Multiple myeloma (MM)

1. Multiple myeloma (MM) The second most common adult haematological malignancy. MM is a clonal malignancy of terminally differentiated plasma cells.

2. 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 Afro-Caribbean 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

3. 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

4. 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

5. Lateral skull X-ray with typical findings of multiple myeloma: multiple "punched-out" holes. The arrow is pointing at one of the larger holes

6. Spinal radiograph showing generalized osteopenia and multiple compression fractures.

7. 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

8. 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.

9. Diagnostic criteria of multiple myeloma • Demonstration of a monoclonal protein (M-protein/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.

10. Patients with multiple myeloma show a "spike" in special regions of the serum protein electrophoresis

11. Bone marrow smear in multiple myeloma

12. 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

13. Diagnostic criteria for MGUS, asymptomatic and symptomatic myeloma

14. 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

15. 100 Symptomatic Asymptomatic Active Myeloma Relapse 50 M Protein (g/l) Refractory Relapse MGUS* or SmolderingMyeloma Plateau Remission 20 Therapy Therapy Therapy *Monoclonal gammopathy of uncertain significance ~15,000 Annual deaths in EU ~19,000 New cases in EU2 ~53,000 Annual patients in the EU2 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

16. 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.

17. 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

18. March/April 2005Bortezomib approved for second-line in USA & Europe 1999First report onthalidomide The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan 2000s Tandem ASCT Melphalan From 1980s Myeloablation + ASCT Bortezomib US licence 2003, EU licence 2004

19. 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

20. 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.

21. 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

22. 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)

23. 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.

24. 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)

25. March/April 2005Bortezomib approved for second-line in USA & Europe 1999First report onthalidomide The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan 2000s Tandem ASCT Melphalan From 1980s Myeloablation + ASCT Bortezomib US licence 2003, EU licence 2004

26. Measuring the response to therapy

27. Treatment algorithms for patients with multiple myeloma Thaldex 2. Line VelDex, VTD MPT MPV • The early intervention in asymptomatic patients has shown no benefit • Transplant candidate or not a transplant candidate

28. 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

29. Risk stratification:International Staging System Greipp et al 2003. For individual patients the best staging systems can predict survival outcome with around 70% sensitivity and specificity.

30. Cytogenetics-based prognostic grouping • The significance of cytogenetic information: • Decision of possibility of stem cell transplantation • indication of molecularly targeted approach of patients

31. Median survival time after transplantation according to the presence or absence of risk factors Moreau P et al, Blood 2006;107:397-403.

32. Approach to newly diagnosed symptomatic myeloma Low risk High risk Transplant candidate Not a transplant candidate Dex or Thal-Dex or VAD x 4 cycles Stem Cell Harvest for 2 transplants Conventional chemother (HDC, melphalan 200 mg/m2) to plateau phase. Tx1 at relapse Early Tx1; Tx2 in relapse Rajkumar SV 2004.

33. 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

34. March/April 2005Bortezomib approved for second-line in USA & Europe 1999First report onthalidomide The changes in the treatment of multiple myeloma 1990s Supportive care 1962 Prednisone + melphalan 2000s Tandem ASCT Melphalan From 1980s Myeloablation + ASCT Bortezomib US licence 2003, EU licence 2004

35. Melphalan + prednisone is the standard of care for induction therapy in not transplant candidate elderly patients with multiple myeloma Facon T et al. Blood 2006;107:1292-1298.

36. 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.

37. 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

38. 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

39. Comparison of results of MP and MPT treatment in older patients with newly diagnosed multiple myeloma Facon T et al, J Clin Oncol 2006;24:1s More than 50% of patients reaching a PR within the first 2 months of therapy

40. 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.

41. 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

42. Proteasome inhibition is a new second- or third-line treatment possibility in multiple myeloma Bortezomib seems able to enhance chemosensitivity and overcome chemoresistance

43. Summary: Mechanism of Action of Bortezomib (VELCADE) The 26S proteasome is alarge protein complex that degrades tagged proteins 1 Bortezomibis a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome 2 Inhibition of the 26S proteasome prevents proteolysis of tagged proteins which can affect multiple signaling cascades with the cell 3 Nonclinical studies showed bortezomib to be cytotoxic to a variety of cancer cell types 4 Millennium Pharmaceuticals, Inc., 2003. Adams J. Drug Discov Today. 2003;8:307-315.

44. Bortezomib (VELCADE)  Cytokine  Angiogenesis  Adhesion MM cells  TNFa  IGF-I BMSC X  VEGF  BM Vessels IL-6 IL-6, VEGF Blockactivation Intracellular level IkB/NFkB  Apoptosis Inhibitors (IAP, FLICE) X X FAS PI3K MAPK Caspases 8,3 antiapoptotic proliferation Inhibition DNA-repair effectors Decreased Proliferation Increased Apoptosis Disruption of unfolded protein response San Miguel J. Hematol J. 2003;4(suppl 3):201-207.

45. 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

46. REPEAT CYCLE 10-day RESTPERIOD Day 1 Bortezomib1.3 mg/m2 Day 4 Bortezomib 1.3 mg/m2 Day 8 Bortezomib 1.3 mg/m2 Day 11 Bortezomib 1.3 mg/m2 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 • At least a 72-hr rest period between doses is required • Allows for restoration of proteasome function towards baseline Alkalmazási előirat Janssen-Cilag 2005

47. Clinical studies 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)

48. 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

49. Plasmacytomas Pretreatment After 4 Cycles Velcade + DexamethasoneThe evidence of remission: PET Scan Jagannath et al. ASH 2004; Abstract 333

50. Past and current treatment algorithms for not transplant candidate patients with multiple myeloma Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347.