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Multiple myeloma (MM) The second most common adult haematological malignancy. MM is a clonal malignancy of terminally differentiated plasma cells. Multiple myeloma: Epidemiology and incidence • Annual incidence of approximately 30-50 per million. • Median age at presentation of about 70 years. Approximately 15% of patients are aged <60 years and a further 15% are aged between 60 and 65 years. Fewer than 2% of myeloma patients are under 40. • Myeloma has a higher incidence in AfroCaribbean ethnic groups compared with Caucasians. • Median survival: – From the diagnosis: 3-5 years – From the first relapse: 1-3 years – In case of refracter disease: 6-9 months Myeloma: Clinical presentation • Symptoms of bone disease: tipically persistent, unexplained backache • Impaired renal function • Anaemia: typically normochromic, normocytic. Less frequently leukopenia and thrombocytopenia • Hypercalcaemia • Recurrent or persistent bacterial infections • Hyperviscosity • Symptoms suggestive of spinal cord/nerve root compression • Features suggestive of amyloidosis • Raised erythrocyte sedimentation rate The role of RANKL/RANK/OPG system in myeloma bone disease Myeloma cells induce the RANKL expression Myeloma cells decrease the OPG avaiability Increased osteoclast activity, decerased osteoblast function Lateral skull X-ray with typical findings of multiple myeloma: multiple "punched-out" holes. The arrow is pointing at one of the larger holes Spinal radiograph showing generalized osteopenia and multiple compression fractures. Renal impairment in multiple myeloma • Prevalence in up to 30% of patients at presentation and up to 50% of patients at some stage of disease. • Light-chain component of the immunglobulin can cause proximal tubular damage. – Other factors: dehydration, hypercalcaemia, hyperuricaemia, infection and use of nephrotoxic drugs, amyloid, plasma cell infiltration and use of NSAIDs Anaemia and immundeficiency in MM • Anaemia is present in two-thirds of patients at presentation and becomes more common in patients with progressive disease • Myeloma patients have B-cell defects with hypogammaglobulinaemia. • Disturbed T-cell function has also been demonstrated. • During chemotherapy neutropenia may occur. • High-dose corticosteroid treatment also compromise defences against fungal and viral infections. Diagnostic criteria of multiple myeloma • Demonstration of a monoclonal protein (Mprotein/paraprotein) in the serum or urine and • lytic lesions on X-ray together with • an increased number (>10%) of plasma cells in the bone marrow. Patients with multiple myeloma show a "spike" in special regions of the serum protein electrophoresis Bone marrow smear in multiple myeloma Other conditions in which an Mprotein may be present • Monoclonal gammopathy of undetermined significance (MGUS; prevalence 3% in those over 70 years old) • AL amyloidosis • Solitary plasmocytoma (skeletal or extra medullary) • B-cell non-Hodgkin lymphoma • CLL Diagnostic criteria for MGUS, asymptomatic and symptomatic myeloma MGUS Asymptomatic myeloma Symptomatic myeloma <30 g/l >30 g/l No specific level required Bone marrow <10% clonal plasma cells >10% >10% Myelomarelated organ or tissue impairment and/or symptoms No Yes (hypercalcemia, renal insuff., anaemia, bone lesions, symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections M-protein in serum No Progression of MGUS and asymptomatic myeloma to active disease • The average risk of progression from MGUS to active myeloma is about 1% per year – Only proven prognostic factor for progression to myeloma is serum M-protein level. The risk of progression in 10 years equal with paraprotein level in g/l • The median time to progression from asymptomatic to symptomatic myeloma is 12-32 months Multiple Myeloma Disease 1 Progression 100 Symptomatic M Protein (g/l) Asymptomatic Active Myeloma Relapse 50 20 Refractory Relapse MGUS* or Smoldering Myeloma Plateau Remission Therapy *Monoclonal gammopathy of uncertain significance ~19,000 New cases in EU2 Therapy ~53,000 Annual patients in the EU2 Therapy ~15,000 Annual deaths in EU 1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission. 2. International Agency for Research on Cancer, World Health Organisation; Ferlay J, Bray F, Pisani, P and Parkin DM. Globocan 2000 Diagnostic Tests for Multiple Myeloma • Blood and urine tests1 – Complete blood count (CBC) to detect if red blood cells, white blood cells, or platelets are outside of normal range – Chemistry profiles including blood urea nitrogen (BUN)2, calcium, creatinine, and lactate dehydrogenase (LDH) – 24-hour urine collection to measure levels of protein in the urine – Serum protein electrophoresis or urine electrophoresis to measure levels of immunoglobulins – Immunoelectrophoresis or immunofixation to provide more specific information about the type of abnormal immunoglobulins present – ESR • Bone tests1 – Bone (skeletal) survey utilizing X-ray or magnetic resonance imaging (MRI) to assess bone involvement and number/size of lytic lesions – Bone marrow aspiration/bone marrow biopsy to measure number of plasma cells in the marrow 1. The Washington Manual of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 2. The Merck Manual of Diagnosis and Therapy. Sec II, ch 140, plasma cell dyscrasias. Available at: http://www.merck.com/pubs/mmanual/sectionII/chapter 140/140d.htm. Accessed March 25, 2003. The use of imaging techniques in myeloma • Plain radiographs is the standard method for radiological screening at diagnosis • CT scanning: higher sensitivity than plain X-ray at detecting small lesions • MR imaging: is useful for the assessment of the extent and nature of soft tissue disease. For investigation of patients with neurological symptoms suggestive of cord compression. Essential investigation in the differential diagnosis of solitary plasmacytoma and myeloma. • PET scanning: Useful in detecting occult sites of disease in myeloma and solitary plasmacytoma The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan Melphalan 1999 First report on thalidomide From 1980s Myeloablation + ASCT March/April 2005 Bortezomib approved for second-line in USA & Europe 2000s Tandem ASCT Bortezomib US licence 2003, EU licence 2004 Treatment of hypercalcemia (occurs in up to 30% of myeloma patients, typically in active disease) • In mild hypercalcemia (se Ca:2,6-2,9 mmol/l) oral rehydration • In moderate-severe hypercalcemia (se Ca ≥2,9 mmol/l) – rehydrate with intravenous fluids and give loop-diuretic drug. – Start bisphosphonate immediately – Additional therapy in refractory patients General recommendation for bisphosphonate therapy • Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident. • Treatment should be continued at least 2 years. • Oral clodronate (1600 mg/day) and monthly iv. pamidronate ( 90 mg) or zoledronic acid (4 mg) are equivalent in efficacy. • Renal function should be monitored, in case of severe renal failure the dose should be reduced • No proven indication of bisphosphonates in asympromatic patients. Prevention and management of renal failure • • • • • Maintenance of a high fluid intake (3l/d) Nephrotoxic drugs should be avoided Hypercalcaemia must be corrected Infection must be treated In case of progressive renal failure plasma exchange (theoretically beneficial in cast nephropathy) • Dialysis Management of anaemia • Anaemia usually improves with response to chemotherapy. • The use of EPO may be considered in patients with symptomatic anaemia. • Serum EPO concentration should be measured (high EPO concentration, high transfusion requirement and a low-platelet count are negative prognostic factor for a response to EPO) Infections in myeloma • Febrile myeloma patient should be treated promptly with broad-spectrum antibiotics that will cover S. pneumoniae, H. influenzae and E. coli, which are the most common causes of infections. • Administration of immunglobulins should be reserved for patients with recurrent infections. Other complications of multiple myeloma • Cord compression – Occurs in 5% of patients. MRI, ther.: dexamethasone, local radiotherapy • Peripheral neuropathy – Paraproteinaemic neuropathy should be considered in any patients with monoclonal protein presenting with weakness, numbness, paraesthesiae and hyporeflexia. IVIG therapy may be effective. • Hyperviscosity – In patients with high paraprotein levels. Symptomatic patients should be treated by plasma exchange. Chemotherapy should be started promptly • Amyloidosis – Complications: cardiac failure, renal impairment and neuropathy, lead to increased toxicity with various threpautic options (anthracyclins, thalidomide, streoids) The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan Melphalan 1999 First report on thalidomide From 1980s Myeloablation + ASCT March/April 2005 Bortezomib approved for second-line in USA & Europe 2000s Tandem ASCT Bortezomib US licence 2003, EU licence 2004 Measuring the response to therapy Complete remission No M-protein detected in serum or urine. Fewer than 5% plasma cells in bone marrow, no hypercalcemia Partial remission >50% reduction in serum paraprotein level and/or 90% reduction in urine free light chain excretion. In non-secretory disease at least 75% reduction in bone marrow plasma cells number Minimal response 25-49% reduction in serum M-protein or <90% reduction in urinary light chain excretion. Plateau No evidence of continuing myeloma-related organ damage, less than 25% change in serum Mprotein levels for 3 months Progressive disease Organ damage continuing despite therapy or its re-appearance in plateau-phase Relapse Reappearance of disease in patients previously in CR Treatment algorithms for patients with multiple myeloma MPT MPV Thaldex 2. Line VelDex, VTD 1. The early intervention in asymptomatic patients has shown no benefit 2. Transplant candidate or not a transplant candidate Criteria to decide which patient is eligible for high dose chemotherapy followed by stem cell rescue • Age – Initial studies tended to enroll patients younger than 65 years of age – Recent studies indicate that transplant is safe in at least same who are over the age of 70 • Co-morbid medical conditions • Risk stratification – Poor-risk chromosomal features have a short time to progression after auotologous transplantation Risk stratification: International Staging System Stage Criteria Median survival (months I Se β2 microglobulin <3,5 mg/l and se albumin >35 g/l 62 II Se β2 microglobulin between 3,5- 45 5,5 mg/l or Se β2 microglobulin <3,5 mg/l but se albumin <35 g/l III Se β2 microglobulin >5,5 mg/l 29 Greipp et al 2003. For individual patients the best staging systems can predict survival outcome with around 70% sensitivity and specificity. Cytogenetics-based prognostic grouping Risk group Cytogenetics Median Overall Survival Poor t(4;14) t(14;16) p13- 24,7 months Intermediate -13q14 42,3 months Good All others 50,5 months The significance of cytogenetic information: -Decision of possibility of stem cell transplantation - indication of molecularly targeted approach of patients Median survival time after transplantation according to the presence or absence of risk factors Risk factor combinations at diagnosis Median survival time Low β2-microglobulin level and > 111 months absence of Δ13 High β2-microglobulin level and absence of Δ13 or Low β2-microglobulin and presence of Δ13 High β2-microglobulin level together with Δ13 Moreau P et al, Blood 2006;107:397-403. 47 months 25 months Approach to newly diagnosed symptomatic myeloma Low risk Not a transplant candidate High risk Transplant candidate Dex or Thal-Dex or VAD x 4 cycles Stem Cell Harvest for 2 transplants Early Tx1; Tx2 in relapse Rajkumar SV 2004. Conventional chemother (HDC, melphalan 200 mg/m2) to plateau phase. Tx1 at relapse Induction therapy in transplant candidate patients • VAD (repeated monthly) – Vincristin 0.4 mg 1-4. days. – Adriamycin 9 mg/m2 1-4. days – Dexamethason 40 mg 1-4., 9-12., 17-20. days • Dex (repeated monthly) – 40 mg/day on day 1 trough 4, 9 through 12, and 17 through 20 • Thal-Dex (repeated monthly) – Thal 200 mg/d p.o. with Dex on day 1 trough 4, 9 through 12, and 17 through 20 The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan Melphalan 1999 First report on thalidomide From 1980s Myeloablation + ASCT March/April 2005 Bortezomib approved for second-line in USA & Europe 2000s Tandem ASCT Bortezomib US licence 2003, EU licence 2004 Melphalan + prednisone is the standard of care for induction therapy in not transplant candidate elderly patients with multiple myeloma Melphalan+ Melphalan+ prednisone Dex Dex Dex+ Interferon Partial response 41% 70% 40% 42% Complete response 1% 3% 1% 1% Median progression-free survival 21.1 mos 22.9 mos. 12.2 mos. 15.2 mos Severe pyogenic infection 11% 20% 13% 11% Any severe toxicity 18% 33% 31% 31% Facon T et al. Blood 2006;107:1292-1298. Induction therapy of multiple myeloma in patients who are not candidate for stem cell transplantation • The dose of Melphalan = 7-12 mg/m2/day, 4-7 days, given on an every 4-6 weeks schedule until plateau phase. – Side effects: nephrotoxicity, myelotoxicity. • Combined chemotherapy can improve the remission rate together with higher prevalance of side effects. The story of thalidomide • First marketed in the 1950s for the treatment of pregnancy-related morning sickness and later as a sedative. • It was withdrawn because of serious adverse events in pregnant women including teratogenicity and dysmelia. • Interest in the drug resurfaced in the 1990s because of its antiangiogenic and immunmodulatory effects Thalidomide in multiple myeloma: mechanisms of action • Antiangiogenic effects, mediated via inhibition of VEGF (vascular endothelial growth factor) and βFGF(fibrobalst growth factor) • Inhibition of multiple myeloma growth factors, including IL-6, TNFα, and VEGF • Down-regulation of binding of myeloma cells to bone marrow stromal cells • Immunmodulatory effects, evidenced by upregulation of natural killer cells (through the release of interferon gamma and IL-2), producing MM cell lysis • Direct proapoptotic effects, arrests G1 growth phase of myeloma cells Richardson et al.: J Clin Oncology 2006;24(3):1-2., San Miguel JF, Haemat Rep, 2005;1(11):2-6 Facon T et al, J Clin Oncol 2006;24:1s Comparison of results of MP and MPT treatment in older patients with newly diagnosed multiple myeloma Response quality Melphalan+ Prednisone (MP) Melphalan+Prednisone + Thalidomide (MPT) Complete response 2% 16% At least a partial response 40% 81% 17.1 mos. 32.2 mos. 27.6 mos 53.6 mos Response durability - Progression-free survival - Overall survival More than 50% of patients reaching a PR within the first 2 months of therapy Regimens not based on MP • Thal/dex 200-400 mg thalidomide/day + dexamethasone 40 mg/day on 1-4., 9-12. and 17-20. days. (remission rate: 64%) as first-line therapy. • Thalidomide+pegylated liposomal doxorubicin+dexamethasone. Comparable response rates (84%) in untreated patients as well as those with relapsed/refractery disease. Thalidomide toxicity • Thromboembolic episodes (involving venous or arterial events) • Neutropenia, thrombocytopenia • Constipation • Infections (pneumonia, herpes zoster) • Peripheral neuropathy • Psychiatrical problems (letargy, fatigue) • Skin reactions and cardiac events Lenalinomid: more potent thalidomide, and has a more favorable toxicity profile than thalidomide Proteasome inhibition is a new second- or third-line treatment possibility in multiple myeloma Bortezomib seems able to enhance chemosensitivity and overcome chemoresistance Summary: Mechanism of Action of Bortezomib (VELCADE) 1 The 26S proteasome is a large protein complex that degrades tagged proteins 2 Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome 3 Inhibition of the 26S 4 Nonclinical studies showed bortezomib to be cytotoxic to a variety of cancer cell types proteasome prevents proteolysis of tagged proteins which can affect multiple signaling cascades with the cell Millennium Pharmaceuticals, Inc., 2003. Adams J. Drug Discov Today. 2003;8:307-315. Bortezomib (VELCADE) Cytokine Adhesion MM cells Angiogenesis TNFa IGF-I BMSC X VEGF IL-6 BM Vessels IL-6, VEGF Block activation FAS IkB/NFkB Intracellular level Apoptosis Inhibitors (IAP, FLICE) PI3K Caspases 8,3 antiapoptotic Increased Apoptosis San Miguel J. Hematol J. 2003;4(suppl 3):201-207. MAPK proliferation Decreased Proliferation Inhibition DNA-repair effectors Disruption of unfolded protein response Normal Cells Survive Effects of VELCADE™ • Normal cells can recover from transient proteasome inhibition – 72 hour rest period • Cancer cells are more susceptible – Pre-existing dysregulation of cell cycle, growth, differentiation and apoptotic mechanisms – Myeloma cells are 100-1000 times more sensitive to effects of VELCADE™ • Absence of side-effects such as mucositis and alopecia – Common with other cytotoxic agents that target all dividing cells Velcade: Dosing and schedule • 1.3 mg/m2 as a 3- to 5-second bolus IV injection via peripheral or central IV catheter – Follow with a standard saline flush Day 1 Bortezomib 1.3 mg/m2 • Day 4 Bortezomib 1.3 mg/m2 Day 8 Bortezomib 1.3 mg/m2 Day 11 Bortezomib 1.3 mg/m2 10-day REST PERIOD REPEAT CYCLE At least a 72-hr rest period between doses is required – Allows for restoration of proteasome function towards baseline Alkalmazási előirat Janssen-Cilag 2005 Clinical studies SUMMIT CREST APEX Study design Phase II, openlabel, multicenter Phase II, open-label, multicenter, randomized; two dose levels bortezomib ± dexamethasone Phase III, international, openlabel, randomized to bortezomib or dexamethasone Patients Relapsed or refractory MM; n=202 Relapse during/following front-line therapy for MM; n=54 Relapsed MM; n=669 Endpoints Primary: overall response rate (CR + PR + MR) Secondary: safety, quality of life, clinical benefit Overall response rate (CR + PR + MR) Primary: time to progression (TTP) Secondary: overall/1-year survival, response rate, duration, time to response, safety Richardson et al. N Engl J Med 2003;348:2609; Jagannath et al. Br J Hematol 2004;127:165; Richardson et al. ASH 2004 (abstract 336.5) Updated Results of APEX Trial ►SURVIVAL Overall and 1-Year Survival P=.0272 – Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib – Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272 1-year survival rate: 80% vs 67%; P = 0.0002 Richardson P, et al. ASH 2005, abstract #2547 Velcade + Dexamethasone The evidence of remission: PET Scan Plasmacytomas Pretreatment After 4 Cycles Jagannath et al. ASH 2004; Abstract 333 Past and current treatment algorithms for not transplant candidate patients with multiple myeloma Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347. BP=: bendamustine+prednisone; MDT= Melphalan+Prednisone+Thalidomide; MP=melphalan+prednisone; R-MP=melphalan+prednisone+lenalidomide; ThaDD=thalidomide+pegylated liposomal doxorubicin+dexamethasone; VMP=melphalan+prednisone+bortezomib Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347. A hypothetical future treatment algorithm for patients with multiple myeloma Waldenström’s macroglobulinaemia • Malignancy of lymphoplasmacytoid cells that secrete IgM. • Rare disease, 2% of hematological malignancies • The disease associates with lymphadenopathy and hepatosplenomegaly, but the major clinical manifestation is the hyperviscosity syndrome. • Slightly more common in men and occuring with increased incidence with age (median age at presentation is 63 year). • The disease involves bone marrow, but unlike myeloma, it does not cause bone lesion or hypercalcaemia. Waldenström’s macroglobulinaemia • Malignant lymphocytes are present in the peripheral blood. • Like myeloma, a serum M component is present in the serum in excess of 30 g/l, but inlike myeloma, the size of the IgM paraprotein result in little renal excretion. Therefore, renal disease is not common. • Median survival is about 5 years (in appr. 10% of patients is more than 15 years). The differential diagnosis of WM from other B-lymphoproliferative disorders Ghobrial I, Witzig T: Waldenström Macroglobulinemia. Current Treatment Options in Oncology. 5(3):239-247. Clinical symptoms and physical abnormalities in patients with WM Symptom Frequency Physical abnormality Frequency Weakness 66% Hepatomegaly 20% Loss of apetite 25% Splenomegaly 19% Peripheral neuropathy 24% Lymphadenopathy 15% Weight loss 17% Purpura 9% Fever 15% Other bleedings (retinal hemorrhages) 7% Raynaud’s phenomenon 11% Tarkovács G: Waldenström macroglobulinaemia. in Fókuszban az onkológia és az onkohematológia, ed.: Dank M, Demeter J, 2006. Melinda Kiadó Characteristic features of WM Retinal hemorrhage from hyperviscosity BM showing increased numbers of BM showing IgM in cytoplasm of lymphoid and plasmacytoid cells lymphoid cells with immunofluorescence The serum protein electrophoretic pattern is characterized by a tall, narrow peak (bottom center) or dense band Frequency of laboratory abnormalities at the presentation of WM Parameter Frequency Anaemia (Hb<120 g/l) 63% Leukopenia (<3x109/l) 4% Throbocytopenia (<100x109/l) 16% IgM (monoclonal) -kappa/lambda ratio - >30 g/l -Cryoglobulins 80/20 35% 10% of macroglobulins Serum béta2-microglobulin >3 mg/l 62% Serum viscosity >4 17% Indications of the therapy in patients with WM • Appearence of general symptoms (fever, fatigue caused by anaemia, loss of body weight) • Progressive hepatosplenomegaly, symptoms related to lymphadenomegaly • Severe anaemia and/or thrombocytopenia • Hyperviscosity (plasmapheresis) • Amyloidosis (cardiomyopathy, nephrotic syndrome, peripheral neuropathy) • Cryoglobulinaemia with symptoms ( Raynaud’s phenomenon) Treatment of WM Major response rate (>50% reduction of IgM concentration) Median duration of response 75% 46 months Fludarabine -first-line treatment -Salvage-treatment 75.5% 33.7% BM depression, 40-60 months opportunic infections, 30-32 months Coombs + hemolysis Cladribine -first-line treatment -Salvage-treatment 56.6% 42.6% 20-39 months 8-12 months Rituximab 44-48% 16-29 months In patients with cytopenia. Temporary IgM Thalidomide ? ? Corticosteroid Mostly in patients with cryoglobulinaemia and iimmune vasculitis Chlorambucil