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 VAD, formerly widely used, has been superseded, and is not discussed.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 Has superseded previously used C-VAD.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). Zoledronic acid, check creatinine before each infusion, ensure hydration; not recommended i f creatinine >265micromol/L. Monitor for osteonecrosis of jaw with zoledronate (risk factor poor dentition). Role on asymptomatic myeloma not clear and currently not recommended. 354 CHAPTER 8 Paraproteinaemias Thromboprophylaxis37 \200 Risk of VTE in malignancy i (see Table 8.13). \200 Thalidomid e-containing regimens: associated with i VTE incidence. Thromboprophylaxis indicated in hig h-risk patients and patients with a history of thrombosis or other risk factors. Lenalidomide monotherapy no i risk and thromboprophylaxis not indicated; i incidence with R ev/Dex (up to 23%) and Rev/ cyclophosphamide (14%). LMW heparin: reduces VTE frequency in several Thal combinations; may be preferable due to shorter half-life and lower risk of hemorrhage but generally not r ecommended in renal failure. Aspirin 75mg/d reduces VTE risk with several Thal or Rev combinations, but not Thal + doxor ubicin or multiagent chemotherapy; convenient and may be useful in lower-risk patients. \200 Risk factors: initial therapy, high tumor load, hyperviscosity, high-dose Dex, doxoru bicin, multiagent chemotherapy, concurrent EPO; age, obesity, history of VTE, diabetes, inf ection, renal disease, cardiac disease, surgery, immobility, HRT, thrombophilia. Unless contraindicated, prophylaxis for all patients receiving Thal or Rev in combination with other agents especially as initial therapy; continue for 4 \200 \2236 months or duration of Thal or Rev therapy; consider longer if additional patient- or treatment-related factors. Select prophylaxis on individual patient basis, balancing risks of VTE and hemorrhage. Treat VTE according to standard protocol; Thal or Rev should be briefl y discontinued and m ay be cautiously resumed when full anticoagulation established; 710% risk of 2nd DVT; conti nue anticoagulation for duration of Thal or Rev therapy; discontinue 1 month after completi on if no further DVT (minimum 3 months therapy).37 355 MULTIPLE MYELOMA Table 8.13 Proposed risk assessment model for VTE management in MM patients treated with th alidomide or lenalidomide37 Risk factors Actions If no risk factor or any one risk factor present: \200 Aspirin 75 \200\223325mg od Individual \200 Obesity \200 Previous VTE \200 Central venous catheter or pacemaker If \211 2 risk factors present: \200 LMW heparin (enoxaparin 40mg od or equivalent) Associated disease \200 Cardiac disease \200 Chronic renal disease \200 Diabetes \200 Acute infection \200 Immobilization (or \200 Full dose warfarin (target INR 2 \200\2233)) Surgery \200 General surgery \200 Any anesthesia \200 Trauma Medications \200 EPO Blood clotting disorders Myeloma-related factors \200 Diagnosis \200 Hyperviscosity If any of these therapies used: \200 LMWH (enoxaparin 40mg od or Myeloma therapy \200 High-dose dexamethasone (>480mg/month) equivalent) Doxorubicin \200 Immunomodulatory dug (or \200 Full dose warfarin (target INR 2 \200\2233)) combinations Reproduced from Palumbo, A. et al. (2008). Prevention of thalidomide- and lenalidomide- ass ociated thrombosis in myeloma. Leukemia, 22, 414 \200\22323, with permission from Macmillan Publishers Ltd, copyright 2007 Radiotherapy \200 Important modality of treatment in myeloma at all stages of disease; lo cal radiotherapy (8 \200\22330Gy) often a rapidly eff ective treatment for bone pain associ ated with pathological fracture or lytic lesions. \200 Urgent radiotherapy is indicated f or patients with spinal cord compression. Follow-up \200 Monitor response to therapy with serial quantitation of serum paraprotein, SFLC, or BJP (+ FBC, renal biochemistry and serum Ca2+ group) at 4 \200\2236 w eekly intervals to plateau (stable values 25% over 3 months) or SC mobilization. Patients in established plateau phase should be monitored for progression at 6 \200\2238 week intervals. 356 CHAPTER 8 Paraproteinaemias Autologous stem cell transplantation (ASCT)38 \200\22342 \200 ASCT not curative but prolo ngs median OS by 712 months; in the era of the new agents and targeted treatment its role m ight change but currently ASCT remains recommended to younger/fi t patients in 1st response . High-dose melphalan (HDM; 200mg/m2) + ASCT achieves high CR rates (25 \200\22380%) after in itial therapy. Median response duration 2 \200\2233 years; treatment of choice for patients <65 years; best responders have best survival, median >5 years; improved PFS (32 vs 20 mon ths) and OS (54 vs 42 months) vs conventional therapy in randomized study. Side eff ects: myelosuppression, infection, delayed regeneration. \200 No convincing bene fi t for \200\230double/tandem \200\231 ASCT but benefi t for those converted from PR to CR after 2nd procedure. No benefi t from SC purging procedures. \200 Same OS whether ASCT early (after induction) or delayed (as salvage after relapse). 2nd autologous transplant has a role in patients who have achieved a durable response post 1st autograft and who have achieved a further response with 2nd-line treatment. Allogeneic stem cell transplantation43 \200\22345 \200 Allogeneic SCT should be considere d for eligible patients with progressive disease after ASCT. Applicable to fi t patients \211 50 years; transplant-related mortality with standard conditioning regimens is high (733%) due to infection and GvHD; 35 \200\22345 % long-term survival (>5 years); 733% chance of durable remission and possible cure; 733% c hance of survival with recurrence. Reduced-intensity regimens have a lower toxicity, increase the age limit, but reduce the response rate. Reduced-intensity allogeneic SCT after ASCT has achieved 52 \200\22383% CR with 2 \200\2233 year, with an OS of 62 \200\22378% and PFS 755% and may be a useful app roach as either consolidation or salvage therapy; poor OS associated with chemoresistant MM , >1 prior SCT, and no chronic GvHD. Allogeneic SCT should be discussed with patients <50 years with a suitable sibling donor or young patients with a matched unrelated donor. Morbidity and mortality rates remain high. There is evidence of a graft-versus-myeloma eff ect; DLI can re-induce responses in patients with recurrence after allogeneic SCT. Preferentially in the context of a clinical trial. Maintenance therapy \200 Maintenance chemotherapy does not prolong response or survival but adds toxicity (BM suppression); maintenance dexamethasone not convincingly benefi cial. Thalidomide: Trials of thalidomide maintenance post ASCT showed signifi cantly benefi t in 3-year EFS an d 4-year OS; median duration 15 months; median dose 200mg; 39% discontinued due to toxicity ; side eff ects neuropathy 68%, fatigue 34%; constipation 20%.46 357 MULTIPLE MYELOMA 50 \200\223100mg dose recommended; thromboprophylaxis not required unless individual risk factors are present. Guidelines12 suggest maintenance therapy with thalidomide in high-risk patients who fail to achieve a CR post autograft. Lenalidomide or bortezomib maintenance: remains investigational. Treatment of primary refractory disease \200 Patients who are refractory to their 1st-lin e treatment should be switched to an alternative regimen if appropriate. Many schedules are approved for 1st-line and 2nd-line use. Response criteria are listed in Tables 8.11 and 8.12. Poor prognosis. \200 Consolidate with ASCT if possible after response achieved with 2nd- line treatment. Patients with 1 progressive myeloma may achieve good response to ASCT; 1- year PFS of 70% reported and compares to 83% in responders to initial therapy. Salvage therapy for disease progression Treatment of disease progression before the develop ment of novel therapies consisted of progressively shorter responses to available agents wi th the ultimate development of drug resistance and evolution of adverse features. The devel opment of novel agents has signifi cantly improved the outlook for patients with relapsed m yeloma. Generally speaking patients will switch to a treatment regimen they did not receive before. (See Table 8.14.) \200 Patients who achieve a durable response ( \211 18 months) to initial therapy may respond to the same regimen. Patients who relapse early after initial therapy (<6 months) will require a diff erent regimen to achieve a further response. Patients who relapse after prolonged response to HDM and ASCT (>18 months) with a PBSC harv est suffi cient for 2 procedures or with a further successful harvest may benefi t from a 2 nd HDM after re-induction with an alternative regimen. Allogeneic SCT should be considered for eligible patients with progressive disease after ASCT. Alternative salvage regimens are generally given. The list of treatment schedules is the sa me as listed on E pp.351 \200\223353. Choice of regimen will be dependent on patient-specif i c factors as well as on disease characteristics. Cyclophosphamide (50 \200\223100mg/d PO) is a well-tolerated palliative therapy for patient s with advanced refractory disease or cytopenia who are intolerant of thalidomide, dexameth asone or unable to tolerate other schedules such as Vel/Dex or Rev/Dex. 358 CHAPTER 8 Paraproteinaemias Table 8.14 Salvage treatment options for relapsed MM outside a clinical trial Relapse after initial treatment Early <12 months Consider alternative regimen Late \211 18 months Consider same regimen or alternative regimen Relapse after ASCT Early <12 months Consider alternative regimen and allo-SCT if appropriate/eligible. Late \211 18 months Consider alternative regimen Consider allo-SCT or 2nd ASCT Relapse after allo-SCT Consider DLI ASCT autologous stem cell transplantation; allo-SCT allogeneic stem cell transplantation; D LI donor lymphocyte infusion. 359 MULTIPLE MYELOMA Prognosis Analysis of patient outcome showed improved median OS from relapse for patients r elapsing after 2000 (24 months) compared to those relapsing before 2000 (12 months). Patients diagnosed between 2000 and 2010 had a 50% improvement in overall survival (45 mont hs vs 30 months). The improvements during that time are due predominantly to the introducti on of novel agents and in part to improved supportive care. With high-dose therapy followed by autologous stem cell transplanta- tion, the median survi val in 2003 was 4.5 years, compared to a median of approximately 3.5 years with \200\230st andard \200\231 therapy. With the advent of new targeted treatments and regimens this numbe r will have improved but mature data is pending. The International Staging System helps predict survival (E p.344). Median survival is 62 mo nths for stage 1 disease, 44 months for stage 2 disease, and 29 months for stage 3 disease, but it has to be kept in mind this data was analyzed on patients treated before many new a gents were widely available. It is likely prognosis will continue to improve. Younger patie nts have much longer survival rates. References 1. Kyle, R.A. and Rajkumar, S.V. (2007). Epidemiology of the plasma cell disorde rs. Best Pract Res Clin Haematol, 20, 637 \200\22364. 2. Chn,g W.J. et al. (2007). Genetic events in the pathogenesis of multiple myeloma. Best P ract Res Clin Haematol, 20, 571 \200\22396. 3. Podar, K. et al. (2007). The malignant clone and the bone-marrow environment. Best Pract Res Clin Haematol, 20, 597 \200\223612. 4. UK Myeloma Forum and Nordic Myeloma Study Group (2005). Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol, 132, 410 \200\22351. M http://www. bcsh guidelines.com/pdf/multiplemyeloma0206.pdf 5. NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma V.2.2008 M http://www. nccn.org/professionals/physician_gls/PDF/myeloma.pdf 6. D \200\231Sa, S. et al. (2007). Guidelines for the use of imaging in the management of m yeloma. Brit J Haematol, 137, 49 \200\22363. M http://www.bcshguidelines.com/pdf/myeloma_ma nagement_ guidelines.pdf 7. Pratt, G. (2008). The evolving use of serum free light chain assays in hematology. Br J Haematol 141, 413 \200\22322. International Myeloma Working Group (2003). Criteria for the classifi cation of monoclonal gammopathies, multiple myeloma and related disorders: a repor t of the International Myeloma Working Group. Brit J Haematol 121, 749 \200\22357. 8. 9. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 10. Avet-Loiseau, H. (2007). Role of genetics in prognostication in myeloma. Best Practice and Res Clin Haematol, 20, 625 \200\22335. 11. Dispenzieri, A. et al. (2007). Treatment of newly diagnosed multiple myeloma based on Mayo stratifi cation of myeloma and risk-adapted therapy (mSMART): consensus statement. May o Clin Proc, 82, 323 \200\22341. 12. Durie, B.G. and Salmon, S.E. (1975). A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to tr eatment, and survival. Cancer, 36, 842 \200\22354. 13. Greipp, PR. et al. (2005). International staging system for multiple myeloma. J Clin On col, 23, 3412 \200\22320. 14. Durie, B.G.M. et al. (2006). International uniform response criteria for multiple myelo ma. Leukemia, 20,1467 \200\22373. 360 CHAPTER 8 Paraproteinaemias 15. Blad , J. et al. (1998). Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high dose therapy and haemopoietic stem cell tran splantation. Brit J Haematol, 102, 1115 \200\22323. 16. MacLennan, I.C.M. et al. (1992). Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet, 339, 200 \200\2235. 17. Bergsagel, D.E. (1995). The role of chemotherapy in the treatment of multiple myeloma. Baillieres Clin Haematol, 8, 783 \200\22394. 18. Palumbo, A. et al. (2006). Oral melphalan and prednisolone chemotherapy plus thalidomid e compared with melphalan and prednisolone alone in elderly patients with multiple myeloma: randomized controlled trial. Lancet, 367, 825 \200\22331. 19. Facon, T. et al. (2007). Melphalan and prednisolone plus thalidomide versus melphalan a nd prednisolone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet, 370, 1209 \200\2231 8. 20. Jagannath, S. et al. (2006). Long term follow-up of patients treated with bortzomib alone and in combination with dexamethasone as frontline therapy for multiple myeloma. Bloo d, 108, 238a. 21. Orlowski, R.Z. et al. (2007). Randomized phase III study of pegylated liposomal doxorub icin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol, 25, 3892 \200\223901. 22. Cavo, M. et al. (2007). Bortezomib (Velcade)-thalidomide-dexamethasone (VTD) vs thalido mide-dexamethasone (TD) in preparation for autologous stem cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma. Blood, 110, 30a. 23. Wang, M. et al. (2007). Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology, 12, 235 \200\2239. 24. Popat, R. et al. (2008). Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Brit J Haematol, 141, 512 \200\22316. 25. Richardson, P.G. et al. (2008). Safety and effi cacy of lenalidomide (len), bortezomib (Bz) and dexamethasone (Dex) in patients with newly diagnosed multiple myeloma: a phase I/II stu dy. J Clin Oncol 25, 459s abstact 8520. 26. Palumbo, A. et al. (2007). Melphalan, predsisolone and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA-Italian Multiple Myeloma Network. J Clin Oncol , 25, 4459 \200\22365. 27. Alexanian, R. et al. (1992). Primary dexamethasone treatment of multiple myeloma. Blood , 80, 887 \200\22390. 28. Kumar, S. et al. (2002). Single agent dexamethasone for induction in patients with mult iple myeloma undergoing autologous stem cell transplants. Blood, 100, 432a. 29. Cavo, M. et al. (2005). Superiority of thalidomide and dexamethasone over vincristine- doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous trans- pla ntation for multiple myeloma. Blood, 106, 35 \200\2239. 30. Rajkumar, S.V. et al. (2006). Phase III clinical trial of thalidomise plus dexamethason e alone in newly diagnosed multiple myeloma: a clinical trial conducted by the Eastern Coop erative Oncology Group. J Clin Oncol, 24, 431 \200\2236. 31. Rajkumar, S.V. et al. (2005). Combination therapy with lenalidamide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood, 106, 3050 \200\2233 32. Rajkumar, S.V. et al. (2007). A randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple m yeloma: a trial co-ordinated by the Eastern Co-operative Oncology Group. Blood, 110, 31a. 33. McCloskey, E.V. et al. (2001). Long-term follow-up of a prospective, double-bind, place bo- controlled randomized trial of clodronate in multiple myeloma. Br J Haematol, 113, 1035 \200\22343. 34. Berenson, J.R. et al. (1998). Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 16, 593 \200\223602. 35. Berenson, J.R. et al. (2001). Zoledronic acid reduces skeletal events in patients with osteolytic metastases. Cancer, 91, 1191 \200\2231200. 36. Kyle, R.A. et al. (2007). American Society of Clinical Oncology 2007 clinical practice update on the role of bisphosphonates in multiple myeloma. J Clin Oncol, 25, 2464 \200\22372. 37. Palumbo, A. et al. (2008). Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia, 22, 414 \200\22323. 361 MULTIPLE MYELOMA 38. Attal, M. et al. (1996). A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N En gl J Med, 335, 91 \200\2237. 39. Child, J.A. et al. (2003). High-dose chemotherapy with hematopoietic stem-cell rescue f or multiple myeloma. N Engl J Med, 348, 1875 \200\22383. 40. Moreau, P. et al. (2002). Comparison of 200mg/m2 melphalan and 8Gy total body irradiation plus 140mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: fi nal analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood, 99, 731 \200\2235. 41. Attal, M. et al (2003). Single versus double autologous stem cell transplantation for multiple myeloma. N Engl J Med, 349, 2495 \200\2232502. 42. Fermand, J.P. et al (1998). High dose therapy and autologous peripheral blood stem ce ll transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial Blood, 92, 3131 \200\2236. 43. Garban, F. et al. (2006). Prospective comparison of autologous stem cell transplantatio n followed by dose reduced allograft (IFM99-03 trial) with tandem autologous stem cell tran splantation (IFM99-04) in high risk de novo multiple myeloma. Blood, 107, 3474 \200\22380. 44. Kr ger, N. (2005). Autologous-allogeneic tandem stem cell transplantation in patients with multiple myeloma. Leuk Lymphoma, 46, 813 \200\22321. 45. Crawley, C. et al. (2005). Outcome for reduced intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors for the Chronic Leukemia Working Party of the EBMT. Blood, 105, 4532 \200\2239. 46. Attal, M. et al. (2006). Maintenance therapy with thalidomide improves survival in pati ents with multiple myeloma. Blood, 108, 3289 \200\22394. Further reading Bird, J.M. et al. (2014). The Diagnosis and Management of Multiple Myeloma. London: British Society for Hematology. Herndon, T. et al. (2013). U.S. Food and Drug Admi nistration Approval: Carfi lzomib for the Treatment of Multiple Myeloma. Clin Cancer Res, 1 9(17), 4559 \200\22363. Kortuem, K.M. et al. (2013). Carfi lzomib. Blood, 121(6), 893 \200 \2237. Kuhn, D.J. et al. (2011). Second generation proteasome inhibitors: carfi lzomib and immunoproteasome-specifi c inhibitors (IPSIs). Curr Cancer Drug Targets, 11(3), 285 \200 \22395. National Comprehensive Cancer Network (2013). Multiple Myeloma. Fort Washington, PA : NCCN. Terpos, E. et al. (2013). Pomalidomide: a novel drug to treat relapsed and refracto ry multiple myeloma. Onco Targets Ther, 6, 531 \200\2238. Wang, T.F. et al. (2013). The cha racteristics and outcomes of patients with multiple myeloma dual refractory or intolerant t o bortezomib and lenalidomide in the era of carfi lzomib and pomalidomide. Leuk Lymphoma, 5 5(2), 337 \200\22341. 362 CHAPTER 8 Paraproteinaemias Variant forms of myeloma Non-secretory myeloma \200 1% of MM cases. \200 No detectable serum or urine paraprotein by immunofi xation, but SFLC-ratio abnormal in 75%. Clonal plasma cells \211 10% in BM or plasmacytoma on biopsy; myeloma-related end-organ damage. Treatment as on E p.351; response rates comparable to secretory MM; SFLC assay provides a sensitive marker for monitoring response and identifying relapse in most patients; alternatives in others are surrogate markers ( 2-M, CRP) and repeated BM assessment. IgD myeloma \200 71% of cases of MM; very small or no visible monoclonal spike on routine electrophoresis; younger mean age (50 \200\22360 years). High rate of Bence Jones proteinuria and associated higher frequency of acute and chronic r enal failure; tendency to present with other poor prognostic features (high 2-M; low Hb); extramedullary involvement and amyloidosis may be more frequent. Treat as for other myeloma. IgM myeloma \200 Very rare; <0.5% of MM; 1% of all IgM gammop athies; plasma cell infi ltrate in BM as opposed to lympho-plasmacytoid infi ltrate characteristic of WM; aberrant PC phenotype; characterized by CD20 \210\222ve, CD56 \210\222ve, CD117 \210\222 ve phenotype and t(11;14).1 \200 Often associated with osteolytic lesions; no lymphadenop athy or splenomegaly. Overall outcome not established; may have inferior outcome to IgG or IgA MM. Diff erential diagnosis with WM essential. IgE myeloma \200 Rarest form of MM; younger ag e; high incidence of plasma cell leukemia; possible shorter survival. Plasma cell leukemia \200 Defi ned as PB plasma cells >2 \227 109/L or 20% of diff erent ial count; may occur de novo at presentation or in the terminal stages of otherwise typical MM. Aggressive disease associated with BM failure and organomegaly; poor response to conventional dose therapy; few survive >6 months; better responses to HDM. Reference 1. Feyler, S. et al. (2008). IgM myeloma: a rare entity characterized by a CD20 \200\223 CD56 \200\223 CD117 \200\223 immunophenotype and the t(11;14). Br J Haematol, 140, 547 \200\22351. Further reading Hamidah, N.H. et al. (2010) Non-secretory multiple myeloma with diagnostic challenges. Clin Ter, 161(5), 445 \200\2238. Mishra, J. et al. (2012). Seemingly insignifi cant, but crucial morphological leads in the diagnosis of non-secretory multiple myeloma in an adolescent. Indian J Pathol Microbiol, 55(1), 130 \200\2232. Yasuyama, M. et al. (2012) . Non-secretory immunoglobulin E myeloma associated with immunoglobulin G monoclonal gammop athy of undetermined signifi cance. Hematol Rep, 4(2), e11. 363 CRYOGLOBULINAEMIA Cryoglobulinaemia Classi \201 cation and pathogenesis \200 3 types: Type I (10 \200\22315%) single monoclonal Ig (usually IgM, less often IgG, occasionally LC- only). Associated with hematological disorders (plasma cell dyscrasia, NHL). Type II (50 \200\22360%) polyclonal IgG plus monoclonal IgM with rheumatoid factor (RF) activity (i.e. anti-IgG). Type III (25 \200\22330%) polyclonal IgG and IgM usually with small monoclonal component on high resolution assay. Types II and III referred to as mixed cryoglobulinaemia (MC): 775% associated with HCV infection. \200 Chronic stimulus may initiate multistep process of B-cell clonal expansion leading to LPDs. Serology refl ects progression from polyclonal to oligoclonal to monoclonal IgM-RF and clonal expansion. Associated with wide range of conditions: Lymphoproliferative and hematological disorders. \200 Auto-immune diseases. \200 Infect ions (esp. HCV). \200 Renal and liver disorders. Clinical features and diagnosis \200 Type I rarely associated with vasculitis but with si gns of peripheral vessel obstruction and hyperviscosity: purpura, acrocyanosis, Raynaud \200\231s phenomenon, dystrophic manifestations, leg ulcers, gangrene; usually clinically i ndistinguishable from Waldenstr m macroglobulinaemia (WM), MM, or CLL; rare complication o f paraprotein precipitation at low temperature. MC characterized by purpura, weakness, and arthralgias with multisystem involvement includi ng chronic hepatitis, glomerulonephritis or peripheral neuropathy due to small and medium v essel vasculitis; biopsy of cutaneous lesions shows vasculitis. Diagnose by precipitation at 2 \200\2234 C in serum prepared from blood collected and allowed to clot at 37 C; immunofi xation for assessment of clonality and typ ing; serum immunoglobulins, plasma viscosity, complement levels, and RF activity. Exclude underlying LPD in cases with monoclonal IgM with type I or II cryoglobulinaemia. Treatment \200 Type I: treat underlying MM, WM or CLL and avoid the cold. \200 HCV-rela ted MC: interferon alfa ribavirin to eradicate HCV; may be followed by regression of established lymphoma. Non-HCV-related MC: mild \200\223moderate symptoms, low dose prednisolone and analgesia; severe symptoms, Cyclophosphamide prednisolone plasmapher esis; rituximab may control B-cell clone and also improve renal function in HCV-related dis ease. Further reading Tedeschi, A. et al. (2007). Cryoglobulinaemia. Blood Rev, 21, 183 \200\2232 00. 364 CHAPTER 8 Paraproteinaemias POEMS syndrome (osteosclerotic myeloma) Clinical features \200 Synonym: Crow \200\223Fukase syndrome. \200 Clonal plasma-cell d yscrasia. \200 Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes: rare paraneoplastic syndrome 2 to a plasma cell neoplasm. Other features: papilloedema, extravascular fl uid overload (oedema, pleural eff usions, as cites), lymphadenopathy, diabetes mellitus, male gynaecomastia and impotence, female amenor rhoea, hypertrichosis and hyperpigmentation, sclerotic bone lesions, thrombocytosis, Castle man disease, polycythaemia, and clubbing. Association of osteosclerotic plasmacytoma with chronic infl ammatory demyelinating progressive polyneuropathy causing predominantly motor disabili ty. Endocrinopathy occurs in 784% usually hypogonadism then thyroid abnormalities, diabetes and adrenal insuffi ciency; majority multiple. 11 \200\22330% have Castleman disease or Castleman-like disease with angiofollicular lymph node hyperplasia which may be unifocal or multifocal and associated with B-symptoms, auto-i mmune phenomena, more subtle sensory neuropathy, and polyclonal gammopathy. Diagnosis \200 Confi rm diagnosis by demonstrating monoclonal plasma cells in osteosclero tic plasmacytoma (>95% have monoclonal plasmacytoma or BM infi ltration) and elevated pl asma or serum levels of VEGF. (See Table 8.15.) BM usually <5% plasma cells (almost always monoclonal ); low-level paraprotein, usually I gG or IgA (median 11g/L, rarely >30g/L). Anemia, hypercalcaemia, and renal impairment are rare. \200 Diff erential diagnosis: Chronic infl ammatory demyelinating polyneuropathy (CIDP). \200 Guillain \200\223Barr s yndrome. \200 Monoclonal gammopathy-associated peripheral neuropathy. \200 AL amyloidos is. Treatment \200 Treat solitary sclerotic bone lesion with aggressive radiotherapy (45Gy) surgery ( \211 50% response); widespread lesions or diff use BM involvement requi res systemic therapy; treatments as for myeloma used. Autologous peripheral blood stem cell transplantation is the 1st- line treatment for younge r patients with normal organ function. High response rate and durable remission. Transplant ation-related morbidity and mortality signifi cantly reduced over the past 5 years. Melphalan and dexamethasone: eff ective and well-tolerated treatment for older patients or those with organ dysfunction. 365 POEMS SYNDROME (OSTEOSCLEROTIC MYELOMA) Systemic symptoms and skin changes may respond in 1 month, neuropathy may begin to respond at 3 \200\2236 months with maximum benefi t often taking 2 \200\2233 years. Prognosis is good with median survival 14.7 years; number of features does not aff ect survival; respiratory symptoms predict adverse outcome. Table 8.15 Criteria for the diagnosis of POEMS syndrome1 1. Polyneuropathya 2. Monoclonal plasma cell neoplasm Major criteria (almost always )a 3. Sclerotic bone lesions 4. Castleman disease 5. VEGF elevation Minor criteria 1. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) 2. Extravascular volume overload (oedema, pleural eff usion, or ascites) 3. Endocrinopathy (adrenal, thyroid,b pituitary, gonadal, parathyroid, pancreaticb) 4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora, acrocyanosis, fl ushing, white nails) 5. Papilloedema 6. Thrombocytosis/polycythaemia c Other symptoms and signs Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease Possible associations Arthralgias, cardiomyopathy (systolic dysfunction) and fever a Polyneuropathy and monoclonal plasma cell neoplasm present in all patients; diagnosis req uires at least 1 other major criterion and 1 minor criterion. b Because of high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone insuffi cient to meet this minor criterion. c Anemia and/or thrombocytopenia are distinctly unusual in POEMS synd rome unless Castleman disease present. Reproduced from Dispenzieri, A. et al. (2007). POEMS syndrome. Blood Rev, 21, 285 \200\2239 9, with permission from Elsevier 2007 Reference 1. Dispenzieri, A. et al. (2007). POEMS syndrome. Blood Rev, 21, 285 \200\22399. Further reading Li, J. et al. (2013). New advances in the diagnosis and treatment of POEMS syndrome. Br J Haematol, 161(3), 303 \200\22315. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 366 CHAPTER 8 Paraproteinaemias Plasmacytoma Solitary plasmacytoma of bone (SPB) Clinical features and diagnosis \200 Sol itary area of lytic bone destruction due to clonal plasma cells in an otherwise asymptomatic patient. Generally no serum/urine paraprotein though there may be small monoclonal band. BM from uninvolved site contains <5% plasma cells. \200 Otherwise n skeletal survey and M RI of spine and pelvis (exclusion of other lesions on MRI). No myeloma-related organ or tissue impairment (end-organ damage). \200 75% of plasma cell neoplasms: \231\202: \231\200 ratio 2:1; median age 55 years. \200 Lesion usually in ax ial skeleton; 66% in spine. \200 Generally presents with bony pain; may cause cord/root c ompression. \200 Diagnosis requires biopsy or FNA. \200 Diff erential diagnosis of MM a nd other malignancy. \200 Serum/urine paraprotein detected in 24 \200\22372%; generally l ow level. \200 Adverse prognostic factors for progression to MM include persistence of paraprotein >1 year after radiotherapy, immuneparesis and lesion >5cm. \210\222ve MRI of spine is good prognostic feature. Treatment and prognosis \200 Treat with fractionated radical radiotherapy 40Gy (50Gy for lesions >5cm); local control 80 \200\22395%; curative in 50% if solitary lesion; DFS 740% a t 5 years.