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Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Multiple Myeloma Monitoring and Therapy Angela Dispenzieri, M.D. IMF Patient Workshop November.

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Presentation on theme: "Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Multiple Myeloma Monitoring and Therapy Angela Dispenzieri, M.D. IMF Patient Workshop November."— Presentation transcript:

1 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Multiple Myeloma Monitoring and Therapy Angela Dispenzieri, M.D. IMF Patient Workshop November 4, 2014 Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

2 Multiple Myeloma Staging and Prognosis

3 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

4 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

5 TUMOR BIOLOGY: DISEASE AGGRESSIVENESS Myeloma Risk-Stratification  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)  t(4;14) (FGFR3/ MMSET) High-Risk Intermediate-RiskStandard-Risk msmart.org *Presence of trisomies ameliorates high risk

6 What do we mean by ‘prognostic’ factors? Different patients’ myeloma acts almost like different diseases! Markers to help differentiate those patients with the ‘gentlest’ myeloma from those with the ‘meanest’ myeloma

7 Myeloma Risk-Stratification  Del 17p  t(14;16)  t(14;20)  GEP defined high- risk  Trisomies  t(11;14)  t(6;14)  t(4;14) High-Risk* Intermediate-Risk*Standard-Risk msmart.org*Presence of trisomies ameliorates high risk CR appears criticalBortezomib CriticalExcellent Outcome

8 Treating Multiple Myeloma

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

10 Only Clinical Trials Will Provide Answers.

11 Different Drugs Available Now Cortico- steroids AlkylatorsIMiDsProteasome inhibitors Other PrednisoneMelphalanThalidomide Bortezomib (Velcade) Doxo- rubicin Dexame- thasone Cyclophos- phamide Lenaldiomide (Revlimid) Carfilzomib (Kyprolis) Benda- mustine Prednisolone Pomalidomide (Pomalyst) Etoposide Cisplatin Mix and match to make recipes against myeloma

12 Different Drugs Available Now + New Drugs Likely Coming Soon Cortico- steroids AlkylatorsIMiDsProteasom e inhibitors Other PrednisoneMelphalanThalidomideBortezomib Doxo- rubicin Dexame- thasone Cyclophos- phamide LenaldiomideCarfilzomib Cisplatin Prednisolone Benda- mustine PomalidomideIxazomibEtoposide Oprozomib Monoclonal Antibodies: Elotuzumab, Daratumumab, SAR Kinase Inhibitors: Afuresertib, Dinaciclib Kinesin Spindle Protein Inhibitor: ARYY520 Histone deacetylase inhibitors: pabinostat, vorinostat

13 Monitoring Disease 1. Symptoms 2. Blood 3. Urine 4. Radiographic images 5. Bone marrow

14 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

15 Managing Complications of Therapy Cortico-steroidsAlkylatorsIMiDsProteasome inhibitors PrednisoneMelphalanThalidomideBortezomib Dexame-thasoneCyclophos- phamide LenaldiomideCarfilzomib PrednisolonePomalidomide Insomnia, moodLow bloodConstipation Neuropathy Hunger, diabetesFatigueDiarrhea Fatigue InfectionRash Low platelets Blood clots Infection Prevention is the best therapy. ll your doctor if side-effects

16 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

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

18 Antibody Proteins Two light chains Kappa or Lambda 5 heavy chains IgA or IgG or IgD or IgM and IgE Heavy chains Light chains

19 Abnormal Serum Protein Electrophoresis 3514g/L 21 g/L Normal M-spike

20 Serum Immunofixation (IFE)

21 Myeloma protein Myeloma cells Bone marrow No protein secreted Non-secretoryOligosecretory Little protein secreted Bence Jones Or light chain myeloma Light chain secreted (no heavy chain) Most myeloma cases Bone marrowBlood stream

22 Urine protein electrophoresis Total urine protein = 2.8 g/24 hours Urine

23 Antibody Proteins Heavy chains Light chains FREE Light chains Intact ImmunoglobulinFree Light Chains exposed surface hidden surface Previously hidden surfaces Antisera recognize epitopes of FLC’s, but do not detect light chains associated with intact immunoglobulin

24 What is the immunoglobulin free light chain ratio? Normal range for ratio normal range for  & Clonal  Clonal

25 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

26 Myeloma Response Measurement PRVGPRCRsCR Blood M-protein 50% reduction 90% reduction Complete disappearance Urine M- protein 90% reduction < 100 mg/24 hours Complete disappearance Serum immunoglo- bulin FLC Us if no other measure NA Normal ratio Bone marrow plasma cells NA < 5% Complete disappearance

27 Mr. W.: Going Strong 13 years after diagnosis Thal -dex ASCT Vel -dex ASCT Suni- tinib Pom -dex CTX- pred Obs Dendr vaccine Obs Diagnosed in February 2001 DSS 3A; ISS 2; Normal FISH and Cytogenetics Best response was VGPR after second ASCT Relapsed myeloma 27 MLN 9708

28 Imaging in Myeloma Simple bone radiographs CT bone PET-CT MRI T1T1 +gad C D

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

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

31 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.

32 Thank You for Your Attention

33

34 mSMART – Off-Study Transplant Ineligible a In patients treated with Rd, continuing treatment is an option for patients responding well with low toxicities; Dex is usually discontinued after first year b Bortezomib containing regimens preferred in renal failure or if rapid response needed c CyBorD is considered a less toxic variation of VMP; VMP can be used as alternative d Continuing Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year *Clinical trials strongly recommended as the first option Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013;88: v12 //last reviewed March 2014 VRd* for ~12 months Bor as maintenance for ≥ 1 year Weekly CyBorD for ~12 months c Bor-based therapy maintenance x ≥ 1 year Followed by observation Weekly CyBorD for ~12 months c Rd a, b Until progression d Del 17p, t(14;16), t(14;20) t 4;14 Trisomies only Standard-Risk Intermediate-Risk High-Risk t(11;14), t(6;14), Trisomies + IgH

35 mSMART – Off-Study Transplant Eligible a Bortezomib containing regimens preferred in renal failure or if rapid response needed b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor c Continuing Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year * Consider risks and benefits; If used, consider limited duration months Collect Stem Cells b Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013;88: v12 //last reviewed March cycles of Rd a Continue Rd c 4 cycles of VRd Autologous stem cell transplant, especially if not in CR Bor or CyBorD for minimum of 1 year Autologous stem cell transplant 2 cycles of Rd consolidation; then Len maintenance if not in VGPR but Len responsive* 4 cycles CyBorD Standard-Risk Intermediate-Risk High-Risk Autologous stem cell transplant Bor based therapy for minimum of 1 year 4 cycles of CyBorD Del 17p, t(14;16), t(14;20) t(4;14) Trisomies onlyt(11;14), t(6;14), Trisomies + IgH


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