_myeloma semmelweis多发性骨髓瘤 课件

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 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 M- protein 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 MGUSAsymptomatic myeloma Symptomatic myeloma M-protein in serum 30 g/lNo specific level required Bone marrow clonal plasma cells 10%10% Myeloma- related organ or tissue impairment and/or symptoms NoNoYes (hypercalcemia, renal insuff., anaemia, bone lesions, symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections 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 Progression1 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 Asymptomatic 20 50 100 Refractory Relapse MGUS* or Smoldering Myeloma Active Myeloma Plateau Remission Symptomatic Relapse Therapy 53,000 19,000 New cases in EU2 15,000 Annual deaths in EU Annual patients in the EU2 M Protein (g/l) *Monoclonal gammopathy of uncertain significance TherapyTherapy 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 2002. 2. The Merck Manual of Diagnosis and Therapy. Sec II, ch 140, plasma cell dyscrasias. Available at: /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 MelphalanFrom 1980s Myeloablation + ASCT 2000s Tandem ASCT 1999 First report on thalidomide 1962 Prednisone + melphalan Bortezomib US licence 2003, EU licence 2004 1990s Supportive careMarch/April 2005 Bortezomib approved for second-line in USA 14) t(14;16) p13- 24,7 months Intermediate-13q1442,3 months Good All others50,5 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 2-microglobulin level and absence of 13 111 months High 2-microglobulin level and absence of 13 or Low 2-microglobulin and presence of 13 47 months High 2-microglobulin level together with 13 25 months Moreau P et al, Blood 2006;107:397-403. Approach to newly diagnosed symptomatic myeloma Low riskHigh risk Not a transplant candidate Transplant candidate Dex or Thal-Dex or VAD x 4 cycles Stem Cell Harvest for 2 transplants Early Tx1; Tx2 in relapse Conventional chemother (HDC, melphalan 200 mg/m2) to plateau phase. Tx1 at relapse Rajkumar SV 2004. 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 MelphalanFrom 1980s Myeloablation + ASCT 2000s Tandem ASCT 1999 First report on thalidomide 1962 Prednisone + melphalan Bortezomib US licence 2003, EU licence 2004 1990s Supportive careMarch/April 2005 Bortezomib approved for second-line in USA 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 FGF(fibrobalst growth factor) Inhibition of multiple myeloma growth factors, including IL-6, TNF, 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 Comparison of results of MP and MPT treatment in older patients with newly diagnosed multiple myeloma Response qualityMelphalan+ Prednisone (MP) Melphalan+Prednison e+ Thalidomide (MPT) Complete response2%16% At least a partial response 40%81% Response durability - Progression-free survival - Overall survival 17.1 mos. 32.2 mos. 27.6 mos 53.6 mos More than 50% of patients reaching a PR within the first 2 months of therapy Facon T et al, J Clin Oncol 2006;24:1s 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) The 26S proteasome is a large protein complex that degrades tagged proteins Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome Inhibition of the 26S proteasome prevents proteolysis of tagged proteins which can affect multiple signaling cascades with the cell Nonclinical studies showed bortezomib to be cytotoxic to a variety of cancer cell types 1 2 3 4 Millennium Pharmaceuticals, Inc., 2003. Adams J. Drug Discov Today. 2003;8:307-315. BortezomibBortezomib (VELCADE (VELCADE ) ) IkB/NFkB Apoptosis Inhibitors (IAP, FLICE) Caspases 8,3 FAS MAPK PI3K DecreasedDecreased ProliferationProliferation antiapoptotic Intracellular level X X proliferation IncreasedIncreased ApoptosisApoptosis IL-6, VEGF BlockBlock activationactivation InhibitionInhibition DNA-DNA-repairrepair effectorseffectors Adhesion Cytokine Angiogenesis BMSCBMSC MM cells VEGF IGF-I TNFa IL-6 BM Vessels X DisruptionDisruption ofof unfoldedunfolded proteinprotein responseresponse San Miguel J. Hematol J. 2003;4(suppl 3):201-207. 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 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 At least a 72-hr rest period between doses is required Allows for restoration of proteasome function towards baseline 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 REPEAT CYCLE 10-day REST PERIOD Velcade: Dosing and schedule Alkalmazsi elirat Janssen-Cilag 2005 Clinical studies SUMMITCRESTAPEX Study designPhase II, open- label, multicenter Phase II, open-label, multicenter, randomized; two dose levels bortezomib dexamethasone Phase III, international, open- label, randomized to bortezomib or dexamethasone PatientsRelapsed or refractory MM; n=202 Relapse during/following front-line therapy for MM; n=54 Relapsed MM; n=669 EndpointsPrimary: 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) 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 Updated Results of APEX Trial Richardson P, et al. ASH 2005, abstract #2547 SURVIVAL Overall and 1-Year Survival P=.0272 Pretreatment After 4 Cycles Plasmacytomas Jagannath et al. ASH 2004; Abstract 333 Velcade + Dexamethasone The evidence of remission: PET Scan Past and current treatment algorithms for not transplant candidate patients with multiple myeloma Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347. A hypothetical future treatment algorithm for patients with multiple myeloma 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. Waldenstrms 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. Waldenstrms 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: Waldenstrm Macroglobulinemia. Current Treatment Options in Oncology. 5(3):239-247. Clinical symptoms and physical abnormalities in patients with WM Tarkovcs G: Waldenstrm macroglobulinaemia. in Fkuszban az onkolgia s az onkohematolgia, ed.: Dank M, Demeter J, 2006. Melinda Kiad SymptomFrequencyPhysical abnormalityFrequency Weakness66%Hepatomegaly20% Loss of apetite25%Splenomegaly19% Peripheral neuropathy 24%Lymphadenopathy15% Weight loss17%Purpura9% Fever15%