi ltrates of mast cells ( \211 15 mast cells per aggregate) in BM and/ or other extracutaneous organ(s) confi rmed by tryptase immunohistochemistry Minor criteriaa 1. In biopsy sections of BM or other extracutaneous organs >25% of mast cells show an abnormal spindle- shaped morphology or >25% of mast cells in BM aspirate smears are immature or atypical 2. Detection of c-KIT mutation D816V or other activating mutation at codon 816 in extracuta neous organ(s); marrow is recommended for screening 3. KIT+ MCs in BM or other extracutaneous organs express CD2 or/and CD25 4. Serum tryptase >20ng/mL (does not count in patients who have AHNMD-type disease) a If at least 1 major and 1 minor criterion or at least 3 minor criteria are fulfi lled, th e diagnosis of SM can be established. 318 CHAPTER 7 Myeloproliferative neoplasms BM aspirate \200 \211 5% mast cells suggests an unfavorable prognosis; \211 20% defi ne s mast cell leukemia; mild myelodysplasia is found in most patients with SM.3 Mast cells in SM show aberrant morphological features.3 \200 Non-metachromatic myeloblast s suggest AHNMD and dysplasia; >5% SM-MDS and >20% SM-AML. Aspirate can be negative whilst trephine is diagnostic. Flow cytometry \200 Neoplastic SM mast cells usually aberrantly express CD25 CD2. \200 BM cells should be analyzed; minimum recommended panel includes CD2, CD25, CD45, and CD117; CD34 may be added when CD117 expression low (frequent in KIT mutation8) to defi ne M C as CD34-/ CD117+/CD45+.3 KIT-D816V and other KIT mutation analysis \200 Neoplastic mast cells in >80% adults with SM have activating KIT mutation at codon 816; D816V most common (SM 70 \200\22390%; CM 10 \200\22330%), all others rare.3 RT-PCR and RFLP analysis of unfractionated BM cells after RBC-lysis or marrow mononuclear c ells; PB is not an acceptable alternative as often \210\222ve in ISM.3 If \210\222ve result with small infi ltrate, interpret with caution; if large infi ltrate, confi rm \210\222ve result in reference laboratory as wt-KIT and certain othe r mutants confer imatinib-sensitivity. Serum tryptase \200 Almost all patients with SM have serum tryptase level >20ng/mL. \200 In severe allergic reactions, tryptase may be markedly elevated so wait 2d after clinical resolution before measuring; if elevated, consider SM.3 \200 Also elevated in myeloid no n-mast cell disorders, AML, CML, MPN, and MDS; therefore a minor criterion only in absence of AHNMD. \200 Tryptase level higher with high mast cell burden; in ISM level remains rea sonably constant over years; in ASM or mast cell leukemia levels often increase as disease progresses. In ASM or mast cell leukemia tryptase levels often decrease with successful cytoreduction.3 FBC and \201 lm \200 No characteristic features; circulating mast cells very rare (2%) unless very advanced disease or mast cell leukemia. Mild-to-moderate anemia 745%; eosinophilia up to 25%; thrombocytopenia 720%; monocytosis 715%; pancytopenia may develop due to BM infi ltration o r hypersplenism. Other investigations \200 Bone scan/skeletal survey shows bone lesions in 60%; generalize d osteosclerosis, focal sclerosis, osteopenia, osteoporosis, or osteolysis. Bone densitometry (DEXA scan) in all patients with SM. \200 Ultrasound abdomen. \200 Se rum biochemistry. 319 SYSTEMIC MASTOCYTOSIS Coagulation screen. \200 Endoscopy in patients with GI symptoms. \200 EEG: if clinicall y indicated. Variants of SM \200 Indolent SM (ISM): most common form of SM (766%); no \200\230B \200 \231 or \200\230C \200\231 fi ndings; mast cell burden low; usually involves skin and BM; associated with maculopapular skin lesions (90%); fl ushing and abdominal cramps frequently reported; slow involvement of organs; prolonged course and good prognosis in almost all wi th survival >20 years; poor quality of life if inadequate control of mediator symptoms; sma ll number transform into ASM or SM-AHNMD.2,5,6 Subvariants identifi ed:4 \200 BM mastocyt osis (BMM): rare subvariant of ISM with isolated marrow involvement and no skin lesions or multiorgan involvement, low MC burden and good pr ognosis.2 Smoldering SM (SSM): as ISM with 2 or more \200\230B \200\231 fi ndings but no \200\230C \200\231 fi nding; some have prolonged stable course others develop ASM or AHNMD.2,3,5,6 Aggressive SM (ASM): 75% of all SM patients; \211 1 \200\230C \200\231 fi nding; may present with hepatosplenomegaly and/or generalized lymphadenopathy without typical skin les ions; characterized by impaired organ function due to progressive infi ltration of BM, live r, spleen, GI tract, or skeletal system; predisposition to severe mediator release attacks with haemorrhagic complications; median survival 3 \200\2235 years:2,6 \200 Lymphadenopat hic mastocytosis with eosinophilia: rare subvariant of ASM; progressive lymphadenopathy wit h PB eosinophilia often with extensive bone involvement and hepatosplenomegaly but usually without skin lesions.2,6 SM with associated hematological non-mast cell disease (SM-AHNMD): 20 \200\22330% of SM pat ients; <50% have skin lesions; 80 \200\22390% myeloid, most commonly CMML; 10 \200\22320% l ymphoid, most commonly myeloma; classify using WHO criteria; prognosis poor, largely determ ined by accompanying disorder and poorer survival than patients without SM.2,6 Mast cell leukemia: rare; \211 20% MC in BM aspirate and \211 10% in PB (aleukaemic varia nt <10%); diff use infi ltration on trephine biopsy; no skin lesions, severe peptic ulcer d isease, hepatosplenomegaly, anemia, multiorgan failure; poor response to chemotherapy and s hort survival (most <1 year).2,5,6 Mast cell sarcoma (MCS): extremely rare; unifocal tumor consisting of atypical mast cells; high grade cytology; locally destructive growth; no skin or systemi c involvement at diagnosis; prognosis grave; rapid progression with terminal phase resembli ng Mast cell leukemia.2,6 \200 Extracutaneous mastocytoma: extremely rare; most reported cases involve lung; unifocal tumor; low-grade cytology; non-destructive growth pattern; no skin or systemic involvement.2,6 320 CHAPTER 7 Myeloproliferative neoplasms Diff erential diagnosis Diagnosis often delayed due to non-specifi c symptoms and presentat ion. Exclude reactive mast cell hyperplasia, mast cell activation syndromes, MPNs with i ma st cells, carcinoid syndrome, phaeochromocytoma, liver disease, CEL/HES, and lymphoma. Management \200 No curative therapy; management consists of prevention of mediator eff ects, an attempt to control organ infi ltration by mast cells by cytoreductive therapy where appropriate, and treatment of accompanying hematological disease where prese nt. \200 Selection of intensive therapy should be based on signs and symptoms of aggressive disease (C-fi ndings). \200 B-fi ndings: borderline benign; wait a nd watch. \200 C-fi ndings: consider cytoreduction with chemotherapy or with targeted drugs. Patients should avoid factors triggering acute mediator release: extremes of temperature, pressure, friction, aspirin, NSAIDs, opiates, alcohol, specifi c a llergies. In SM-AHNMD, treat the associated hematological disorder as for cases without SM and treat SM component as required.3 Generally patients achieve a short partial remission at best; sp lenectomy may help pancytopenic patients. SCT should be considered in appropriate patients. SM-CEL with FIP1L1-PDGFRA fusion gene will respond to imatinib. Treatment of acute mast cell mediator release \200 Anaphylaxis: epinephrine (adrenaline) adult dose every 10 \200\22315min as needed. Refractory hypotension and shock: fl uid resuscitation and epinephrine (adrenaline) IV bolus plus infusion; add inotropes if unresponsive. Patients at risk of severe hypotension should be advised to carry 2 or more epinephrine (adrenaline) self-injectors.3 Commence H1 plus H2-receptor antagonists and steroids. Treatment of chronic mast cell media tor release \200 H1 plus H2 receptor antagonists: H1 antihistamines: diphenhydramine (25 \200\22350mg PO 4 \200\2236-hourly; 10 \200\22350mg IM/IV), hydroxyzine (25mg PO tid or qid ; 25 \200\223100 mg IM/IV) or loratadine (non-sedating; 10mg PO od); H2 antihistamines: ran itidine (150mg PO bd; 50mg IV) or cimetidine (400 \200\2231600mg/day PO in divided doses; 3 00mg IV). Titrate doses for individual patient requirements. GI symptoms unresponsive to H1 and H2 antagonists may respond to sodium cromoglicate or short-term corticosteroids; prednisolone 40 \200\22360 mg/d PO fo r malabsorption, tailing dose. Bisphosphonates for osteoporosis; analgesia for bone pain, radiotherapy in severe cases; osteolysis is a sign of advanced disease and an indication fo r cytoreductive therapy/IFN.3 PUVA for urticaria pigmentosa. \200 A small number of patients gain symptomatic relief fr om interferon alfa or ciclosporin for refractory symptoms. 321 SYSTEMIC MASTOCYTOSIS Cytoreductive treatment3,5 \200 First establish diagnosis of ASM, Mast cell leukemia, or MCS and KIT mutation status. ISM or SSM: cytoreductive treatment generally not required, but in SSM with rapidly progressive B-fi ndings: \200 Consider interferon alfa (3 million units SC tiw) corticosteroids (50 \200\22375mg/d, commence before interferon alfa and monitor carefully during initial da ys of treatment5). \200 Cladribine: CR but prolonged remission rare. KIT-D816V \210\222ve (wild type or other mutation) ASM or mast cell leukemia: consider imatinib; N.B. KIT-D816V+ SM is imatinib resistant. ASM with slow progression: interferon alfa (15 \200\22320% major clinical responses in ASM/ MCL6) corticosteroids; if interferon alfa intolerant, or no response, consider cladribin e. ASM with rapid progression: polychemotherapy, e.g. cytarabine fl udarabine and/or daunorubicin; consider SCT in selected cases who respond to polychemoth erapy; Alternatives: IFN, cladribine, splenectomy for hypersplenism, hydroxycarbamide as pa lliation. \200 Mast cell leukemia: AML-type polychemotherapy cladribine interferon alfa; consider SCT; splenectomy for hypersplenism; hydroxycarbamide as pallia tion. Novel therapies: nilotinib, dasatinib, midostaurin, NF- B inhibitors, HSP90 inhibitors, ge ldanamycin, alemtuzumab, and gemtuzumab are all being studied.9,10 Case reports have shown thalidomide to achieve durable major responses. Response assessment Response criteria for patients receiving cytoreductive drugs have been agreed and relate to C-fi ndings.3,9 \200 Major response: complete resolution of \211 1 C-fi nding and no progression in other C-fi ndings: \200 Complete remission: disappearance of mast cell inf i ltrates in aff ected organs and decrease of serum tryptase to <20ng/mL and disappearance of SM-associa ted organomegaly. Incomplete remission: decrease in mast cell infi ltrates in aff ected organs and/or substantial decrease of serum tryptase level and/or visible regression of spl enomegaly. Pure clinical response: without decrease in mast cell infi ltrates, without decrease in try ptase levels and without regression of splenomegaly. Partial response: incomplete regression of \211 1 C-fi nding without complete regression and without progression: \200 Good partial response: >50% regression; no progression in other C-fi ndings. Minor response; <50% regression; no progression in other C-fi ndings. No response: C-fi nding(s) persistent or progressive. Stable disease: C-fi nding parameters show constant range. \200 Progressive disease: \211 1 C-fi nding shows progression. 322 CHAPTER 7 Myeloproliferative neoplasms Prognosis Most patients with SM have only slowly progressive disease and many survive sever al decades. The life expectancy of patients with pure CM, ISM and BMM is similar to that of individuals without mastocytosis.8 733% of patients with SM evolve into a hematological ma lignancy, fre- quently leukemia. Mast cell leukemia is resistant to intensive chemo- therap y and has a survival of only a few months. References 1. Valent, P. and Metcalfe, D.D. (2004). Mast cell proliferative disorders: diag nosis, classifi cation and therapy. Hematology 2004, 153 \200\22362. 2. Valent, P. et al. (2001). Mastocytosis (mast cell disease). In Jaff e, E.S. et al. (eds. ) World Health Organization Classifi cation of Tumors. Pathology and Genetics. Tumors of Ha ematopoietic and Lymphoid Tissues, vol 1, pp.291 \200\223302. Lyon: IARC Press. 3. Valent, P. et al. (2007). Standards and standardization in mastocytosis: Consensus state ments on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest, 3 7, 435 \200\22353. 4. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 5. Valent, P. and Metcalfe, D.D. (2004). Mast cell proliferative disorders: diagnosis, clas sifi cation and therapy. Hematology 2004, 153 \200\22362. 6. Horny, H.P. et al. (2007). Mastocytosis: state of the art. Pathobiology 74, 121 \200\223 32. 7. Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myeloprolif erative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia, 22, 14 \200\22322. 8. Orfao, A. et al. (2007). Recent advances in the understanding of mastocytosis: the role of KIT mutations. Br J Haematol, 138, 12 \200\22330. 9. Valent, P. et al. (2010). How I treat patients with advanced systemic mastocytosis. Bloo d, 116, 5812 \200\22317 10. Bouvier, S. et al. (2013). Systemic mastocytosis. Blood, 121(7), 1071. Further reading Valent, P. et al. (2013). Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM) . Am J Blood Res, 3(2), 174 \200\22380. Valent, P. (2013). Mastocytosis: a paradigmatic exa mple of a rare disease with complex biology and pathology. Am J Cancer Res, 3(2), 159 \200 \22372. 323 MPN \200\224UNCLASSIFIABLE MPN \200\224unclassi \201 able This is a group of MPN-like disorders that do not meet the diagnostic criteria for either the classic or non-classic MPNs and may account for 10 \200 \22320% of MPNs.1,2 Most cases fall into 2 groups: \200 Initial stages of PV, PMF, or ET presenting before characteristic features have developed. Advanced MPN where marked myelofi brosis, osteosclerosis, or transformation obscures the underlying disorder. The former should be screened for MPN-associated mutations and monitored until a clear diag nosis can be determined. The latter have advanced disease and should be monitored and treat ed appropriately. References 1. Thiele, J. et al. (2001). Chronic myeloproliferative disease, unclassifi able . In Jaff e, E.S. et al. (eds.) World Health Organization Classifi cation of Tumors. Pathology and Genetics. Tumors of Haematopoietic and Lymphoid Tissues, vol 1, pp.42 \200\2234. Lyon: IARC Press. 2. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. This page intentionally left blank 325 Chapter 8 Paraproteinaemias Paraproteinaemias 326 Monoclonal gammopathy of undetermined signifi cance (MGUS) 328 Asymptomatic multiple myeloma ( \200\230smoldering \200\231 myeloma) 332 Multiple myeloma 336 Variant forms of myeloma 362 Cryoglobulinaemia 363 POEMS syndrome (osteosclerotic myeloma) 364 Plasmacytoma 366 Waldenstr m macroglobulinaemia 368 Heavy chain disease 378 AL (1 systemic) amyloidosis 380 326 CHAPTER 8 Paraproteinaemias Paraproteinaemias A heterogeneous group of disorders characterized by deranged prolif- erat ion of a single clone of plasma cells or B lymphocytes and usually associated with detectab le monoclonal immunoglobulin (paraprotein or M-protein) in serum and/or urine. Conditions associated with paraprotein production Stable production \200 Monoclonal gammo pathy of undetermined/uncertain signifi cance (MGUS). Asymptomatic myeloma ( \200\230smoldering \200\231 myeloma). \200 Cryoglobulinaemia. Progressive production \200 Multiple myeloma (MM): Complete immunoglobulins: IgG, IgA, or IgD; very rarely IgM or IgE. Free light chains (LCs): or (Bence Jones proteinuria). \200 Non-secretory. Plasma cell leukemia (PCL). \200 Solitary plasmacytoma of bone (SPB). \200 Solitary ext ramedullary plasmacytoma (SEP). \200 POEMS syndrome. \200 Waldenstr m macroglobulinaem ia (WM). \200 B-LPD (including CLL). \200 NHL (mainly low grade). \200 Heavy chain di sease (HCD). \200 AL amyloidosis (AL). 327 PARAPROTEINAEMIAS 328 CHAPTER 8 Paraproteinaemias Monoclonal gammopathy of undetermined signi \201 cance (MGUS) MGUS describes an asymptomat ic premalignant disorder characterized by limited monoclonal plasma cell proliferation and the presence of a stable monoclonal paraprotein in serum or less commonly in urine in the a bsence of clinicopathological evidence of MM, WM, AL, or another lymphoproliferative disord er (LPD). Epidemiology Prevalence 3.2% \211 50 years in large population-based study. Slight \231 \202 excess (1.3 \227). Prevalence rises with age: 1.7% age 50 \200\22359; 3% 60 \200\2236 9; 4.6% 70 \200\22379; 6.6% \211 85 years. In USA, >2 \227 more frequent in African Americ ans compared to Caucasians. Median age 72 years; 2% <40; 59% \211 70 years. MGUS diagnosed 74 \227 as frequently as MM. Pathophysiology MGUS appears to arise from a pre-germinal center cell whose progeny pass th rough the germinal center and undergo mutation. Antigenic stim- ulation related to autoimmu ne, infectious, or infl ammatory disorders (but not allergies) may be an initiating event. There is genomic instability on molecular analysis and 90% of patients have abnormalities. Progression to MM may be due to outgrowth of a single clone but the precise trigger is uncl ear. There is a continuing rate of progression to MM, WM, AL, or other LPDs. This constant rate suggests a random 2nd hit. FISH demonstrates the same MM cytoge- netic abnormalities i n MGUS often acquired over time, e.g. \210\22213 (in 50% MGUS). Expression microarrays sho w MGUS much closer to MM than to normal plasma cells. Natural history \200 >50% die of unrelated causes after >25-year follow-up. \200 1% per annum progress to MM, WM, AL, or other LPD or CLL. \200 Actuarial rate of progression 17 % at 10 years; 39% at 25 years but true probability is lower when other causes of death are taken into account. 69% who progress develop MM, 12% AL, 11% WM, and 8% LPD. \200 Some may show an i in parap rotein \211 30g/L or BM PC >10% without developing symptomatic MM or WM or requiring therapy. Clinical features \200 Typically asymptomatic and an incidental fi nding on investigation of i ESR/PV or i globulin on routine LFTs. No abnormal physical fi ndings (end-organ damage) except due to unrelated pathology. Lack of progression and absence of additional evidence of progressive plasma cell or B-cell lymphoproliferative malignancy. 329 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE Investigations and diagnosis (See Table 8.1.) \200 Check FBC, renal biochemistry, serum c alcium, serum immunoglobulins, serum protein electrophoresis and paraprotein quantitation, serum free lig ht chains (SFLC) (and/or urine for Bence Jones proteinuria), and skeletal survey. BM aspirate and trephine biopsy indicated if paraprotein \211 15g/L or non-IgG paraprotein present and abnormal FBC, serum creatinine, serum calcium, SFLC ratio, or skeletal survey. FBC: no anemia or other cytopenia except due to unrelated causes. \200 Serum chemistry: n o hypercalcaemia or otherwise unexplained renal impairment. Serum protein electrophoresis with immunofi xation and densitometry to detect, characterize, and quantitate paraprotein levels: SFLCs: 730% have abnormal : ratio. \200 Urine electrophoresis: identifi es low levels of Bence Jones proteinuria in up to 30%; 760% , 740% ; generally <1g/24h, 715% >150mg/24h. Skeletal radiology: no evidence of lytic lesions or pathological fracture; osteoporosis may co-exist from other causes e.g. postmenopausal \231\200. Serum 2-microglobulin levels n (unless renal impairment). \200 BM aspirate: <10% plasma cells in BM; median 75%. \200 BM cytogenetics: n by conventional techniques but all abnormalities in MM described in MGUS by FISH; del(13), t(4;14), ras mutations, p16 and p53 inactivation less common. BM trephine biopsy: no evidence of diff use plasma cell infi ltration or osteoclast erosion of trabeculae. Note: patients with MGUS should have stable paraprotein and other parameters on prolonged observation. Diff erential diagnosis \200 Exclude conditions with associated paraprotein, notably MM, WM, and AL amyloidosis. Bone pain/damage, unexplained anemia, or impaired renal function suggests MM. Lymphadenopathy or splenomegaly with an IgM paraprotein suggests WM. The presence of neuropathy attributable to the monoclonal gammopathy would be termed \200 \230monoclonal gammopathy associated with neuropathy \200\231. Risk factors for progression No specifi c features at initial presentation predict the pati ents who will progress but risk of progression i by: \200 Paraprotein level: progression rate at 20 years: 10g/L = 16%; 15g/L = 25%; 20g/L = 41%; 25g/L = 49%. Paraprotein type: IgM > IgA > IgG. \200 Abnormal SFLC ratio (<0.26 or >1.65). \200 BM p lasma cells >5% (2 \227 risk of <5%). \200 Circulating plasma cells by immunofl uorescen ce. 330 CHAPTER 8 Paraproteinaemias Risk strati \201 cation A scoring system has been developed using 3 parameters (Table 8.2) : \200 Quantity of paraprotein (<15g/L vs \211 15g/L). \200 Isotype of paraprotein (Ig G vs any other subtype). \200 SFLC ratio (n vs abnormal). Management \200 No treatment; observation with long-term follow-up and review of clinical and laboratory features required due to risk of progression. Clinical and laboratory (FBC, renal function, serum Ca2+, serum Igs, paraprotein quantitati on, SFLC, and urine electrophoresis) re-evaluation at 6 months then annually. Less frequent follow-up (e.g. every 2 years) may be appropriate in low-risk patients. Where diagnosis in doubt review over 3 \200\2236 months usually diff erentiates MGUS from MM. Advise patients to seek early assessment if relevant or unexplained symptoms develop. Table 8.1 Diagnostic criteria for MGUS 1 Serum monoclonal protein <30g/L 2 Bone marrow plasma cells <10% (IgM MGUS \200\224lymphoplasmacytic cells <10%) 3 No evidence of other B-cell lymphoproliferative disorder 4 No myeloma-related end-organ or tissue impairment, e.g. lytic bone lesions, anemia, hypercalcaemia, or renal failure (IgM MGUS \200\224no anemia, constitutional sympto ms, hyperviscosity, lymphadenopathy or hepatosplenomegaly) Reproduced with permission of Wiley-Blackwell publishing 2003 Table 8.2 Risk stratifi cation system for MGUS1 20-year progression risk with death as competing risk (%) Relative risk Absolute risk of progression at 20 years (%) Risk group Number of patients 449 1 5 2 Low-risk: M-band <15g/L; IgG isotype; normal SFLC ratio (0.26 \200\2231.65) 420 5.4 21 10 Low \200\223intermediate risk (any 1 factor: M-band \211 15gIP, non-IgG- isotype, or abnor mal SFLC ratio) 226 10.1 37 18 High \200\223intermediate risk (any 2 factors) High risk (all 3 factors) 53 20.8 58 27 Reproduced with permission, copyright. American Society of Hematology 331 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE Reference 1. Rajkumar, S.V. et al. (2005). Serum free light chain ratio is an independent r isk factor for progression in monoclonal gammopathy of undetermined signifi cance (MGUS). Blood, 106, 812 \200\2237. Further reading Agarwal, A. et al. (2013). Monoclonal gammopathy of undetermined signifi ca nce and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratifi cation, and management of myeloma precursor disease. Clin Cancer Re s, 19(5), 985-94 Caers, J. et al. (2013). Diagnosis and follow-up of monoclonal gammopathie s of undetermined signifi cance; information for referring physicians. For the Multiple Mye loma Study Group of the Belgian Hematological Society. Ann Med, 45(5 \200\2236), 413 \200 \22322. Chng, W.J. et al. (2007). Genetic events in the pathogenesis of multiple myeloma. B est Practice and Res Clin Haematol, 20, 571 \200\22396. Kyle, R.A. et al. (2002). A long-te rm study of prognosis in monoclonal gammopathy of undetermined signifi cance. N Engl J Med, 346, 564 \200\22369. Kyle, R.A. et al (2004). Long-term follow-up of 241 patients with mon oclonal gammopathy of undetermined signifi cance: the original Mayo Clinic series 25 years later. Mayo Clinic Proceedings, 79, 859 \200\22366. Kyle, R.A. et al. (2006). Prevalence of monoclonal gammopathy of undetermined signifi cance. N Engl J Med, 354, 1362 \200\2239. Ky le, R.A. and Rajkumar, S.V. (2007). Epidemiology of the plasma cell disorders. Best Pract R es Clin Haematol, 20, 637 \200\22364. Morris Brown, L. et al. (2007). Risk of multiple myel oma and monoclonal gammopathy of undetermined signifi cance among white and black male Unit ed States veterans with prior autoimmune, infectious, infl ammatory and allergic disorders. Blood, 111, 3388 \200\22394. Rajkumar, S.V. et al. (2007). Monoclonal gammopathy of undete rmined signifi cance and smoldering multiple myeloma. Blood Reviews, 21, 255 \200\22365. Sw erdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid T issues, 4th ed. Lyon: IARC. 332 CHAPTER 8 Paraproteinaemias Asymptomatic multiple myeloma ( \200\230smoldering \200\231 myeloma) Asymptomatic or smolde ring MM (SMM) identifi es patients with a paraprotein >30g/dL and/or >10% plasma cells in t he BM but in whom the natural history is that of MGUS rather than MM, i.e. no clinical evi- dence of complications associated with MM or progression. Incidence Account for 715% of all new cases of myeloma. Pathogenesis Almost all have either translocation involving IgH (50%) or hyperdiploidy (740 %). Prognosis \200 Clinical stability may persist for months or years but most patients progress to symptomatic MM. Risk of progression is higher than MGUS and time dependent: 10% per annum for fi rst 5 year s, 73% per annum for next 5 years, and 1% per annum for next 10 years. Cumulative probabili ty of progression 73% at 15 years. Median time to progression 75 years. \200 Some evidence suggests early treatment for pati ents with \200\230high-risk \200\230 smoldering myeloma delays progression to active disease and increases overall survival.1 Survival is the same as for newly diagnosed myeloma from the time chemotherapy is started. Clinical and laboratory features \200 Absence of symptoms or physical signs attributable to myeloma. \200 Perform investigations listed for MM. \200 FBC: hemoglobin >10g/dL. \200 Serum chemistry: post-rehydration creatinine <130 micromol/L; n serum Ca2+. 2-microglobulin: n or minimally raised. \200 BM aspirate: plasmacytosis >10% but normal ly <25%. \200 BM cytogenetics: FISH identifi es the abnormalities associated with MM; some patients have detectable chromosomal abnormalities by standard karyotype analysis. Skeletal radiology normal \200 Stable paraprotein and other parameters on prolonged obser vation. Diff erential diagnosis Exclude MGUS, MM, WM, and AL amyloidosis (see Table 8.3). 333 ASYMPTOMATIC MULTIPLE MYELOMA Table 8.3 Diagnostic criteria for asymptomatic multiple myeloma2 1 Serum monoclonal protein \211 30g/L and/or bone marrow plasma cells \211 10% 2 No evidence of other B-cell LPD 3 No myeloma-related end-organ or tissue impairment (lytic bone lesions, anemia, hypercalcaemia, or renal failure). Reproduced from International Myeloma Working Group (2003). Criteria for the classifi catio n of monoclonal gammopathies, multiple myeloma and related disorders: a report of the Inter national Myeloma Working Group. Brit J Haematol, 121, 749 \200\22357, with permission from wiley-Blackwell publishing 2003. Same criteria in updated 2008 WHO classifi cation of tumors of the haematopoietic and lymph oid tissues. Risk factors for early progression of asymptomatic MM Shorter time to progression associate d with: \200 Serum paraprotein >30g/L. \200 IgA protein type. \200 Urinary Bence Jone s proteinuria >50mg/d. \200 BM plasmacytosis >25%. \200 Suppression of uninvolved Igs. \200 SFLC ratio <0.125 or >8. These risk factors have no impact on survival after progression. Other possible risk factor s for progression are circulating plasma cells, 2-microglobulin >2.5mg/L, and karyotype a bnormalities on conven- tional cytogenetics. Risk strati \201 cation \200 Table 8.4 shows a scoring system using 2 parameters: \200 Quantity of paraprotein (<30g/L vs >30g/L). \200 Isotype of paraprotein (IgG vs IgA). Table 8.5 shows a more recent scoring system including SFLC ratio. 3 parameters, with 1 point awarded for each: \200 BM plasmacytosis \211 10%. \200 Serum M protein \211 30g/L. \200 SFLC ratio <0.125 or >8. Management \200 Chemotherapy is not indicated for these patients until there is evidence of clinical progression; no benefi t for therapy before symptomatic disease develops. Review clinical and laboratory features as for MGUS but more frequently: every 3 \200\2234 months recommended. Median survival following chemotherapy 3 \200\2235 years, identical to that of de novo symptomatic myeloma. 334 CHAPTER 8 Paraproteinaemias Table 8.4 A risk stratifi cation scoring system in SMM (see E p.333)3 Risk group Factors Proportion of patients Median time to progression >4 years Low-risk M-band \211 30g/L and IgG isotype 745% Intermediate-risk M-band >30g/L or 745% 72 years IgA isotype <10% 9 months High-risk M-band >30g/L and IgA isotype Reproduced from Weber, D. et al. (2003). Risk factors for early progression of asymptomatic multiple myeloma. The Hematology Journal, 4(1), S31 \200\2232 with permission Table 8.5 A risk stratifi cation scoring system in SMM (see E p.333)4 Absolute risk at 10 years Number of patients (%) Relative risk (95%CI) Absolute risk at 5 years Risk group Number of factors 1 81 (28%) 1 25% 50% Low-risk Intermediate-risk 2 114 (42%) 1.9 (1.2 \200\2232.9) 51% 65% 3 78 (30%) 4.0 (2.6 \200\2236.1) 76% 84% High-risk Reproduced from Dispenzieri, A. et al. (2008). Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Bloo d, 111, 785 \200\2239 with permission from the American Society of Hematology . References 1. Mateos, M.V. et al. (2013). Lenalidomide plus dexamethasone for high-risk smo ldering multiple myeloma. N. Eng J Med, 369(5), 438-47 International Myeloma Working Group (2003). Criteria for the classifi cation of monoclonal gammopathies, multiple myeloma and related d isorders: a report of the International Myeloma Working Group. Brit J Haematol, 121, 749 \200\22357. Weber, D. et al. (2003). Risk factors for early progression of asymptomatic mul tiple myeloma. Hematol J, 4(1), S31 \200\2232. 2. 3. 4. Dispenzieri, A. et al. (2008). Immunoglobulin free light chain ratio is an independent r isk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood, 111, 785 \200 \2239. Further reading Agarwal, A. et al. (2013). Monoclonal gammopathy of undetermined signifi ca nce and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratifi cation, and management of myeloma precursor disease. Clin Cancer Re s, 19(5), 985 \200\22394. Kyle, R.A. et al. (2007). Clinical course and prognosis of smolde ring (asymptomatic) multiple myeloma. N Engl J Med, 356, 2582 \200\22390. Rajkumar, S.V. et al. (2007). Monoclonal gammopathy of undeter-mined signifi cance and smoldering multiple m yeloma. Blood Reviews, 21, 255 \200\22365. Swerdlow, S.H. et al. (2008). WHO Classifi catio ns of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 335 ASYMPTOMATIC MULTIPLE MYELOMA 336 CHAPTER 8 Paraproteinaemias Multiple myeloma MM is a clonal B-cell malignancy characterized by proliferation of plasma cells that accumulate mainly within BM and usually secrete monoclonal Ig or Ig LCs (parapro tein or M-protein ( \200\230M-band \200\231)). MM may be associated with BM failure, hyperc alcaemia, renal impairment, lytic bone lesions, diff use osteo- porosis, or pathological fr acture. Normal Ig production is usually impaired (immuneparesis; hypogammaglobulinaemia). U ncommon cases are \200\230non- secretory \200\231 with no detectable serum or urine parapr otein. (See Fig. 8.1.) Epidemiology MM accounts for 1% of all malignancies; 10% of hematological malignan- cies. I ncidence 74 per 100,000 per annum. Median age 66 years; <3% <40 years. \231\202: \231\200 ratio 1.5. Incidence in Afro-Caribbeans >2 \227 Caucasians; lowest in Asians. Most present de novo but some documented as arising from MGUS (most cases of MM may follow undetected M GUS). Familial clusters have been reported, suggesting a possible genetic element. The appa rent i incidence of MM is due to improved diagnosis and ageing populations.1 Pathophysiology2,3 MM arises from a post-germinal center B-cell that has undergone antigen selection, VDJ recombination, somatic hypermutation of V regions, and switch-recombination of IgH genes. 2 pathogenetic pathways have been postulated: Hyperdiploid (48 \200\22375 chromosomes): 7 5 0%; typically with multiple triso- mies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 2 1; rarely with a recurrent IgH translocation (usually t(4;14)). Non-hyperdiploid (<48 or >75 chromosomes): aberrant class-switch recombination or somatic h ypermutation may contribute to neoplastic transformation; IgH translocations at 14q32, usua lly within or near switch regions, detected by FISH in 55 \200\22370% of MM; usually associ ated with dysregulation of a gene in 1 of 7 recurrent partner chromosomes grouped by gene a ff ected: \200 Cyclin D: 11q13 (cyclin D1), 20%; 12p13 (cyclin D2), <1%; 6p21 (cyclin D3), 2%. MAF: 16q23 (c-MAF), 5%; 20q11 (MAFB), 2%; 8q24.3 (MAFA), <1%. \200 MMSET/FGFR3: 4p16.3 (M MSET and usually FGFR3), 15%. 2 other early events have been described: \200 Loss of chromosome 13 or 13q14 deletion: o ccurs in 750% MM and 40 \200\22350% MGUS; concurrent 13/13q \210\222 occurs in both pathoge netic pathways; much more prevalent (80 \200\22390%) in t(4;14) or t(14;16) than others (30 \200\22340%); low incidence in hyperdiploid MM. Dysregulation of a cyclin D gene: i levels of cyclin D1 (less commonly cyclin D2) are expressed by almost all MM tumors: 25% due to IgH translocation. 337 MULTIPLE MYELOMA Plasmablasts generated from post-GC B cells, migrate to the BM where they diff erentiate in to long-lived plasma cells. The BM microenviron- ment is also critical to MM clonal expansi on. Adhesion to stromal cells enhances MM cell growth and survival and confers protection a gainst drug-induced apoptosis. MM cells activate the stroma, triggering parac- rine and aut ocrine secretion of a range of cytokines and growth factors including IL-6, IGF-1, VEGF, TN F- , bFGF, MIP-1 , SCF, HGF, and IL-1 . IL-6 is the major growth and survival factor in MM and confers resistance to dexamethasone. VEGF induces MM-cell growth, migration, and sur - vival as does IGF-1 which also confers drug resistance. Angiogenesis is altered (VEGF is main angiogenic factor) and i BM microvascular density correlates with disease progression and poor prognosis. Bone disease in MM is due to osteoclast (OC) activation and osteoblast (OB) inhibition caus ing the characteristic \200\230punched-out \200\231 lytic lesions and hypercalcaemia assoc iated with a normal alkaline phosphatase. OC pro- liferation and activation is triggered by a variety of OC-activating factors (OAFs) produced by MM-cells and stroma (including MIP-1 , RANK-ligand, VEGF, TNF- , IL-1 , PTHrP, HGF, and IL-6). OC activation in turn modu- l ates MM-cell growth and survival. In addition there are d numbers of OBs and d bone formati on due to dysregulation of Runx2/CbfaI, Wnt, and IL-3. BM infi ltration by the neoplastic clone causes anemia. Immuneparesis of normal Ig producti on predisposes to infection. The physico-chemical properties of the paraprotein determine w hether amyloid deposition, renal damage, or hyperviscosity (IgM > IgA > IgG) occur. Clinical features and presentation \200 Spectrum from asymptomatic paraproteinaemia detec ted on routine testing (720%) to a rapidly progressive illness with extensive, destructive bone di sease. IgG and IgA myeloma are most common; IgM myeloma is rare (0.5%). Most patients present with bone (usually back) pain (775%) or pathological fracture; kyphosis and loss of height may occur from vertebral compression fra ctures. Weakness and fatigue (>50%), recurrent infection (10%) and thirst, polyuria, nocturia or oe dema due to renal impairment (710%) are also common presenting symptoms. Acute hypercalcaemia, symptomatic hyperviscosity (mental slowing, visual upset, purpura, hemorrhage), neuropathy, spinal cord compression, amyloidosis, and c oagulopathy are less frequent at presentation. \200\230CRAB \200\231: hyper-calcaemia, renal impairment, anemia, and bone problems. Diff erential diagnosis Exclude MGUS, asymptomatic myeloma, and other conditions associ- at ed with a paraprotein, notably solitary plasmacytoma, systemic AL amyloidosis and LPDs. 338 CHAPTER 8 Paraproteinaemias Investigations and diagnosis A full history and physical examination should be undertaken i n all patients with suspected MM. The investigations detailed in Table 8.6 should be perfor med to confi rm or exclude the diagnosis and if con- fi rmed, to establish tumor burden and prognosis. (See Figs. 8.2 \200\2238.4). Further investigations that are not routine may be necessary in individual patients (e.g. MRI) (E see color plate section, plates 1 \200\2234 ). Diagnostic criteria are listed in Table 8.7. Fig. 8.1 Electrophoresis: from L to R: urine with BJP and generalized proteinuria (albumin band at top of strip, BJP near foot); serum M band in myeloma; poly- clonal gammopathy; nor mal sample, showing albumin, A, B, and globulins (E see color plate section). 339 MULTIPLE MYELOMA Table 8.6 Investigations of patients with suspected myeloma4 \200\2237 Screening tests FBC and fi lm Normochromic normocytic anemia in 60%; fi lm may show rouleaux ESR or PV i in 90% ; not in LC or non-secretory MM (NS MM) Serum urea, creatinine, and electrolytes May identify renal impairment (725%) Uric acid May be i Serum albumin, calcium, phosphate, alk. phos. May reveal low albumin or hypercalcaemia (720%) with normal alk. phos. To detect serum paraprotein (80%)