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Mm final slides sort


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Mm final slides sort

  1. 1. Overview• Identify the diagnostic criteria for multiple myeloma• Compare first & second line therapies, using data from clinical trials• Describe adjunctive & supportive therapies
  2. 2. Multiple Myeloma• Plasma cell malignancy• Second most common hematologic malignancy• Characterized by monoclonal immunoglobulin – MGUS – Smoldering MM – Amyloidosis
  3. 3. MM Epidemiology • 19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S. • Higher incidence in African Americans, Pacific Islanders • Median age 71 yrs • Exposure to radiation, petroleum products, pesticides & Agent OrangeGreenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174
  4. 4. Presenting Features• Bone disease & hypercalcemia• Recurrent infections• Anemia and fatigue• Renal failure due to multiple causes• Neuropathy• Asymptomatic in a minority of the patients
  5. 5. Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients 80 70 79 60 73 66% patients 50 40 30 32 20 19 10 13 12 0 Bone Bone Hb<12 Fatigue Cr >2 Ca >11 Wt loss lesions pain g/dL mg/dL mg/dL (>9 kg) Kyle RA. Mayo Clin Proc 2003;78:21-33
  6. 6. Criteria for DiagnosisMGUS Active MM MM Smoldering• <3 g M spike ∀ ≥10%M spike ∀ ≥3 g PC <10% PC ••MOR ≥10% PC spike + AND AND No anemia, bone lesions Anemia, bone lesions, normal calcium and high calcium or kidney function abnormal kidney function Kyle RA. N Engl J Med 2002; 346: 564
  7. 7. Myeloma Prognostic Factors• Serum β2 microglobulin• Cytogenetics - del13 or 13q-, t(4;14), 17p-, hypodiploid• C-reactive protein• LDH• Plasmablastic morphology• Peripheral blood plasma cells• Gene expression profile
  8. 8. Incidence of Chromosomal Abnormalities in MMGenomic Aberrations Incidence of aberration Del (13) 48% Del (17p) 11% t(4;14) (p16;q32) 14% Hyperdiploidy 39%t(11;14) (q13;q32) 21% • n = 1064 patients • Chromosomal changes observed in 90% of patients
  9. 9. International Staging System (ISS)for Symptomatic Myeloma Median Stage Criteria Survival (mo) β2m < 3.5 mg/L I 62 albumin ≥ 3.5 g/dL II* Not stage I or III 44 III β2m ≥ 5.5 mg/L 29*β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/L, any albuminGreipp et al. J Clin Oncol 2005; 23: 3412-20
  10. 10. Initial Diagnostic Evaluation• Hx and physical examination• Blood work-up – CBC with diff and platelet counts – BUN, Creatinine – Calcium, albumin – Serum protein electrophoresis (SPEP) and immunofixation – Quantitative immunoglobulins – Serum free lyte chains β 2-microglobulin
  11. 11. Initial Diagnostic Evaluation• Urine – Bence Jones quantitation – 24-hr protein electrophoresis (UPEP) and immunofixation• Other – Skeletal survey – Unilateral bone marrow aspirate and biopsy for histology, cytogenetics and FISH
  12. 12. Serum Protein Electrophoresis Normal Monoclonal Protein in MyelomaKyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
  13. 13. Immunofixation to DetermineType of Monoclonal Protein IgG kappa M protein Lambda Light ChainsKyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
  14. 14. Distribution of MonoclonalProteins• M protein found in serum or urine or both at time of diagnosis: 97%• Serum M spike by protein electrophoresis: 80%• Abnormal serum immunofixation: 93%• Abnormal urine immunofixation: 75%• Non-secretory myeloma: 3%
  15. 15. Malignant Plasma Cells inMarrow
  16. 16. Bone Involvement in DifferentTumor Types Disease Bone metastases in Median survival of prevalence in US patients with patients with bone advanced disease metastases (in thousands) (%) (months) Myeloma 49.61 843 37–587 Lung 3271 30–402 8–104 Breast 2,0511 65–752 19–255 Prostate 1,4771 65–752 30–3561. National Cancer Institute. Available at: 1/27/2005. 2. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 3. Kyle RA et al. Mayo Clin Proc.2003;78: 21-33. 4. Smith W et al. Semin Oncol. 2004;31(suppl 4):11-15. 5. Lipton A. J Support Oncol.2004;2:205-213. 6. Tu S-M, Lin S-H. Cancer Treat Res. 2004;118:23-46. 7. Palumbo A et al. Blood.2004;104:3052-3057.
  17. 17. Bone Imaging in MM• Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma• MRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysis• PET scans can be used to detect soft tissue or bone metastases Angtuaco EJ et al. Radiology. 2004;231:11- 23.
  18. 18. Bone Scans in Myeloma CanUnderestimate Bone Involvement
  19. 19. Bone Cell Stimulation inMalignancy Osteoclasts OsteoblastsMultiple myelomaOsteolytic solidtumors includingbreast cancer
  20. 20. Initial Approach to TreatmentClearly not a transplant Potential transplant candidate candidateCan include melphalan- Non-alkylator based based combinations induction Stem cell harvest
  21. 21. Therapy Options: NonTransplant Candidate• Melphalan + Prednisone (MP)• Melphalan + Prednisone + Thalidomide (MPT)• Dexamethasone (Dex)• Thalidomide + Dexamethasone (Thal/Dex)• Lenolidomide + Dexamethasone (Rev/Dex)• Bortezomib +/- Dexamethasone (Vel/Dex) NCCN Practice Guideline-v.2.2008
  22. 22. Melphalan + Prednisone• Response rate: ~ 40%• Duration of response: 18 month• Overall survival: 24-36 months• Cycle is repeated every 4-6 weeks
  23. 23. “Salvage” Therapy• Thalidomide-Dexamethasone• Lenalidomide-Dexamethasone• Bortezomib +/- Dexamethasone• Pegylated-Liposomal Doxorubicin (PLD)- based regimens
  24. 24. VTE Prevention withImmunomodulating Agents• As single agents: minimal risk; prophylaxis may be considered• Concomitant chemotherapy: especially dex, anthracyclines & ESAs, increase risk as much as 58%• Low-dose warfarin: not protective• ASA: adequate in lower risk patients receiving dex & an immunomodulator• LMWH (enoxaparin 40mg QD), full dose warfarin, are recommended for patients at high risk for VTE
  25. 25. Treatment Options-RelapsedPatient• Since no therapy is curative, all options need to be tried sequentially• No good data on optimum sequence or regimen• All patients should be encouraged to participate in ongoing clinical trials• Cumulative toxicities from prior therapies may influence decision
  26. 26. Treatment of Bone Disease• Bisphosphonates• Surgical procedures – Vertebroplasty – Balloon Kyphoplasty• Radiotherapy• Treatment of myeloma
  27. 27. ASCO Guidelines for Treating Bone Loss in Multiple Myeloma MM patients with lytic disease or osteopenia MM patients with lytic disease or osteopenia on plain radiographs or imaging studies on plain radiographs or imaging studies Intravenous pamidronate 90 mg deliver over at least 2 hrs Intravenous pamidronate 90 mg deliver over at least 2 hrs or or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks. zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks. Continue therapy for 2 yrs & consider stopping in Continue therapy for consider patients w/ responsive or stable disease; further use at patients w/ responsive physician’s discretion physician’s discretionKyle RA et al. J Clin Oncol. 2007;25:2464-72.
  28. 28. Issues with BP Therapy• Renal toxicity• Osteonecrosis of the jaw• Decreases skeletal events by 50%; patients still progress but at a slower rate• No clear anti-tumor activity
  29. 29. Osteonecrosis of the Jaw Features of Suspected ONJ • Exposed bone in maxillofacial area associated with dental surgery or occurs spontaneously, with no evidence of healing Working Diagnosis of ONJ • No evidence of healing after 8 weeks of appropriate dental care • No evidence of metastatic disease in the jaw or osteoradionecrosis
  30. 30. Anemia Treatment Goals• Treat the underlying malignancy• Decrease fatigue• Decrease need for PRBC transfusions• Treat the patient, not the number
  31. 31. 2007 ASCO Practice Guidelines for ESA• General: – Review peripheral smear; consider iron, folate, and B12 deficiency as potential causes for anemia, assess for occult blood loss.• Comparative effectiveness: – Agents are considered equivalent in terms of safety and efficacy – No reason to believe that a patient who fails to respond to one ESA will have a response to a different ESA