2 SM with associated hematological non-mast cell disease: <50% have urticaria pigmentosa; g enerally CML or CMML; classified according to FAB/WHO criteria; poorer survival. 2 Mast cell leukemia: defined by \211 20% MC in BM aspirate and \211 10% in PB; diffuse i nfiltration on trephine biopsy; no skin lesions, severe peptic ulcer disease, hepatosplenom egaly, anemia, multiorgan failure and short survival. 2 Mast cell sarcoma: a tumor consisting of atypical MC; locally destruc- tive growth; no systemic involvement. 07-MPD.qxd 10.12.2003 04.16 PM Page 262 Differential diagnosis Diagnosis often delayed due to protean clinical features. Exclude re active mast cell hyperplasia, mast cell activation syndromes, myeloproliferative disorders with increased mast cells, carcinoid syndrome, phaeochromocy- toma, myelofibrosis, liver di sease and lymphoma. Management 2 No curative treatment; management consists of prevention of medi- ator effects and treatment of accompanying hematological disease where present. 2 Avoid factors triggering acute mediator release: extremes of tempera- ture, pressure, fri ction; aspirin, NSAIDs, opiates, alcohol, specific aller- gies. 2 Treat acute mast cell mediator release. 2 Anaphylaxis: epinephrine (adrenaline) 0.3mL of 1:1000 dilution (adult dose) every 10 \200\22315 minutes as needed. 2 Refractory hypotension and shock: fluid resuscitation and epinephrine 262 (adrenaline) IV bolus plus infusion of 1:10,000 dilution (up to 4 \200\22310mg/min); add in otropes if unresponsive. 2 Commence H1 plus H2 receptor antagonists and steroids. 2 Treat chronic mast cell mediator release: H1 plus H2 receptor antago- nists: 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: ranitid ine (150mg PO bd; 50mg IV) or cimetidine (400 \200\2231600mg/day PO in divided doses; 300mg IV). Titrate doses for individual patient require- ments; prednisolone 40 \200\22360 mg/da y PO for malabsorption tailing; bis- phosphonates and radiotherapy for bone pain; PUVA for urticaria pigmentosa; a small number of patients gain symptomatic relief from interferon- or cyclosporin-A for refractory symptoms. 2 Treat any associated hematological disorder: generally achieve short partial remission at best; splenectomy may help pancytopenic patients. SCT should be considered in appropriate patients. 2 Attempt to control organ infiltration by mast cells: daunorubicin plus cytarabine and CVP have been reported to produce partial responses. Prognosis Most patients with SM have only slowly progressive disease and many survive sever al decades. 33% evolve into a hematological malignancy, fre- quently intensive chemotherapy and has a survival of only a few months. leukemia. Mast cell leukemia is resistant to Escribano, L. et al. (2002) Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol, 81, 677 \200\223690; Valent, P. et al. (2001) Diagnostic criteria and classificati on of mastocytosis: a con- sensus proposal. Leuk Res, 25, 603 \200\223625. 07-MPD.qxd 10.12.2003 04.16 PM Page 263 Myeloproliferative disorders 263 07-MPD.qxd 10.12.2003 04.16 PM Page 264 This page intentionally left blank 264 08-plasma cell.qxd 10.12.2003 04.21 PM Page 265 Paraproteinaemias 8 Paraproteinaemias 266 Monoclonal gammopathy of undetermined significance (MGUS) 268 Asymptomatic (smoldering) myeloma 270 Multiple myeloma 272 Variant forms of myeloma 281 Waldenstr m \200\231s macroglobulinaemia (WM) 284 Heavy chain disease (HCD) 288 AL (primary systemic) amy loidosis 288 08-plasma cell.qxd 10.12.2003 04.21 PM Page 266 Paraproteinaemias Heterogeneous group of disorders characterized by deranged prolifera- tion of a single clon e of plasma cells or B lymphocytes and usually associ- ated with detectable monoclonal immu noglobulin (paraprotein or M-protein) in serum and/or urine. Conditions associated with paraprotein production Stable production 2 Monoclonal gammopathy of undetermined significance (MGUS). 2 Asymptomatic (smoldering) myeloma. Progressive production 2 Multiple myeloma (MM). 2 Complete immunoglobulins: IgG, IgA, IgD, IgM, IgE. 2 Free light chains (Bence Jones protein). 2 \200\230Non-secretory \200\231. 2 P lasma cell leukemia (PCL). 2 Solitary plasmacytoma of bone (SPB). 2 Extramedullary plasmacy toma (SEP). 2 Waldenstr m \200\231s macroglobulinaemia (WM). 2 Chronic lymphocytic leukemi a. 2 Malignant lymphoma. 2 Primary amyloidosis (AL). 2 Heavy chain disease. 266 08-plasma cell.qxd 10.12.2003 04.21 PM Page 267 Paraproteinaemias 267 08-plasma cell.qxd 10.12.2003 04.21 PM Page 268 Monoclonal gammopathy of undetermined significance (MGUS) MGUS describes the presence of a stable monoclonal paraprotein in serum or less commonly in urine in the absence of clinicopathological evi- dence of multiple myeloma (MM), Waldenstr m \200\231s macroglobulinaemia (WM), amyloidosis (AL) or other lymphoproliferative disord er. Incidence Median age 66 years. Incidence rises with age. Occurs in 1% population >50 years of age, 3% >70 years, 5% >80 years. More frequent in Afro- Caribbeans than Caucasians. Pathophysiology There is intraclonal variation in the Ig gene mutation and MGUS appears to arise from a pre-germinal center cell whose progeny pass through the germinal center and un dergo mutation. Progression to MM may be due to outgrowth of a single clone. There is a con tinuing rate of progression to MM, WM, AL and other lymphoproliferative disorders. FISH dem on- strates same MM cytogenetic abnormalities in MGUS often acquired over time. Expression microarrays show MGUS much closer to MM than to normal plasma cells. No specific trigger fo r progression yet identified. 268 Natural history 2 >50% patients die of unrelated causes over a 25 year follow-up period. 2 1% progress to MM, WM, AL or other lymphoproliferative disorder per annum. 2 10% progress within 8 years; 26% after 25 years. 2 5% patients do not progress, some may show a 4 in paraprotein levels. Clinical features 2 Typically asymptomatic and often incidental finding on investigation of 4 ESR/PV or 4 globulin on routine LFTs. 2 No abnormal physical findings (end-organ damage) except unrelated. 2 Lack of progression and absence of additional evidence of progressive plasma cell or B-cell lymphoproliferative malignancy. Investigation and diagnosis 2 Perform investigations listed for MM ((cid:9)p273). 2 Serum p rotein electrophoresis with immunofixation and densitometry to detect, characterize and qua ntitate paraprotein levels: IgG 66%; IgA 20%; IgM 10%; biclonal 1%; light chain 1%; median 15g/L. 2 Urine electrophoresis: identifies only low levels of Bence Jones pro- teinuria (generally <1g/24h). 2 Stable paraprotein and other parameters on prolonged observation. 2 Immunoglobulin quanti tation: by nephelometry; only 25% have immuneparesis of uninvolved Ig classes (cf. myeloma). 2 Serum b2-microglobulin levels normal (unless renal impairment). 2 BM aspirate: <10% plasm a cells in BM; median 5%. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 269 Paraproteinaemias 2 BM cytogenetics: normal 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. 2 BM trephine biopsy: no evidence of diffuse plasma cell infiltration or osteo- clast erosion of trabeculae. 2 FBC: no anemia or other cytopenia except due to unrelated causes. 2 Serum chemistry: no h ypercalcaemia or unexplained renal impairment. 2 Skeletal radiology: no evidence of lytic l esions or pathological fracture; osteoporosis may co-exist from other causes e.g. post meno pausal females. 2 Other imaging: not routine; MRI of the spine; FDG-PET and 99mTc-MIBI scan are negative in MGUS. Diagnostic criteria for MGUS 2 Paraprotein <30g/dL. 2 BM plasma cells <10%. 2 No evidence o f other B-cell lymphoproliferative disorder. 2 No myeloma-related organ or tissue impairmen t (end-organ damage, 269 see Myeloma-related organ or tissue impairment below). Differential diagnosis 2 Exclude conditions listed on p266 notably MM, WM and AL. 2 Bone pa in/damage, unexplained anemia or impaired renal function sug- gests MM. 2 Lymphadenopathy or splenomegaly with an IgM paraprotein suggests WM. Risk factors for progression 2 No specific features at initial presentation predict those w ho will progress but risk increased if: 2 Paraprotein >15g/L. 2 Paraprotein type: IgM>IgA>IgG; 2 BM plasma c ells >5%. 2 Circulating plasma cells by immunofluorescence. 2 Other possible risk factors u nder examination: immuneparesis; presence of urinary paraprotein; BM angiogenesis. Management 2 No treatment; long term follow-up with review of clinical and laboratory features required due to risk of progression. 2 Clinical and laboratory (FBC, PV, renal function, serum Ca2+, serum Igs, paraprotein quan titation and urine electrophoresis) re-evaluation at 3 months then 6 months then annually. 2 Where diagnosis in doubt (e.g. elderly woman with paraprotein <30g/L and osteoporosis) review over 3 \200\2236 months usually differentiates MGUS from MM. 2 Advise patients to seek early assessment if unexplained symptoms develop. Kyle, R.A. (1997) Monoclonal gammopathy of undetermined significance and solitary plasmacy- toma. Implications for progression to overt multiple myeloma. Hematol Oncol Clin North Am, 11, 71 \200\22387; Kyle, R.A. et al. (2002) A long-term study of prognosis in monoclonal g ammopathy of undetermined significance. N Engl J Med, 346, 564 \200\223569. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 270 Asymptomatic (smoldering) myeloma Asymptomatic or smoldering myeloma identifies patients with a parapro- tein over 30g/dL and /or more than 10% plasma cells in the bone marrow but in whom the natural history is that o f MGUS rather than MM, i.e. no clinical evidence of progression or of complications associa ted with MM. Prognosis 2 Important to recognize because there is no survival advantage from chemotherapy before progressive or symptomatic disease develops. 2 Clinical stability may persist for months or years and careful clinical follow-up is required. 2 Survival is same as for newly diagnosed myeloma from the time chemotherapy is started. Clinical and laboratory features 2 Absence of symptoms or physical signs attributable to my eloma. 2 Performance status >50%. 2 Perform investigations listed for MM ((cid:9)p273). 2 F BC: pre-transfusion hemoglobin >10g/dL. 2 Serum chemistry: post-rehydration creatinine <130 mol/L; normal 270 serum Ca2+. 2 b2-microglobulin: normal or minimally raised. 2 BM aspirate: plasmacytosis >10% but norma lly <25%. 2 BM cytogenetics: FISH identifies the abnormalities associated with MM; some pat ients have detectable chromosomal abnormalities by standard karyotype analysis. 2 Skeletal radiology: should be normal. 2 Other imaging: not yet routine; CT, MRI of spine FDG-PET and 99mTc- MIBI scan identify bone lesions in 25% of patients with normal con- ven tional radiology. 2 BM plasma cell labeling index: (when measured) <1%. 2 Stable paraprotein and other parame ters on prolonged observation. Diagnostic criteria for asymptomatic (smoldering) myeloma 2 Paraprotein \211 30g/dL and/or 2 BM clonal plasma cells \211 10%. 2 No evidence of other B-cell lymphoproliferative dis order. 2 No myeloma-related organ or tissue impairment (end-organ damage, see Myeloma-related organ or tissue impairment below). Risk factors for early progression of asymptomatic MM Shorter time to progression associate d with: 2 Abnormal MRI (median <2 years vs. 7 years). 2 Serum paraprotein >30g/L. 2 b2-mic roglobulin >2.5mg/L. 2 BM plasmacytosis >25%. 2 Suppression of uninvolved IgM to \211 3g/L . 2 IgA protein type. 2 Urinary Bence Jones proteinuria >50mg/day. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 271 Paraproteinaemias These risk factors have no impact on survival after progression. Other risk factors for pro gression are high plasma cell labeling index; circulating plasma cells and karyotype abnorm alities on conventional cytogenetics. Management 2 Chemotherapy is not indicated for these patients until there is evi- dence of clinical progression. 2 Review of clinical and laboratory features as for MGUS; more frequent review may be appro priate for patients with risk factors for progres- sion. 2 Median survival following chemotherapy is 3 \200\2235 years, i.e. identical to that of de novo symptomatic myeloma. 271 Weber D. et al. (2003) Risk factors for early progression of asymptomatic multiple myeloma. Hematol J. 4(Suppl. 1): S31 \200\223S32. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 272 Multiple myeloma (MM) MM (syn. myelomatosis) is a clonal B-cell malignancy characterized by pro- liferation of pl asma cells that accumulate mainly within bone marrow and usually secrete paraprotein. MM is associated with lytic bone lesions or diffuse osteoporosis and normal Ig production is imp aired by immune- paresis (hypogammaglobulinaemia). <1% cases are non-secretory. Epidemiology MM accounts for 1% of all malignancies; 10% of hematological malignan- cies. I ncidence 4 per 100,000 per annum, 2500 new cases/year in UK. Median age 65 years; <3% <40 years. Incidence in Afro-Caribbeans 2 Caucasians; lowest in Asians. Most present de novo but minority arise from MGUS. Association with radiation, benzene and pesticide exposure a nd farm working. Pathophysiology MM arises from a post germinal center B cell (probably in LN or spleen) tha t has undergone antigen selection, VDJ recombination, somatic hyper- mutation of V regions and switch-recombination of IgH genes. Aberrant class-switch recombination may contribute t o neoplastic transformation (IgH translocations common in MM). BM microenvironment critical to clonal expansion. Secretion of IL-6, IL-1, TNF-a and RANK-ligand stimu- late MM prolife ration and osteoclast proliferation and activation (causes bone destruction plus hypercalca emia). BM infiltration causes anemia. Immuneparesis of normal Ig production predisposes to infection. Physico- chemical properties of paraprotein determine amyloid deposition, renal damage and hyperviscosity (IgA and IgG4). 272 Clinical features and presentation 2 Spectrum from asymptomatic paraproteinaemia detected o n routine testing ( 20%) to rapidly progressive illness with extensive, destructive bony disease. 2 Most present with bone (usually back) pain ( 75%) or pathological fracture; kyphosis and loss of height may occur from vertebral com- pression fractures. 2 Weakness and fatigue (>50%), recurrent infection (10%) and thirst, polyuria, nocturia or oedema due to renal impairment ( 10%) also common. 2 Acute hypercalcaemia, symptomatic hyperviscosity (mental slowing, visual upset, purpura, hemorrhage), neuropathy, spinal cord compres- sion, amyloidosis and coagulopathy less frequent at presentation. Electrophoresis: from L 7 R, urine BJP, serum M band (myeloma); polyclonal Igs; normal. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 273 Paraproteinaemias Investigation of patients with suspected myeloma Screening tests FBC and movie Normochromic normocytic anemia in 60%; movie may show rouleaux 4 in 90% ; not in LC or NS M M May identify renal impairment ( 25%) May be 4 may reveal low albumin or hypercalcaemia ( 20%) with normal alk phos To detect immuneparesis ESR or PV Urea & creatinine Uric acid Serum albumin, calcium, phosphate, alk phos: Serum im munoglobulins Serum protein electrophoresis To detect serum paraprotein (80%) Routine urina lysis Urine electrophoresis with immunofixation: X-ray sites of bone pain To detect proteinuria ( 70%) To detect Bence Jones proteinuria: 22% have BJP only and no se rum M-band: LC myeloma) May reveal pathological fracture(s) or lytic lesion(s) 273 Diagnostic tests BM aspirate Demonstrates plasma cell infiltration \200\224may be only way to diagnose non-secretory (NS ) myeloma Identifies lytic lesions, fractures and osteoporosis (80%; 5 \200\22310% osteopor osis only; 20% normal) Radiological skeletal survey Paraprotein immunofixation Characterizes and quantifies paraprotein; IgG 55%; IgA 22% and densitometry IgD 2%; IgM 0.5%; IgE <0.01%; LC 22%; Note: serum & urine EPS \200\223ve in NS 1% Tests to establish tumor burden and prognosis Serum b2-microglobulin Serum C-reactive prote in Measure of tumor load Surrogate measure of IL-6 which correlates with tumor aggression Meas ure of tumor aggression Hypoalbuminaemia correlates with poor prognosis Clear prognostic va lue (see below) Shows light chain restriction, extent of infiltration and haematopoietic re serve Serum LDH Serum albumin BM cytogenetics BM trephine biopsy with immunohistochemistry Tests which may be useful in some patients Creatinine clearance MRI With 24h protein \200\224to assess renal damage Not routine but useful in patients with cor d compression or solitary plasmacytoma; abnormal in 25% of patients with normal skeletal s urvey Not routine but useful for detailed evaluation of localized sites of disease CT Biopsy for amyloid + SAP scan Where amyloid suspected ((cid:9) p288) Serum free light chain assay Provides treatment response parameter in LC myeloma, amyloidosis and most cases of \200 \230non-secretory \200\231 MM Under evaluation; abnormal in 25% with normal skeletal surve y; persistent positive post-therapy may predict early relapse; identifies focal recurrent d isease and focal extramedullary disease Under evaluation; may identify extensive BM involve ment FDG-PET scan 99mTc-MIBI scan 08-plasma cell.qxd 10.12.2003 04.21 PM Page 274 Diagnostic criteria for multiple myeloma Paraprotein in serum and/or urine (Note: no minimum level). BM clonal plasma cells (Note: no minimum level; 5% have <5% plasma cells) or plasmacytoma. Myeloma-related organ or tissue impairment (end-organ damage) Myeloma-related organ or tissue impairment (end-organ damage) 2 Elevated calcium levels: se rum calcium >0.25mmol/L above upper limit of normal or corrected serum calcium >2.75mmol/L or >11mg/dL. 2 Renal insufficiency: (creatinine >173 mol/L or >2mg/dL). 2 Anemia: Hb 2g/dL below normal range or Hb <10g/dL. 2 Bone lesions: lytic lesions or osteoporosis with compression fractu res recognized by conventional radiology. 2 Others: symptoms of hyperviscosity; amyloidosis; recurrent bacterial infection. 274 Bone marrow aspirate in myeloma showing numerous plasma cells (note binucleate cell, center left). Cytogenetics 2 Using conventional techniques abnormal karyotypes found in 30 \200\22350%; heterogeneous pattern and complex abnormalities are common. 2 FISH techniques demonstrate aneuploidy in nearly all patients: \200\223 Monosomies in vast majority (8, 13, 14, 16, 22). \200\223 Abnormalities involvin g 14q32 (Ig heavy chain locus) in 60 \200\22375% (esp. non-hyperdiploid karyotypes): t(11;14), t(4;14), t(14;16) and non-recurrent. \200\223 Hyperdiploidy in 50 \200\22360% (trisomy 3, 5, 7, 9, 11, 15, 19). \200\223 del(1 3) in 50%. \200\223 del(17p;13.1): loss of p53 tumor suppressor gene also occurs in MM. 2 Prognostic value \200\223 Poor prognosis: t(4;14), t(14;16), del(17p), del(13), hypodiploidy. \200\223 Fav orable prognosis: others including t(11;14). Differential diagnosis 2 Suspect MM in a patient >50 with bone pain, lethargy, anemia, recu r- rent infection, renal impairment, hypercalcaemia or neuropathy or in whom rouleaux or an 4 ESR or PV is detected. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 275 Paraproteinaemias 2 Exclude MGUS and other conditions associated with a paraprotein ((cid:9)p266), notably so litary plasmacytoma, primary amyloidosis and lymphoproliferative disorders. Prognostic factors: adverse prognostic factors at diagnosis 2 Age >65. 2 Performance status 3 or 4. 2 High paraprotein levels (IgG >70g/L; IgA >50g/L; BJP >12g/24h). 2 Low hemoglobin (<10g/dL). 2 Hypercalcaemia. 2 Advanced lytic bone lesions. 2 Abnormal renal function (cre atinine >180mmol/L). 2 Low serum albumin (<30g/L). 2 High b2-microglobulin ( \211 6mg/mL). 2 High C-reactive protein ( \211 6mg/mL). 2 High serum LDH. 2 High % BM plasma cells (>33%) . 2 Plasmablast morphology. 2 Adverse cytogenetics (see above). 2 Circulating plasma cells in PB. 2 High serum IL-6 (measured in only a few centers). 2 High plasma cell labeling inde x (measured in only a few centers). 275 Skull x-ray in myeloma showing multiple lytic lesions. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 276 Myeloma: humerus shows marked osteoporosis, lytic lesions and healing patholog- ical fractu re. Staging systems Durie \200\223Salmon staging system in wide use since 1975 attempts to asse ss tumor bulk but may not provide as good prognostic discrimination as newer systems: 276 Patients staged as I, II or III & A or B; stage represents tumor burden Stage I Low all of the following: Stage II Medium not fitting Stage I or III Stage III High one or more of the following: Tumor cell mass Monoclonal IgG (g/L) <50 >70 Monoclonal IgA (g/L) <30 >50 BJP excretion (g/24h) <4 >12 Hb (g/dL) >10 <8.5 Serum Ca2+ (mmol/L) <2.6 >2.6 Lytic lesions none or one advanced Stage A: serum creatinine <175mmol/L Stage B: serum creatinine >175mmol/L Durie, B.G. & Salmon, S.E. (1975) A clinical staging system for multiple myeloma. Correlati on of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer, 36, 842 \200\223854. Serum b2-microglobulin (b2-M) is most powerful prognostic factor (measure of tumor bulk) an d can be used with serum C-reactive protein (CRP) a surrogate measure for serum IL-6 (measu re of tumor aggres- sion) to assess prognosis: 08-plasma cell.qxd 10.12.2003 04.21 PM Page 277 Paraproteinaemias Low risk Intermed. risk either b2-M or CRP \211 6mg/L High risk both b2-M <6mg/L & CRP <6mg/L median survival 54 mo median survival 27 mo both b2-M \211 6 mg/L & CRP \211 6mg/L median survival 6 mo Bataille, R. et al. (1992) C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system. Blood, 80, 733 \200\223737. International Prognostic Index (IPI) has been devised using serum b2-M and serum albumin (A LB): b2-M <3.5mg/L; ALB \211 35g/L Stage 1 median survival 62 mo b2-M <3.5mg/L; ALB <35g/L or b2-M 3.5 \200\2235.5mg/L b2-M >5.5mg/L Stage 2 median survival 41 mo 277 Stage 3 median survival 29 mo Greipp, PR. et al. (2003) Development of an international prognostic index (IPI) for myelom a: report of the international myeloma working group. Hematol J, 4, (Suppll) 542 \200\22344 . Good and poor risk groups in IPI 2 Age is only additional factor that significantly impacts outcome: \200\223 Survival >5 years associated with age <60 years (very low risk if stage 1). \200\223 Survival <2 years associated with age >60years, platelets <130 109/L or 4 serum LDH. 2 Cytogenetics affect outcome but do not add to impact of age, b2-M and ALB. Management (UKMF Guidelines, Br J Haematol 115, 522 \200\223540) Initial considerations and general aspects 2 Pain control: titrate simple analgesia and opiates (MST + prn Oramorph) NSAIDs (monitor renal function) local radiotherapy (8 \200\22320Gy) spin al support corset for severe back pain. 2 Correction of renal impairment: rehydration with high fluid input (3 \200\2234L/day) and rapid treatment of hypercalcaemia, infection and hyper- uricaemia ma y improve renal function; caution with nephrotoxic drugs including NSAIDs; ?role of plasmap heresis in established renal failure; peritoneal or haemodialysis if required (<5%); VAD-ty pe regimen treatment of choice after response to rehydration or established CRF; follow wit h PBSC harvest (mobilized by G-CSF alone) and HDM (140mg/m2) and SCT in younger patients; a fter response EFS and OS same as other patients. 2 Hypercalcaemia: rehydration (3 \200\2236L/day IV); loop diuretics; IV bisphos- phonate; ( pamidronate 30 \200\22390mg IV or zoledronate 4mg IV; 5 dose in renal impairment); chemothe rapy. 2 Bone disease: local radiotherapy for localized pain (8-20Gy); fixation of fractures/poten tial fractures; long term bisphosphonate prophylaxis. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 278 2 Infection: vigorous antibiotic therapy; annual influenza immunization. 2 Anemia: blood tr ansfusion for symptomatic anemia; Epo for Hb per- sistently \211 10g/dL (10,000IU tiw or 30,000IU once weekly 70% response rate with \211 2g/dL rise in Hb). 2 Hyperviscosity syndrome: plasmapheresis (3L exchange) followed by prompt chemotherapy. 2 Cord compression: MRI scan to define lesion; oral dexamethasone stat; urgent local radiotherapy. Melphalan and prednisolone (M&P) 2 4 day courses of M&P (M 6 \200\2239mg/m2/day PO; P 40 \200\223100mg/day PO) at 4 \200\2236 week intervals achieve \211 50% reduction of paraprot ein in 50 \200\22360% patients; monitor response by serum/urine paraprotein level (serum fr ee light chains in most non-secretors); response often slow; continue treatment to maximum response (9 \200\22312 months); CR uncommon. 2 Patients with \211 50% response may achieve plateau phase (stable para- protein without further treatment; median duration 12 \200\223 18 months); maintenance chemotherapy in plateau ineffective and toxic; monitor paraprotein 6 \200\2238 weekly to detect progression; further responses to M&P after durable plateau; m elphalan resistance ultimately develops in all patients. 278 2 Median survival 36 months; well tolerated; remains appropriate first line treatment for elderly patients treated outside a clinical trial; side effects myelosuppression and steroi d toxicity (add PPI or H2 antagonist). Combination chemotherapy 2 ABCM ((cid:9)p620),VMCP/VBAP and VBMCP showed improved objec- ti ve responses in 3 large studies; CR still <10%; but no survival benefit over M&P on meta-an alysis; ?superior results in younger patients with poor risk disease; side effects myelosup pression and infection; more toxicity in elderly patients. 2 VAD infusional regimen ((cid:9)p624) produces improved overall responses (60 \200\22380%) and CRs (10 \200\22325%); maximum response rapidly achieved ( 12 weeks); responses not durable without consolidation by melphalan-containing regimen; non-t oxic to stem cells thus good initial therapy in patients destined for PBSC harvest, HDT and autograft; useful regimen in patients with renal failure; VAMP gives similar results; no c onvincing advantage for C-VAMP ((cid:9)p622); side effects myelosup- pression, infection (e sp. indwelling IV catheter), alopecia, neuropathy, proximal myopathy (add PPI or H2 antagon ist). Approach to treatment of myeloma in non-trial patients Age \211 65 years M&P to plateau Repeated on progression if durable response to initial therapy Thal-Dex or l ow dose CTX for short response/ refractory disease Age <65 or very fit \211 65 VAD 4 \200\2236; PBSC mobilization; HDM; repeat on progression if durable response; Thal-Dex for short response/refractory disease Thal-Dex, thalidomide + dexamethasone; CTX, cyclophosphamide. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 279 Paraproteinaemias Other agents 2 Bisphosphonates inhibit osteoclast activation; patients on long term therapy experience less bone pain and fewer new bone lesions and fractures; there is evidence of i mproved quality of life and possible prolongation of survival; as yet no evidence for super iority of either daily oral clodronate or monthly IV pamidronate/zoledronate. 2 Interferon- a administered as maintenance therapy during plateau phase at a dose of 3mu/m2 SC tiw improves response duration on a meta-analysis (median 6 mo nths) and has a small effect on survival; side effects reduce patient compliance and cost \200\223utility profile is unfavorable. 2 Cyclophosphamide (300 \200\223500mg PO/IV once weekly; \200\230C-weekly \200\231) may be used as a single agent for patients intolerant of melphalan due to persistent cytopenia an d is capable of achieving durable plateau phase. 279 Radiotherapy 2 Important modality of treatment in myeloma at all stages of disease; local radiotherapy (8 \200\22320Gy) often rapidly effective treatment for bone pain associa ted with pathological fracture. 2 Multiple widespread lesions may be palliated with hemibody irradia- tion: 10Gy for the lo wer hemibody or 6Gy for the upper hemibody; side effect myelosuppression; sequential hemibo dy irradiation may be performed after an interval of 6 weeks. High dose therapy and stem cell transplantation 2 Autologous SCT after high dose melphalan (HDM; 200mg/m2) achieves high CR rates (25 \200\22380%) after initial therapy with a VAD-type regimen and P BSC harvest; median duration of response 2 \200\2233 years; treatment of choice for patient s <65 years; best responders have best survival, median >5 years; improved progression free survival (32 vs. 20 mo) and overall survival (54 vs. 42mo) in large randomized study1; sid e effects: myelosuppression, infection, delayed regeneration; not cura- tive. 2 Addition of TBI to melphalan 140mg/m2 with autologous SCT adds toxicity but no benefit; no convincing benefit for \200\230double/tandem \200\231 auto- gr afts though may be of value for those converted to CR after second procedure; no benefit fr om stem cell purification procedures. 2 Intermediate dose melphalan (60 \200\22380mg/m2) + G-CSF offers an alterna- tive consolid ation treatment for patients with failed PBSC mobilization. 2 Allogeneic SCT: applicable to fit patients \211 50 years; transplant-related mortality with standard conditioning regimens ((cid:9)p310) is high ( 33%) due to infection and GvHD; 35 \200\22345% long term survival (>5 years); 33% chance of durable remission a nd possible cure; 33% chance of survival with recurrence; evidence of graft vs. myeloma ef fect; non-myeloablative regimens ((cid:9)p310) reduce toxicity, increase age limit but redu ce response rate; allogeneic SCT should be discussed with all patients <55 with a suitable sibling donor. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 280 Treatment of primary refractory disease 2 Patients with MM who progress or fail to respond (<25% reduction in paraprotein) to initial therapy with melphalan may respond to single age nt dexamethasone (20 \200\22340mg/d 4 days weekly 3 weeks), VAD- type regimens thalid omide and dexamethasone or combination chemotherapy; failure to respond to VAD is an indica tion for thalidomide based therapy followed by HDM and autologous SCT where possible. Disease progression 2 Patients who achieve a durable response (>12 months) to initial therapy may respond to further treatment with the same regimen (response rate 25 \200\22350 %). 2 Patients who relapse early after initial therapy with M&P or fail to respond at relapse m ay respond to single agent dexamethasone (20 \200\22340mg/day 4 days weekly 3 weeks/m onth initially) or thalido- mide (50 \200\223200mg/day) or these drugs in combination (resp onse rate up to 70%) to which may be added cyclophosphamide (300 \200\223500mg/week) or cla rithromycin (4 responses). 2 Thalidomide (50 \200\223400mg/day) as a single agent achieves up to 30% 280 responses in chemotherapy-resistant myeloma; addition of dexametha- sone (20 \200\22340mg/d ay 4 days/month) 4 response rates (up to 70%); side effects constipation, tremor, headac he, oedema, somnolence; thromboembolism risk esp. in combination with anthracyclines (full dose warfarin or LMW heparin prophylaxis advised). 2 Patients who relapse after prolonged response to HDM (>18 months) with a PBSC harvest suf ficient for 2 procedures or with a further suc- cessful harvest may benefit from second HDM re-induction with VAD. 2 There is evidence of a graft-versus-myeloma effect and DLI has re- induced responses in p atients with recurrence after allogeneic SCT. 2 The immunomodulatory drug Revimid and the p roteosome inhibitor Velcade are both active in refractory and resistant myeloma; studies to define the role of these agents are in progress. 2 Cyclophosphamide (50 \200\223100mg/day PO) is well tolerated palliative therapy for patie nts with advanced refractory disease or cytopenia who are intolerant of thalidomide or dexa methasone. 1 Child, J.A. et al. (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for mul- tiple myeloma. N Engl J Med, 348, 1875 \200\2231883. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 281 Paraproteinaemias Variant forms of myeloma Non-secretory myeloma 2 1% of MM cases; no detectable serum or urine paraprotein by immunofixation; (Note: serum free light chain ratio abnormal in 70%); clonal plasma cells \211 5% in BM or plasmacytoma on biopsy; myeloma- related end-organ damage. 2 Treat as above; response rates comparable to secretory MM; response more difficult to assess in absence of paraprotein; serum free light chain assay provides a lternative to surrogate markers (b2-M, CRP) and BM assessment. IgD myeloma 2 1% of cases of MM; younger mean age; high rate of Bence Jones pro- teinuria and associated higher frequency of acute and chronic renal failure; tendency to present wit h other poor prognostic features (high b2-M; low Hb). 281 2 Treat aggressively when possible. IgM myeloma 2 Very rare; <0.5% of MM; 1% of all IgM gammopathies; plasma cell infil- trate in BM associated with osteolytic lesions as opposed to lympho- plasmacytoid infiltrate char acteristic of WM; response and survival equivalent to MM. IgE myeloma 2 Rarest form of MM; younger age; high incidence of plasma cell leukemia. 2 ?shorter survival. Plasma cell leukemia 2 Defined as PB plasma cells >2 109/L or 20% of differential count; may occur de novo at presentation or in the terminal stages of other- wise typical MM. 2 Aggressive disease associated with BM failure and organomegaly; poor response to conventi onal dose therapy; few survive >6 months; better responses to HDM. Cryoglobulinaemia 2 Rare complication of paraprotein precipitation at low temperature; 2 Le g ulcers, Raynaud \200\231s phenomenon, renal impairment, gangrene, CNS and GI symptoms; biopsy usually shows vasculitis. 2 Treat myeloma and avoid cold. POEMS syndrome 2 Polyneuropathy, Osteosclerosis, Endocrinopathy, M-protein, Skin changes. 2 Association of plasmacytoma with chronic inflammatory demyelinating polyneuropathy causing predominantly motor disability. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 282 2 Confirm diagnosis by demonstrating monoclonal plasma cells in osteosclerotic bone lesion (plasmacytoma). 2 BM usually <5% plasma cells; low level paraprotein; hypercalcaemia and renal impairment rare. 2 Other features: lymphadenopathy, organomegaly, diabetes mellitus, male gynaecomastia and impotence, female amenorrhoea, hypertri- chosis and hyperpigmentation. 2 Treat solitary bone lesions with aggressive radiotherapy (45Gy) surgery. Solitary plasmacytoma of bone (SPB): Diagnostic criteria 2 Generally no paraprotein in seru m or urine though small band may be present. 2 Single area of bone destruction due to clonal plasma cells. 2 BM not consistent with MM. 2 Otherwise normal skeletal survey (and MRI of spine and pelvis). 2 No myeloma-related orga n or tissue impairment (end-organ damage). 2 Represents 5% plasma cell neoplasia: 9 : 3 ra tio 2:1; median age 55. 2 Lesion usually in axial skeleton; 66% in spine. 2 Generally prese nts with bony pain; may cause cord/root compression. 2 Diagnosis requires biopsy or FNA, ex clusion of MM (p273) and exclu- sion of other bone lesions with MRI (FDG-PET/99Tc-MIBI unde r exami- nation). 282 2 Serum or urine paraprotein detected in 24 \200\22372%; generally low level. 2 Adverse pro gnostic factors for progression to MM include persistence of paraprotein >1 year after radi otherapy, immuneparesis and lesion >5cm. 2 Negative MRI of spine is good prognostic feature. 2 Treat with fractionated radical radio therapy 40Gy (50Gy for lesions >5cm); local control 80 \200\22395%; curative in 50% if soli tary lesion; DFS 40% at 5 years. 2 Treat non-responders with chemotherapy as for myeloma (p278). 2 Regular follow-up to moni tor paraprotein; disappears in 25 \200\22350% (often slowly over several years). 2 75% progress to MM; treat as de novo MM (p278); high response rate. 2 Some patients deve lop multiple solitary recurrences; treat each with local radiotherapy. 2 Median survival 10 years. Extramedullary plasmacytoma (SEP) Diagnostic criteria 2 Generally no paraprotein in serum o r urine though small band may be present. 2 Extramedullary tumor of clonal plasma cells. 2 BM not consistent with MM. 2 Normal skelet al survey (and MRI of spine and pelvis). 2 No myeloma-related organ or tissue impairment (e nd-organ damage). 2 Rare; may occur anywhere but 90% in head and neck; most in upper airways. 2 Diagnosis requires biopsy or FNA of the lesion; exclusion of MM and other lesions. 2 <25% have serum or urine paraprotein. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 283 Paraproteinaemias 2 Treat with radical radiotherapy (40Gy; 50Gy if lesion >5cm) including cervical lymph nodes when involved; radical surgery only for SEP outside head and neck. 2 Most cured; <5% local recurrence; relapse <30%; MM, SBP or soft tissue involvement: chemotherapy for refractory or relapsed disease (p278). 2 >70% survival at 10 years. 283 Criteria for the classification of monoclonal gammopathies, multiple myeloma and related di sor- ders: a report of the International Myeloma Working Group (2003) Br J Haematol, 121, 7 49 \200\223757; BCSH UKMF Guidelines Diagnosis and management of solitary plasmacytoma of b one (SBP) and solitary extramedullary plasmacytoma (SEP). www.bcshguidelines.com 08-plasma cell.qxd 10.12.2003 04.21 PM Page 284 Waldenstr m \200\231s macroglobulinaemia (WM) WM is an uncommon indolent chronic B-cell lymphoproliferative disorder characterized by bon e marrow infiltration by lymphoplasmacytic cells and an IgM paraproteinaemia. It is classif ied as a lymphoplasmacytic lymphoma in the REAL and WHO classifications (p195). Epidemiology 2 Incidence <0.5 per 100,000 per annum; mean age 65; rare <40; M:F 2:1. 2 Cause unknown; several familial clusters described; 23% of patients have 1st degree relative with B-cell disorder. Pathophysiology WM appears to arise from IgM+ memory B lymphocytes (suggested by the immuno phenotype and Ig somatic hypermutation without intraclonal variation); slowly progressive; symptoms may be due to infiltration of BM (BM failure) spleen (splenomegaly) or liver (hepa tomegaly) or to hypervis- cosity due increased serum levels of pentavalent monoclonal IgM ( when IgM >30g/L). Autoimmune disorders may also develop due to the para- protein: neuropath y, cold agglutinin disease 284 Clinical features and presentation 2 Occasional diagnosis following routine ESR/PV/FBC/bloo d movie. 2 Usually insidious onset of weakness and fatigue. 2 Often present with symptoms o f anemia, epistaxis, recurrent infec- tion, dyspnoea, CCF and weight loss.