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%) Serum protein electrophoresis with immunofi xation Serum immunoglobulins To detect immuneparesis SFLC To detect LC MM (22%); useful response parameter in LC MM, amyloidosis and 75% of non-secre tory MM To detect proteinuria (770%) To detect Bence Jones proteinuria: (22% have BJP only and no serum M-band: LC MM) Routine urinalysis Urine electrophoresis with immunofi xation: 24h urine collection For creatinine clearance and 24h proteinuria \200\224to assess renal damage X-ray sites of bone pain May reveal pathological fracture(s) or lytic lesion(s) Diagnostic tests BM aspirate Demonstrates plasma cell infi ltration \200\224may be only way to diagnose NS MM Radiological skeletal survey Identifi es lytic lesions, fractures, and osteoporosis (80%; 5 \200\22310% osteoporosis onl y) Characterizes and quantifi es paraprotein; IgG 50%; IgA 20%; LC 20%; IgD/E/M/biclonal <10%. Note: serum and urine EPS \210\222ve in NS 71% but SFLC abnormal in 75% of NS MM Paraprotein immunofi xation and densitometry Tests to establish tumor burden and prognosis Serum 2-microglobulin Serum C-reactive prot ein Surrogate measure of IL-6 which correlates with tumor aggression Measure of tumor burden Serum LDH Measure of tumor aggression; i in plasmablastic MM Serum albumin Hypoalbuminaemia correlates with poor prognosis BM cytogenetics and FISH Clear prognostic value, esp. t(4;14) and del(17p) (see Table 8.8) BM trephine biopsy with immunohistochemistry Shows LC restriction, extent of infi ltration and haematopoietic reserve (continued) 340 CHAPTER 8 Paraproteinaemias Table 8.6 Investigation of patients with suspected myeloma4 \200\2237 (continued) Tests which may be useful in some patients MRI Urgent in patients with suspected cord compression; MRI whole spine/pelvis important in sta ging solitary plasmacytoma of bone to exclude occult disease; useful to clarify ambiguous C T fi ndings; abnormal in 725% of MM patients with n skeletal survey CT For detailed evaluation of localized sites of disease, e.g. extraosseous plasmacytoma, incl uding CT-guided biopsy; urgent CT indicated in suspected cord compression where MRI contrai ndicated or unavailable; useful to clarify ambiguous radiographic fi ndings; may identify l esions that are \210\222ve on radiography FDG-PET scan Not recommended as routine but may clarify extent of extramedullary disease if other imagin g techniques do not do so; identifi es focal recurrent disease and focal extramedullary dis ease; abnormal in 725% with n skeletal survey; persistent +ve post-therapy may predict earl y relapse PET/CT May be useful in solitary plasmacytoma of bone BM fl ow cytometry Confi rms monoclonal PC infi ltration and aberrant phenotype; useful when BM PC <10% Tissue biopsy To diagnose solitary plasmacytoma of bone or extraosseous plasmacytoma Bone densitometry Provides baseline in patients with osteoporosis but not recommended as routine Table 8.7 Diagnostic criteria for MMa 8,9 Monoclonal protein in serum and/or urine (Note: no minimum level). \200 Clonal BM plasma cells (Note: no minimum level; 5% have <10% plasma cells) or plasmacytoma. Myeloma-related organ or tissue impairment (acronym \200\230ROTI \200\231) Elevated Ca2+ levels: serum Ca2+ >0.25mmol/L (>1mg/dL) above upper limit of n or corrected serum Ca2+ >2.75mmol/L (>11mg/dL). Renal insuffi ciency: (creatinine >173 micromol/L or >2mg/dL). \200 Anemia: Hb 2g/dL belo w n range or Hb <10g/dL. \200 Bone lesions: lytic lesions or osteoporosis with compressio n fractures recognized by conventional radiology. Others: symptoms of hyperviscosity; amyloidosis; recurrent bacterial infection. 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 a Criteria identical in WHO classifi cation (2008). 341 MULTIPLE MYELOMA Fig. 8.2 BM aspirate in myeloma showing numerous plasma cells (E see color plate section). Cytogenetics2,9,10 \200 Conventional techniques demonstrate abnormal karyotypes in only 30 \200\22350% due to the low proliferative rate of MM cells and low proportion within samples for cytogenetic analysis; heterogeneous pattern and complex abnormalities common. High-density comparative genetic hybridization arrays show abnormalities in almost 100%. Interphase FISH on sorted or labeled MM-cells demonstrates aneuploidy in nearly all patients: \200 Hyperdiploidy in 750%; median 54 chromosomes. \200 Abnormalities involving 14q32 (IgH locus) in 760% (esp. non- hyperdiploid karyotypes) : t(11;14)(q13;q32) 720%, t(4;14) (p16;q32) 715%, t(14;16)(q32;q23); 75% and non-recurrent abnormalities. del(17p;13.1): 710%; loss of p53 tumor suppressor gene. \200 Prognostic value of cytogene tic fi ndings: see Tables 8.8 and 8.9. 342 CHAPTER 8 Paraproteinaemias Table 8.8 Cytogenetic prognostic groups is MM9 Deletion 13 or aneuploidy by metaphase analysis t(4;14) or t(14;16) or t(14;20) by FISH Del etion 17p13 by FISH Hypodiploidy Unfavorable risk Favorable risk Absence of unfavorable risk cytogenetics and presence of hyperdiploidy, t(11;14) or t(6;14) by FISH Table 8.9 Mayo stratifi cation of myeloma and risk-adapted therapy11 High risk Standard risk 775% of patients All other FISH or cytogenetic abnormalities, including: \200 Hyperdiploi dy \200 FISH t(11;14) \200 FISH t(6;14) 725% of patients Presence of any of the following: \200 FISH del(17p) \200 FISH t(4;14) \200 FISH t(14;16) \200 Cytogenetic del(13q) \200 Cytogenetic hypodiploidy \200 PC labeling index \211 3% Prognostic factors: adverse factors at diagnosis \200 Age >65 years. \200 Performance s tatus 3 or 4. \200 High paraprotein levels (IgG >70g/L; IgA >50g/L; BJP >12g/24h). \200 Low hemoglobin (<10g/dL). \200 Hypercalcaemia. \200 Advanced lytic bone lesions. \200 Abnormal renal function (creatinine >180 micromol/L). \200 Low serum albumin (<30g/L). \200 High 2-microglobulin ( 2-M) ( \211 6mg/mL). \200 High C-reactive protein ( \211 6mg/mL). \200 High serum LDH. \200 High % BM plasma cells (>33%). \200 Plasmablast m orphology. \200 Adverse cytogenetics. \200 Circulating plasma cells in PB (plasma cell leukemia). \200 High serum IL-6 (not routinely done; measured in only a few centers). 343 MULTIPLE MYELOMA Fig. 8.3 Skull x-ray in a patient with myeloma: multiple lytic lesions. Fig. 8.4 Humerus in a patient with myeloma: marked osteoporosis, lytic lesions, and healing pathological fracture. 344 CHAPTER 8 Paraproteinaemias Staging systems The Durie \200\223Salmon staging system (Table 8.10) has been widely used s ince 1975.12 It attempts to assess tumor bulk but may not provide as good prognostic discri mination as more recent systems; Largely superseded by the ISS staging, but still included here. Table 8.10 Durie-Salmon staging system.12 Patients staged as I, II, or III and A or B; stag e represents tumor burden Stage I Stage II Stage III Tumor cell mass Low All of the following: Medium Not fi tting stage I or III High One or more of the following: Monoclonal IgG (g/L) <50 >70 Monoclonal IgA (g/L) <30 >50 BJP excretion (g/24h) <4 >12 Hb (g/dL) Serum Ca2+ (mmol/L) \211 2.6 ( \211 12mg/dL) >10 <8.5 >2.6 (>12mg/dL) Lytic lesions None or one Advanced Stage A: serum creatinine <175 micromol/L (<2.0mg/dL) Stage B: serum creatinine \211 175 micromol/L ( \211 2.0mg/dL) The International Staging System (ISS)13 is another widely used staging system and was devi sed using data from 10,750 untreated patients from America, Europe, and Asia. It uses serum 2-M and serum albumin to defi ne 3 diff erent prognostic groups. Patients with stage I ( serum 2-M <3.5mg/L and serum albumin \211 35g/L) have a median survival of 62 months, pa tients with stage II (serum 2-M <3.5mg/L and serum albumin <35g/L or serum 2-M 3.5 \200 \223<5.5mg/L) have a median survival of 44 months, and patients with stage III (serum 2-M \211 5.5mg/L) have a median survival of 29 months. Mayo Strati \201 cation of Myeloma an d Risk-Adapted Therapy (mSMART)12 defi nes a high-risk group based on cytogenetic and proli feration data (including using conventional cytogenetics to correlate with a high MM cell p roliferative rate) to identify patients who should be managed diff er- ently from standard- risk patients (Table 8.9) Response assessment 2 systems are in current use. The system initially developed by the Eur opean Group for Blood and Marrow Transplant (EBMT)14 for patients treated with SCT has been widely used (Table 8.11) but may be superseded by the more recently published system devel oped by the International Myeloma Working Group14 (Table 8.12). Although primarily designed for clinical trials, these criteria are useful in clinical practice. 345 MULTIPLE MYELOMA Table 8.11 EBMT response criteria for MM15 Response category De \201 nition All of the following: \200 Absence of paraprotein in serum and urine by immunofi xation, Complete response (CR) maintained for \211 6 weeks <5% plasma cells (PC) in BM and trephine biopsy, if performed; if absent paraprotein sustai ned 6 weeks, no need to repeat BM \200 No increase in size or number of lytic bone lesion s (development of a compression fracture does not exclude CR) \200 Disappearance of soft tissue plasmacytom as All of the following: \200 \211 50% d in serum paraprotein, maintained for \211 6 we eks \200 d in 24h urinary LC excretion by either \211 90% or to <200mg, Partial response (PR) maintained for \211 6 weeks For patients with NS myeloma only, \211 50% d in PC in BM aspirate and trephine biopsy, if performed, maintained \211 6 weeks \211 50% d in size of soft tissue plasmacytomas (by radiology or clinical examination) No i in size or number of lytic bone lesions (development of a compression fracture does not exclude PR) All of the following: \200 25 \200\22349% d in serum paraprotein level maintained for \211 6 weeks \200 50 \200\22389% d in 24h urinary LC excretion, which still exceeds Minimal response (MR) 200mg/24h, maintained for \211 6 weeks For patients with NS myeloma only, 25 \200\22349% d in PC in BM aspirate and trephine biopsy, if performed, maintained \211 6 weeks \200 25 \200\22349% d in size of soft tissue plasmacytomas (by radiology or clinical examination) No i in size or number of lytic bone lesions (development of a compression fracture does not exclude MR) No change Not meeting the criteria of either MR or progressive disease Plateau Stable values (within 925% value at the time response is assessed), maintained for \211 3 months Relapse from CR At least one of the following: \200 Reappearance of serum or urine paraprotein on immunof i xation or electrophoresis, confi rmed by at least 1 other study \211 5% PC in BM aspirate or trephine biopsy \200 Development of new lytic bone lesions or soft tissue plasmacytomas or defi nite i in size of residual bone lesions \200 Development of hyperca lcaemia not attributable to other cause (continued) 346 CHAPTER 8 Paraproteinaemias Table 8.11 EBMT response criteria for MM15 (continued) Response category De \201 nition Progressive disease 1 or more of the following: \200 >25% i in serum paraprotein, which must also be an absol ute i of \211 5g/L, confi rmed by \211 1 repeated study >25% i in 24h LC excretion, which must also be an absolute i of \211 200mg/24h, confi rmed by \211 1 repeated study >25% i in PC in BM aspirate or trephine biopsy, which must also be an absolute i of at least 10% Defi nite i in size of existing bone lesions or soft tissue plasmacytomas Development of new bone lesions or soft tissue plasmacytomas \200 Development of hypercal caemia not attributable to other cause Reproduced from Blad , J. et al. (1998). Criteria for evaluating disease response and prog ression in patients with multiple myeloma treated by high dose therapy and haemopoietic ste m cell transplantation. Brit J Haematol, 102, 1115 \200\22323, with permission of Wiley-Bla ckwell publishing 1998 Table 8.12 International Myeloma Working Group uniform response criteria14 Response subcategory Response criteriaa Stringent complete response (sCR) CR as defi ned below, plus: \200 Normal SFLC ratio \200 Absence of clonal cells in BMb by immunohistochemistry or immunofl uorescencec Complete response (CR) All of the following: \200 \210\222ve immunofi xation on the serum and urine \200 Disa ppearance of any soft tissue plasmacytomas \200 \211 5% PC in BMb One of the following: \200 Serum and urine M-protein detectable by immunofi xation but not on electrophoresis Very good partial response (VGPR) \211 90% d in serum M-protein plus urine M-protein level <200mg/24h \211 50% d of serum M-protein and d in urinary Partial response (PR) M-protein by \211 90% or to <200mg/24h If the serum and urine M-protein are unmeasurable, a \211 50% d in the diff erence between involved and uninvolved SFLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable , and SFLC assay is also unmeasurable, \211 50% d in PC is required in place of M-protein, provided baseline BM PC percentage was \211 30%. In addition to the above listed criteria, if present at baseline, \211 50% d in size of so ft tissue plasmacytomas is also required. (continued) 347 MULTIPLE MYELOMA Table 8.12 International Myeloma Working Group uniform response criteria14 (continued) Response subcategory Response criteriaa Not meeting criteria for CR, VGPR, PR, or progressive disease Stable disease (SD) Not recommended for use as an indicator of response; stability of disea se is best described by providing the time to progression estimates Any one or more of the following: \200 i of \211 25% from baseline in: Progressive disease To be used for calculation of time to progression and progression-free survival end-points for all patients including those in CR (includes primary progressive di sease and disease progression on or off therapy) Serum M-component and/or (absolute i must be \211 5g/L)d Urine M-component and/or (absolute i must be \211 200mg/24h) Only in patients without measurable serum and urine M-protein levels: the diff erence betwe en involved and uninvolved SFLC levels (absolute i must be >100mg/L) BM PC percentage (absolute % must be \211 10%)e \200 Defi nite development of new bone l esions or soft tissue plasmacytomas or defi nite i in size of existing bone lesions or tissue plasmacytoma s Development of hypercalcaemia (corrected serum calcium > 2.65mmol/L (>11.5mg/dL)) solely at tributable to the PC proliferative disorder Any one or more of the following direct indicators of increasing disease and/or end organ d ysfunction (CRAB features):d \200 Development of new soft tissue plasmacytomas or Clinical relapse Not used in calculation of time to progression or progression-free surviva l but is listed as something that can be reported optionally or used in clinical practice bone lesions Defi nite i in size of existing plasmacytomas or bone lesions; defi nite i is defi ned as a 50% (and \211 1cm) i as measured serially by sum of the products of the cross-diameters o f measured lesion Hypercalcaemia (>2.65mmol/L ( \211 11.5mg/dL)) \200 Decrease in hemoglobin of \211 2g/dL \200 Rise in serum creatinine by \211 177 micromol/L ( \211 2mg/dL) (continued) 348 CHAPTER 8 Paraproteinaemias Table 8.12 International Myeloma Working Group uniform response criteria14 (continued) Response subcategory Response criteriaa Relapse from CR To be used only if the end-point studied is DFSf Any one or more of the following: \200 Reappearance of serum or urine M-protein by immunofi xation or electrophoresis \200 Development of \211 5% PC in the BM \200 Appea rance of any other sign of progression (i.e. new plasmacytoma, lytic bone lesion, or hyperc alcaemia) a All response categories require 2 consecutive assessments made at any time before the ins titution of any new therapy; all categories also require no new evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not requi red to satisfy these response requirements. b Confi rmation with repeat BM not needed. c Pr esence/absence of clonal cells is based upon the / ratio. An abnormal / ratio by im munohistochemistry and/or immunofl uorescence requires a minimum of 100 plasma cells for an alysis. An abnormal ratio refl ecting the presence of an abnormal clone is / of >4:1 or <1:2. d For progressive disease, serum M-component increases of \211 10g/L are suffi cien t to defi ne relapse if starting M-component is \211 50g/L. e Relapse from CR has the 5% c ut-off versus 10% for other categories of relapse. f For purposes of calculating time to pr ogression and progression-free survival, CR patients should also be evaluated using criteri a listed above for progressive disease. Reproduced from Durie, B.G.M. et al. (2006). International uniform response criteria for mu ltiple myeloma. Leukemia, 20, 1467 \200\22373, with permission from Macmillan Publishers Lt d. 2007 Management Partial and complete responses are achieved in a high proportion of patients wit h MM using a range of chemotherapeutic regimens but these responses are transient. Further responses are commonly achieved with the same or alternative regimens. MM is not curable wi th conventional regimens and only a small number of patients may have been cured by allogen eic SCT. The recent introduction of novel agents has changed the treatment options in MM an d more than doubled OS in the last decade. Risk-adapted therapy is now feasible as new prog nostic factors more clearly defi ne risk groups. Initial management considerations and general aspects Pain control \200 Titrate simple analgesia (e.g. paracetamol 1g 4 \200\2236-hourly) for m ild- to-moderate pain, weak opioids (co-codamol 2 tabs 6-hourly or dihydrocodeine 30 \200 \22360mg up to 4-hourly) for moderate pain and strong opioids (morphine sulfate solution 5 \200\22310mg 4-hourly converting to slow release preparation, when daily requirement establ ished with 5 \200\22310mg morphine sulfate solution prn for \200\230breakthrough \200\231 pain) for moderate- to-severe pain; commence simple laxative with opioids. (See Fig. 8.5.) \200 Avoid NSAIDs (if essential, use caution and monitor renal function). \200 Local ra diotherapy (8 \200\22330Gy) often extremely eff ective. \200 A spinal support corset ofte n helpful for severe back pain. \200 Neuropathic pain may be relieved by non-analgesic ad juvants, e.g. amitriptyline, carbamazepine, or gabapentin. 349 MULTIPLE MYELOMA Pain persisting or increasing Pain persisting or increasing Opioid for moderate \200\223 severe pain non-opioid analgesia adjuvant Opioid for mild \200\223 moderate pain non-opioid analgesia adjuvant Pain Non-opioid analgesia adjuvant Fig. 8.5 WHO pain treatment ladder. Reproduced with permission from the World Health Organi zation, Palliative Care: Symptom management and end of life care, p.12. Renal impairment \200 All patients should be instructed to maintain a high fl uid intake ( \211 3L/d); use caution with nephrotoxic drugs, including NSAIDs. \200 Prompt intervent ion to correct early renal impairment may prevent long-term renal damage. Aim for urine output >3L/d, and rapid treatment of hypercalcaemia, infection and hyperuricaemia may improve renal function. Seek advice of nephrologist if renal failure does not improve within 48h; peritoneal or haemodialysis may be required (<5%). Renal impairment related to MM: bortezomib (and dexamethasone)- based regimen are used foll owed by PBSC harvest and high-dose melphalan (HDM) in renally reduced dose (140mg/m2) with autologous SCT in younger patients; after response EFS and OS same as other patients; allo- SCT not recommended for patients undergoing haemodialysis. Hypercalcaemia \200 Vigorous rehydration with IV saline (3 \200\2236L/d IV) with close mo nitoring of fl uid balance and renal function. Loop diuretics (furosemide) increase Ca2+ excretion and maintain fl uid balance. IV bisphosphonate (pamidronate disodium 30 \200\22390mg IVI over 2h or zoledronic acid 4mg IV over 5min; d dose and infusion rate in renal impairment); zoledronic acid gives higher C R rate (50% by d4) and duration of eff ect; repeat if necessary. IV corticosteroids if refractory; chemotherapy to treat underlying cause (MM). Bone disease \200 Local radiotherapy for localized pain. \200 Fixation of fractures/pot ential fractures followed by radiotherapy. \200 Vertebroplasty or kyphoplasty may be cons idered in patients with persistent back pain and vertebral collapse. Long-term bisphosphonates: prevention of further damage. Infection \200 Prompt and vigorous broad-spectrum antibiotic therapy. 350 CHAPTER 8 Paraproteinaemias Prophylactic antibiotics are currently not recommended. \200 Annual infl uenza immunizati on and immunization against Streptococcus pneumonia and Haemophilus infl uenza is recommended. Anemia \200 Blood transfusion for symptomatic anemia; use caution if high paraprotein due to risk of hyperviscosity. EPO can be used if Hb persistently \211 10g/dL (10,000IU tiw or 30,000IU once weekly; 770% response rate with \211 2g/dL rise in Hb); not recommended until respons e to chemotherapy assessed then consider 6 \200\2238 week trial in patients with symptomati c anemia on chemotherapy; discontinue if Hb has not risen by 1 \200\2232g/dL after 6 \200 \2238 weeks. Hyperviscosity \200 May develop in patients with high serum paraprotein levels, IgM > IgA > IgG causing cerebral, pulmonary, and renal manifestations and bleeding. Patients with levels of IgG >60 g/L, IgA >40g/L and IgM >30g/L are at particular risk. Symptomatic patients should be treated by plasmapheresis (3L plasma exchange) followed by prompt chemotherapy. Initial isovolaemic venesection with saline repl acement can be used as a holding measure if plasmapheresis is not immediately or readily av ailable. Cord compression \200 Medical emergency; requires immediate treatment \200 Commonly pre sents with sensory loss, paraesthesiae, limb weakness, diffi culty walking, and sphincter d isturbance (cauda equina syndrome). Urgent MRI scan to defi ne lesion (CT if MRI unavailable or contra-indicated). Commence oral dexamethasone stat. Dosing schedules vary. The 2013 BCSH guidelines recommend 40mg dexamethasone for 4d. Local radiotherapy should be commenced within 24h. \200 Surgery is indicated if there is spinal instability. Hemorrhage \200 Uncommon; several possible mechanisms: direct inhibition of fi brin polym erization, heparin-like anticoagulants, acquired von Willebrand \200\231s syndrome and, in the presence of AL amyloid, factor X defi ciency; treatment must be individualized. Speci \201 c treatment of MM The aim of treatment is: (i) to control disease, (ii) to maxi mize quality of life, and (iii) to prolong survival. Chemotherapy and good supportive care are both essential to these aims. It is important that, wherever pos- sible, patients are t reated within clinical trials to determine the optimum combination and sequence of the eff ective new agents that have radi- cally altered treatment options in recent years. An early decision must be whether the patient is a candidate for high-dose therapy (HDT) an d autologous SCT, based on age, co-morbidities, and risk-assessment. Advanced age and renal dysfunction are not absolute con- traindications to SCT. An initial regimen that minimizes stem cell toxicity (non-alkylator regimen) must be selected for potential candidates for S CT. 351 MULTIPLE MYELOMA Many agents and combinations are available and approved for use in the treatment of MM. Eve n a geographical diff erence for regimens used exists (diff erent preferences in the USA an d UK). Treatment must be tailored for specifi c patients and response followed closely. Treatment on clinical trial recommended Initial therapy (treatments are not discussed in any particular order) No regimen is clearl y superior. VAD, formerly widely used, has been superseded, and is not discussed. CTD is us ed in many UK centers as standard 1st-line treatment, whereas in the USA bortezomib regimen s are mainly used in 1st line. Cyclophosphamide, thalidomide, and dexamethasone (CTD) \200 CTD (C 500mg PO/IV once weekl y; T 50 \200\223200mg/d; D 40mg PO d1 \200\2234 and 15 \200\22318; 21d cycle) \227 4 \200\2236 courses. Eff ective and wel l tolerated initial therapy pre-HDT. Has superseded previously used C-VAD. Prophylactic ant icoagulation recommended in high risk patients; pregnancy prevention program mandatory. 1st -choice treatment pre-SCT in many centers. Cyclophosphamide, thalidomide, and dexamethasone \200\224attenuated (CTDa) \200 C 500mg P O once weekly; T 50 \200\223200mg/d; D 20mg PO d1 \200\2234 and d15 \200\22318; 28d cycle). Eff ective and well-tolerated initial therapy in elderly patients; Antithrombotic therapy recommended; pregnancy prevention program mandatory. Cyclophosphamide16 \200 \200\230C-weekly \200\231 (300 \200\223500mg PO once weekly) may be used as a single agent for patients intolerant of melphalan or other schedules due to p ersistent cytopenia and thalidomide; durable plateau phases achieved. Well tolerated. Melphalan and prednisolone (MP)17 \200 Historically and until recently standard initial t herapy for elderly patients with MM (since 1960); (M 6 \200\2239mg/m2/d PO; P 40 \200\223100mg/d PO for 4d eve ry 4 \200\2236 weeks); achieves \211 50% reduction of paraprotein in 50 \200\22360% patien ts; response often slow; continue to maximum response (9 \200\22312 months); CR uncommon (< 5%); well tolerated; side eff ects myelosuppression and steroid toxicity. Median duration 12 \200\22318 months. \200 At progression after durable plateau patients may further respond to MP. Melphalan resistance ultimately develops in all patients. Median survival 36 months. \200 Option for patients unable or unwilling to tolerate thali domide. Melphalan, prednisolone, and thalidomide (MPT)18,19 \200 Thalidomide is an immuno modulatory agent with multiple actions on MM-cells and the microenvironment: inhibition of angiogenesis, inhibition of growth and sur vival of MM cells, altered cytokine production, altered expression of adhesion molecules an d T-lymphocyte stimulation; Side eff ects of thalidomide: constipation, sedation, rash, dizziness, and peripheral neuro pathy; VTE is a risk when used in combination and patients at high risk of, or with a histo ry of VTE should receive VTE prophylaxis; pregnancy prevention program mandatory. 352 CHAPTER 8 Paraproteinaemias MPT (MP +T 100 \200\223400mg/d) shows superior response (OR 76% vs 48%; CR+nCR 28% vs 7%) a nd progression-free survival (PFS: 54% vs 27% at 2 years) vs MP in 2 randomized trials; 1 a lso demonstrated superior median OS (52 months vs 33 months) and 3-year OS (48% vs 25%). MPT has higher toxicity than MP (48% vs 25%): thromboembolism 12% vs 2%; neuropathy 10% vs 1%; infections 10% vs 2%; GI events 6% vs 1%; thromboembolic events markedly reduced by int roduction of LMWH prophylaxis. Doses and administration diff er; optimum schedule unclear. \200 Well tolerated in elderl y patients. Bortezomib (Velcade) and dexamethasone (Vel/Dex) ( Cyclo) \200 Bortezomib is a 1st-in-c lass proteasome inhibitor; multiple eff ects on both MM-cells and the microenvironment; sid e eff ects are transient thrombocytopenia, peripheral neuropathy, neuropathic pain, constip ation, nausea, vomiting, and neutropenic fever. Bortezomib (1.3mg/m2 SC 2 \227 weekly (d1, 4, 8, 11) for 2 weeks in 3-week cycle \227 4 \200\2238) approved as 2nd-line treatment in relapsed/ refractory MM; 740% OR in newly diag nosed patients. Cyclophosphamide can be added: improved RR. \200 Vel/Dex: Dex 40mg/d usually added on day of and day after Vel. \200 ORR 90%, 19% CR + nCR; rapid response 50% after cycle 2; 75% required Dex, improving response in 64%; manageable toxicities; SC harvest not compromised. 20,21 Mayo Clinic guidelines: bortezomib-containing regimen is considered in patients with high-r isk features (t(4;14), t(14;16), or del(17p)). Bortezomib (Velcade), thalidomide, and dexamethasone (VTD) \200 VTD has been compared wit h Thal/Dex in a randomized trial in 187 patients giving a better CR + nCR rate (38% vs 7%) with similar toxicity apart from i g rade 3 skin rashes and was not adversely aff ected by poor-risk cytogenetic abnormalities; better CR + nCR rate persisted after SCT (57% vs 28%).22 A rapid response rate was demonstrated for VTD in a study of 38 untreated patients with 16% CR and 87% \211 PR after \211 3 cycles.23 Bortezomib (Velcade), doxorubicin, and dexamethasone (PAD) \200 Initial therapy: Vel 1.3 (PAD1) or 1.0 (PAD2) mg/m2 d1, 4, 8, 11, Dox 9mg/m2 d1 \200\2234, Dex 40mg/d d1 \200\22344: CR + VGPR in 62% (PAD1) and 42% (PAD2), translating to 81% and 53% after HDM + SCT; Median responses of 29 and 24 months and 2-year OS of 95% and 73% respectively.24 Bortezomib (Velcade), lenalidomide, and dexamethasone (VRD) \200 High response rates with 28% CR + nCR and 98%.25 Bortezomib (Velcade), melphalan, and prednisolone (VMP) \200 Vel 1.3mg/m2 SC 2 \227 weekly. Advantage for VMP over MP in RR (89% vs 42%), 16 months EFS (83% vs 51%), and 16 months OS (90% vs 62%); a phase 3 study in 680 patients was terminated early when VMP showed superiority over MP in all measures: CR 35% vs 5%; duration of CR 24 months vs 13 months, median time to progression 24 months vs 1 3 months; similar adverse eff ects. 353 MULTIPLE MYELOMA Melphalan, prednisolone, and Revlimid (lenalidomide) (MPR)26 \200 M 0.18mg/kg/d and P 2mg /kg/d, R d1 \200\2234, 10mg/d, d1 \200\22321 every 28d for 9 cycles. 81% PR, 48% VGPR, 24% CR, and 1-year EFS and OS of 92% and 100%; grade 3+ 4 toxicity: 52% neutropenia, 24% thrombocytopenia; 5% VTE. High-dose dexamethasone (Dex)27, 28 \200 Single agent Dex (40mg/d PO on d1 \200\2234, 9 \200\22312, and d17 \200\22320; 28 d cycle) Responses \211 PR achieved in 43 \200\22363%. Thalidomide and dexamethasone (ThalDex)29,30 \200 Addition of thalidomide (200mg/d PO) to Dex improved RRs (63% vs 41%) but added toxicity (45% vs 21%), in particular DVT (17% vs 3%), also rash, bra dycardia, and neuropathy; prophylactic anticoagulation recommended; pregnancy prevention pr ogram mandatory. Lenalidomide (Revlimid) and dexamethasone (Rev/Dex) \200 Lenalidomide is a thalidomide an alog, immunomodulatory drug (IMiD); multiple eff ects on both MM-cells and the microenvironment and diff erent side eff ect profi le; main side eff ects \200\224constipation, cytopenia, VTE, and possible birth defects. Rev/Dex (Len 25mg/d PO d1 \200\22321 and Dex 40mg/d PO d1 \200\2234, 9 \200\22312, and 17 \200\22320; 28-d cycle) is approved as therapy for relapsed/refractory MM. 91% RR with 6% CR and 32% VGPR; prophylactic anticoagulation recommended.31,32 Carfi lzomib \200 Next-generation proteasome inhibitor. FDA approved in 2nd relapse. ORR 225; Median duration of response 7 \200\2238 months. Combination studies pending Pomalidomide \200 Immune-modulatory drug. RR seen in patient refractory to bortezomib and lenalidomide. Further trial results awaited. Other therapy Bisphosphonates33 \200\22336 \200 Inhibit OC activation; patients on long-t erm therapy experience less bone pain and fewer new bone lesions and fractures; evidence of improved QoL and possible prolonged survival. All patients with active MM should receive bisphosphonate therapy. \200 No evidence for s uperiority of either monthly pamidronate disodium (90mg IVI) or zoledronic acid (4mg IV).