Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Multiple Myeloma Monitoring and Therapy Angela Dispenzieri, M.D. IMF Patient Workshop November 3, 2014 Scottsdale, Arizona Rochester, Minnesota Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center Jacksonville, Florida Multiple Myeloma Plasma cell malignancy Calcium Renal Anemia Bone Making the diagnosis of multiple myeloma Not all increases in plasma cells are myeloma • MGUS – Monoclonal Gammopathy of Unknown Significance Precancer Cousin diseases • Smoldering myeloma Localized • Solitary Plasmacytoma cancer • Multiple myeloma • Primary systemic amyloidosis • POEMS syndrome • Waldenström’s macroglobulinemia What tests should be done with new diagnosis of multiple myeloma? 1. Protein electrophoresis of blood and urine and quantitative immunoglobulin 2. Serum immunoglobulin free light chain 3. Blood hemoglobin, creatinine, calcium, albumin, beta-2 microglobulin, and LDH 4. Bone radiographs 5. Bone marrow aspirate with FISH and immunophenotype Prognostic factor Important to monitor for complications and to establish response therapy Multiple Myeloma Staging and Prognosis 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 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 msmart.org TUMOR BIOLOGY: DISEASE AGGRESSIVENESS Myeloma Risk-Stratification Standard-Risk All other FISH including: Trisomies t(11;14) (CCND1) t(6;14) (CCND3) Intermediate-Risk t(4;14) (FGFR3/ MMSET) High-Risk Del 17p t(14;16) (C-MAF) t(14;20) (MAF-B) High risk GEP *Presence of trisomies ameliorates high risk 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 Treating Complications of Myeloma Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients 80 Percent of patients 70 79 73 60 50 66 40 30 32 20 19 10 13 12 0 Bone Bone lesions pain Hb<12 g/dL Kyle et al Mayo clinic Proc. 2003;78:21-33 Fatigue Cr >2 Ca >11 Wt loss mg/dL mg/dL (>9 kg) Complications of Myeloma COMPLICATION • Painful bone lesions • Kidney failure TREATMENT • Pain medications, physical therapy, rarely surgery and radiation • Fluids, ± plasmapheresis, ± dialysis • High calcium • Zolendronic acid, fluids Treating Multiple Myeloma The good news…. ….there are many treatment options The bad news…. ….there are many treatment options Only Clinical Trials Will Provide Answers. Different Drugs Available Now Corticosteroids Alkylators IMiDs Prednisone Melphalan Dexamethasone Prednisolone Proteasome inhibitors Other Thalidomide Bortezomib (Velcade) Doxorubicin Cyclophosphamide Lenaldiomide (Revlimid) Carfilzomib (Kyprolis) Cisplatin Bendamustine Pomalidomide (Pomalyst) Etoposide Mix and match to make recipes against myeloma Different Drugs Available Now + New Drugs Likely Coming Soon Corticosteroids Alkylators IMiDs Proteasom e inhibitors Prednisone Melphalan Thalidomide Bortezomib Dexamethasone Cyclophosphamide Lenaldiomide Carfilzomib Prednisolone Bendamustine Pomalidomide Ixazomib Other Doxorubicin Cisplatin Etoposide Oprozomib • • • • Monoclonal Antibodies: Elotuzumab, Daratumumab, SAR 650984 Kinase Inhibitors: Afuresertib, Dinaciclib Kinesin Spindle Protein Inhibitor: ARYY520 Histone deacetylase inhibitors: pabinostat, vorinostat The Anatomy of a Myeloma Therapeutic Plan General Treatment Strategy YOUNG AND FIT ELDERLY OR FRAIL Rd, CVD, VRD, PAD, VTD, CTD Rd, MPV, MPT 2. Stem cell collection For 1-2 transplants -- 3. Stem cell transplant 1 or 2 transplants -- 4. Consolidation Controversial -- 5. Maintenance Controversial Controversial 6. Relapse 1, 2, 3, etc Many options Many options 1. Induction 20 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? Myeloma Risk-Stratification Standard-Risk Trisomies t(11;14) t(6;14) Excellent Outcome Intermediate-Risk* t(4;14) Bortezomib Critical *Presence of trisomies ameliorates high risk High-Risk* Del 17p t(14;16) t(14;20) GEP defined highrisk CR appears critical msmart.org Monitoring Disease 1. Symptoms 2. Blood 3. Urine 4. Radiographic images 5. Bone marrow Bone marrow Blood stream Antibodies Immunoglobulins Fight infection Harmful Use Myeloma Plasma cells cells a.k.a. Monoclonal antibody M-protein M-spike Eat away at bones Myeloma protein Crowd bone marrow causing anemia Immunoglobulin Ig Myeloma: Poison kidneys Antibody Proteins Light chains Heavy chains • Two light chains • Kappa or • Lambda • 5 heavy chains • IgA or • IgG or • IgD or • IgM and IgE Abnormal Serum Protein Electrophoresis Normal g/L 35 M-spike 14 21 21 g/L Serum Immunofixation (IFE) Bone marrow Bone marrow Blood stream Myeloma protein Oligosecretory Little protein secreted Myeloma cells Light chain secreted (no heavy chain) No protein secreted Non-secretory Bence Jones Or light chain myeloma Most myeloma cases Urine protein electrophoresis Urine Total urine protein = 2.8 g/24 hours 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 What is the immunoglobulin free light chain ratio? Normal range for ratio Serum FLC Lambda (mg/L) 100000 Clonal l 10000 1000 100 10 Clonal k 1 0.1 0.1 normal range for k&l 1 10 100 1000 Serum FLC Kappa (mg/L) 10000 100000 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 Myeloma Response Measurement Partial Response Very good partial response Complete response Stringent complete response Blood M-protein 50% reduction 90% reduction Complete disappearance Complete disappearance Urine Mprotein 90% reduction < 100 mg/24 hours Complete disappearance Complete disappearance Serum immunoglobulin FLC Us if no other measure NA NA Normal ratio Bone marrow plasma cells NA NA < 5% Complete disappearance Date 10/7/2011 6/7/2011 2/7/2011 10/7/2010 6/7/2010 Obs 2/7/2010 10/7/2009 6/7/2009 Pom -dex 2/7/2009 10/7/2008 6/7/2008 Sunitinib 2/7/2008 10/7/2007 6/7/2007 Vel -dex 2/7/2007 10/7/2006 Obs 6/7/2006 2/7/2006 10/7/2005 ASCT 6/7/2005 Dendr vaccine 2/7/2005 10/7/2004 6/7/2004 2/7/2004 10/7/2003 6/7/2003 2/7/2003 10/7/2002 4 3.5 3 2.5 2 1.5 1 0.5 0 6/7/2002 Thal -dex 2/7/2002 10/7/2001 6/7/2001 2/7/2001 M-spike 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 CTXpred MLN 9708 Obs 34 What are goals of therapy? Need to weigh Survival Quality of Life Side-effects Response Imaging in Myeloma D • Simple bone radiographs • CT bone • PET-CT • MRI C T1 T1 +gad Treating Complications of Myeloma Therapy Managing Complications of Therapy Cortico-steroids Alkylators IMiDs Proteasome inhibitors Prednisone Melphalan Thalidomide Bortezomib Dexame-thasone Cyclophosphamide Lenaldiomide Carfilzomib Prednisolone Pomalidomide Insomnia, mood Low blood Constipation Hunger, diabetes Fatigue Diarrhea Infection Rash Blood clots Prevention is the best therapy. Tell your doctor if side-effects Neuropathy Fatigue Low platelets Infection Survival for MM patients has doubled to tripled past 15 years due to new treatments! 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. Thank You for Your Attention