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Scottsdale, Arizona

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Multiple Myeloma Monitoring and Therapy. Angela Dispenzieri, M.D. IMF Patient Workshop November 3, 2014. Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center. Multiple Myeloma

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Scottsdale, Arizona

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  1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Multiple Myeloma Monitoring and Therapy Angela Dispenzieri, M.D. IMF Patient Workshop November 3, 2014 Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

  2. Multiple Myeloma Plasma cell malignancy Calcium Renal Anemia Bone

  3. Making the diagnosis of multiple myeloma

  4. Not all increases in plasma cells are myeloma • MGUS – Monoclonal Gammopathy of Unknown Significance • Smoldering myeloma • Solitary Plasmacytoma • Multiple myeloma • Primary systemic amyloidosis • POEMS syndrome • Waldenström’smacroglobulinemia Pre- cancer Localized cancer Cousin diseases

  5. What tests should be done with new diagnosis of multiple myeloma? • Protein electrophoresis of blood and urine and quantitative immunoglobulin • Serum immunoglobulin free light chain • Blood hemoglobin, creatinine, calcium, albumin, beta-2 microglobulin, and LDH • Bone radiographs • Bone marrow aspirate with FISH and immunophenotype Important to monitor for complications and to establish response therapy Prognostic factor

  6. Multiple MyelomaStaging and Prognosis

  7. Myeloma Staging Systems • Durie Salmon: IA-IIIB • Size of M-protein, extent of anemia, calcium, kidney function, and number of bone lesions • International staging system: I-III • Blood albumin and beta-2 microglobulin

  8. Most Important Prognostic Factors • Age • Frailty • Renal function • Myeloma stage • Myeloma cells • FISH (fluorescent in situ hybridization) of myeloma cells • Aberrant flow phenotype • Gene expression profiling

  9. Del 17p t(14;16) (C-MAF) t(14;20) (MAF-B) High risk GEP All other FISH including: Trisomies t(11;14) (CCND1) t(6;14) (CCND3) msmart.org TUMOR BIOLOGY: DISEASE AGGRESSIVENESSMyeloma Risk-Stratification Standard-Risk Intermediate-Risk High-Risk • t(4;14) (FGFR3/ MMSET) *Presence of trisomies ameliorates high risk

  10. What do we mean by ‘prognostic’ factors? • Different patients’ myeloma acts may vary very significantly—almost like different diseases! • Markers to help differentiate those patients with the ‘gentlest’ myeloma from those with the ‘meanest’ myeloma

  11. Treating Complications of Myeloma

  12. Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients 80 79 70 73 60 66 50 40 Percent of patients 30 32 20 19 13 12 10 0 Bone Bone Hb<12 Fatigue Cr >2 Ca >11 Wt loss mg/dL lesions mg/dL (>9 kg) pain g/dL Kyle et al Mayo clinic Proc. 2003;78:21-33

  13. Complications of Myeloma COMPLICATION • Painful bone lesions • Kidney failure • High calcium TREATMENT • Pain medications, physical therapy, rarely surgery and radiation • Fluids, ± plasmapheresis, ± dialysis • Zolendronic acid, fluids

  14. Treating Multiple Myeloma

  15. The good news…. ….there are many treatment options The bad news…. ….there are many treatment options

  16. Only Clinical Trials Will Provide Answers.

  17. Different Drugs Available Now Mix and match to make recipes against myeloma

  18. Different Drugs Available Now + New Drugs Likely Coming Soon • Monoclonal Antibodies: Elotuzumab, Daratumumab, SAR 650984 • Kinase Inhibitors: Afuresertib, Dinaciclib • Kinesin Spindle Protein Inhibitor: ARYY520 • Histone deacetylase inhibitors: pabinostat, vorinostat

  19. The Anatomy of a Myeloma Therapeutic Plan

  20. General Treatment Strategy

  21. How to use Drugs Against Myeloma? • 1-at a time? • 2-at a time? • 3-at a time? • 4-at a time? • More at a time? • High-dose with stem cell support?

  22. Del 17p t(14;16) t(14;20) GEP defined high-risk Trisomies t(11;14) t(6;14) Myeloma Risk-Stratification Standard-Risk Intermediate-Risk* High-Risk* • t(4;14) Excellent Outcome Bortezomib Critical CR appears critical *Presence of trisomies ameliorates high risk msmart.org

  23. Monitoring Disease Symptoms Blood Urine Radiographic images Bone marrow

  24. Fight infection Harmful Use • Myeloma: • Poison kidneys • Eat away at bones • Crowd bone marrow • causing anemia Bone marrow Blood stream Antibodies Immunoglobulins Myeloma cells Plasma cells a.k.a. Monoclonal antibody M-protein M-spike Myeloma protein Immunoglobulin Ig

  25. Antibody Proteins • Two light chains • Kappa or • Lambda • 5 heavy chains • IgA or • IgGor • IgD or • IgM and IgE Light chains Heavy chains

  26. Abnormal Serum Protein Electrophoresis Normal M-spike g/L 35 21 14 21 g/L

  27. Serum Immunofixation (IFE)

  28. Oligosecretory Little protein secreted Light chain secreted (no heavy chain) No protein secreted Non-secretory Bence Jones Or light chain myeloma Bone marrow Blood stream Myeloma protein Bone marrow Most myeloma cases Myeloma cells

  29. Urine protein electrophoresis Urine Total urine protein = 2.8 g/24 hours

  30. Immunoglobulin Free Light Chains Light chains FREE Light chains hidden surface exposed surface Previously hidden surfaces Heavy chains Intact Immunoglobulin Free Light Chains Antisera recognize epitopes of FLC’s, but do not detect light chains associated with intact immunoglobulin

  31. What is the immunoglobulin free light chain ratio? Normal range for ratio Clonal l Clonal k normal range for k & l

  32. Know your proteins and other things • Know your monoclonal protein type • IgG kappa, IgG lambda, IgA kappa, IgA lambda, kappa only, lambda only, IgD kappa, IgD lambda • Know which test(s) your doctor is following and the starting amount of your monoclonal protein • Hemoglobin, creatinine, and calcium

  33. Myeloma Response Measurement

  34. Mr. W.: Going Strong 13 years after diagnosis Diagnosed in February 2001 DSS 3A; ISS 2; Normal FISH and Cytogenetics Best response was VGPR after second ASCT Relapsed myeloma ASCT ASCT Suni- tinib Pom -dex CTX- pred MLN 9708 Thal -dex Dendr vaccine Vel -dex Obs Obs Obs

  35. Quality of Life Survival Response Side-effects What are goals of therapy? Need to weigh

  36. C T1 T1 +gad Imaging in Myeloma D • Simple bone radiographs • CT bone • PET-CT • MRI

  37. Treating Complications of Myeloma Therapy

  38. Managing Complications of Therapy Prevention is the best therapy. Tell your doctor if side-effects

  39. Survival for MM patients has doubled to tripled past 15 years due to new treatments!

  40. The landscape is changing for patients with myeloma thanks to investigators all over the world and patients like you, who are willing to participate in clinical trials.

  41. Thank You for Your Attention

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