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Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division.

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Presentation on theme: "Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division."— Presentation transcript:

1 Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

2 Disclosures Grant Support –Celgene –Millenium –Onyx Honoraria –Celgene –Millenium –Onyx –Novartis –Sanofi/Genzyme Most important I am a transplanter

3 Initial Presentation 45-year-old woman Presents with proteinuria. Normal Physical Laboratory findings –Hemoglobin 11 gm/dl normal iron stores –Total proteinuria 5.82 g/day –Bence Jones protein (BJP) 3.6 g/day –Hypogammaglobulinemia –Albumin 3.9 g/dL –β2-microglobulin 4.7 mg/L –Creatinine 1.7 mg/dl –No paraprotein peak but kappa light chain with lambda light chain at 0.01 –Kappa/lambda ratio=

4 Bone marrow biopsy –Cellularity 80% with 25% plasma cells –Cytogenetics 46, XX, inversion 9 (p11;q13) FISH no abnormalities Skeletal survey: extensive lytic bone disease with healing fractures of left 7 th and the 8 th ribs MRI of the spine: diffuse hyper-intense homogenous signal on STIR sequence MRI of the pelvis: diffuse marrow infiltrative changes due to myeloma Comorbidities: Diabetic on metformin, no history of coronary artery disease or other comorbidities

5 Multiple Myeloma: Analysis 3 decades Myeloma M0 M1M2M3M4M5M6M7 Hyperdiploidy t(6:14) SC PreProEarlyMidSHMICSPC t(14;16) t(4:14) t(11;14) Images courtesy of Raphael Fonseca, MD.

6 Multiple Myeloma Treatment Lines a Induction Consolidation Front-line treatment Maintenance Rescue Relapsed IMID:Thal-Len Proteosome Inhibitor: Bor-Car Steroids: Dex-Pred Alkylator: Cyclo-Mel Anthracycline: LipoDnr-Adr SCT Observation IMID:Thal-Len Proteosome Inh-Bor Steroids:Dex-Pred IMID:Thal-Len-Pom Proteosome Inh:Bor-Car Steroids: Dex-Pred Alkylators:Mel-Cy-Benda Investigational a Transplant eligible patients. Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin. NCCN, 2009.

7 IS THERE AN OPTIMAL INDUCTION REGIMEN? What we know…

8 Protocol GIMEMA MMY-3006 VTD vs TD incorporated into double ASCT for MM RANDOMIZATION INDUCTION VEL-THAL-DEX TRANSPLANTATION MEL 200 CONSOLIDATION VEL-THAL-DEX MAINTENANCE DEX INDUCTION THAL-DEX PBSC COLLECTION CTX CONSOLIDATION THAL-DEX

9 RESPONSE TO PRIMARY THERAPY % of patients RESPONSEVTD(n=129)TD(n=127) P value CR+nCR369<0.001  VGPR 6027<0.001 < PR Progression EBMT criteria (with added nCR and VGPR categories)

10 RESPONSE (CR+nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIES  13 t(4;14) P=0.06P=0.1  13 pos t(4;14) pos P<0.001P=0.002 negposnegpos VTDVTD vs TD VTD TD

11 GIMEMA: Results Secondary endpoints –PFS –OS 96% (VTD) vs 91% (TD); P =.2 Primary endpoint: CR + nCR (VTD vs TD as induction therapy) Cavo M, et al. ASH Abstract 158. Response, % VTD (n = 226) TD (n = 234) P Value CR + nCR3212<.001 ≥ VGPR6229<.001 ≥ PR9479<.001 Progression Modified EBMT and Uniform Criteria (nCR and VGPR categories) Mos 2-yr rates P =.009 VTD (n = 226): 90% TD (n = 234): 80%

12 Meta-analysis

13 Phase II Study of Len, Bortezomib, and Dex (RVD) in Newly Diagnosed MM (Richardson et al) Pts 35 enrolled in phase II; median age 59 (22-86) yrs; ISS Stage II/III 54%/11% Dose Lenalidomide 25 mg/d, d 1-14 in 21 day cycle Bortezomib 1.3 mg/m2 d 1, 4, 8, 11 Dexamethasone 20 mg day of and after bortezomib Aspirin and antiviral prophylaxis Safety Grade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality Response n = 35 evaluable CR/nCR52% < VGPR74% ORR (≥PR)100% Results At 19 mos of follow-up, TTP, PFS, At 19 mos of follow-up, TTP, PFS, and OS have not been reached and OS have not been reached Median stem cell collection in 15/35 Median stem cell collection in 15/35 patients: 4.4 x 106 CD34+ cells/kg patients: 4.4 x 106 CD34+ cells/kg Newly Diagnosed MM

14 Kaplan-Meier analyses of treatment outcomes. Kumar S et al. Blood 2012;119: ©2012 by American Society of Hematology

15 Stem Cell Collection After 4 cycles of RVD she achieves a VGPR with kappa light chains reduced to 10 and lambda light chains recovered to 0.1. Her marrow reveals 4% kappa restricted plasma cells. MRI demonstrates significant resolution of infiltrative images. She agrees to proceed to stem-cell collection and transplantation.

16 OPTIMAL MOBILIZATION STRATEGY What we know…

17 Effect of Lenalidomide Duration of Therapy on Stem Cell Collection Paripati H. Leukemia. 2008;22: CD34+ Count (Cells µ l -1 ) CD34+ Count (in Millions) Days Percentage Mean Peripheral Blood CD34+ Count Total CD34+ Cells collected (Mean x 10 6 cells Kg -1 ) Mean number of days of collection Percentage of patients who failed first collection Lenalidomide TherapyOther Induction Therapies n=16 n=40 n=18 P value = P value=0.0025P value = 0.07P value =

18 Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization Utilizing Plerixafor Plerixafor + G-CSF –N = 60 patients with myeloma frontline mobilization: 20 patients & CUP: 40 pts –Median CD34 collected 5.6 x 10 6 CD34/kg –87% collected ≥ 2 x 10 6 CD34/kg –63% collected ≥ 5 x 10 6 CD34/kg –Up front pts: 100% (≥ 2) & 95% (≥ 5) –CUP pts: 80% (≥ 2) & 48% (≥ 5) Micallef I, et al. Haematologica. 2009;94(suppl 2):0718; Tarantolo S, et al. Biol Blood Marrow Transplant. 2009;15(2 suppl 2):91.

19 What we don’t know Is VRD superior to VTD or CyBorD? Should the goal be ‘X” number of cycles and proceed to SCT or should patients continue induction until best response? Is “response adapted” therapy appropriate? Is there a role for carfilzomib based induction? Should anybody be chemomobilized in the era of plerixafor?

20 Stem Cell Transplantation She collects 10 million CD34 cells per kg over 3 days and is ready to be admitted for high dose melphalan and autologous stem cell transplantation. She asks what is it going to be like and does she really need a SCT?

21 ROLE OF SCT IN THE ERA OF IMIDS AND PROTEOSOME INHIBITION What we don’t know…

22 Figure 2 Source: Biology of Blood and Marrow Transplantation 2007; 13: (DOI: /j.bbmt )Biology of Blood and Marrow Transplantation 2007; 13: Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and ConditionsTerms and Conditions BENEFIT OF AUTOGRAFTING FOR MYELOMA Koreth et all BBMT

23 Early-vs-Late SCT Study? m A A m m A A A A Risk profile Optimal induction regimen Maintenance COLLECT HD THERAPY + SCT HARVEST AND HOLD SCT UPON RELAPSE

24 IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates) VRD x 3 VRD x 2 VRD x 5 Lenalidomide 12 mos Melphalan 200mg/m 2 * + ASCT Induction Consolidation Maintenance CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg VRD x 3 CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg Randomize, stratification ISS & FISH Collection Lenalidomide 12 mos SCT at relapse MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140mg/m 2 k=1

25 Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following Lenalidomide/Dexamethasone (Ld) Induction Primary end point: PFS RANDOMIZERANDOMIZE Lenalidomide: 25 mg, days 1–21 Low-dose Dex: 40 mg, days 1, 8, 15, 22 q 28 days ×4 Consolidation n=402 <65 years RANDOMIZERANDOMIZE No maintenance Maintenance lenalidomide: 10 mg/d, Days 1–21 q 28 days until relapse Palumbo A et al. Blood. 2009;114:Abstract 350. MPR (n=202) Melphalan: 0.18 mg/kg/d, days 1–4 Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21 q 28 days ×6 Tandem MEL200 ASCT stem cells mobilized with cyclophosphamide + G-CSF

26 Median follow-up 26 months Progression Free Survival HR P = MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; PFS, progression free survival; HR, hazard ratio; mos, months 2-years PFS MPR MEL200 54% 73% Median PFS Not reached mos Patients (%) Months 49.4% Reduced Risk of Progression

27 MPR MEL200 P value CR 20% 25% P= months 54% 73% P= months 87% 90% P=0.19 Less G3-4 hematologic toxicity in MPR arm (P<0.001) Less mucositis and infections in MPR arm (P<0.001) No difference in term of early deaths Significantly longer PFS after ASCT (P<0.001) Longer follow up is needed to assess OS Conclusions MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation

28 eastern cooperative oncology group E4A03: Landmark Analysis at Median Follow-up of 36 mo Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages , January patients alive at 4 cycles Off therapy at 4 cycles n=183 Primary therapy beyond 4 cycles n=248 no transplant N=93 (median age 68) Transplant n=90 (median age 57) Ld n=140 (median age 66) LD n=108 (median age 65)

29 eastern cooperative oncology group Outcomes in pts Age <65 Progression Free SurvivalOverall Survival

30 What we don’t know Should everybody be collected upfront? –How much? Who should undergo upfront SCT? –All patients? –Only those with suboptimal response?  What is suboptimal? –PR –VGPR –Near CR –Who is truly transplant ineligible? –What about low risk patients in CR? What role does risk stratification play in deciding therapies?

31 FUNCTIONAL ASSESSMENT

32 32 Aging Heterogeneity Community Dwelling, Typical Institutionalized, Frail Ages 84,81 Community Dwelling, Healthy Age 82 Community Dwelling, Frail Ages 19, 82, 23

33 Xz12_56.ppt Transplant-related Mortality after Autologous Hematopoietic Cell Transplantation for Malignant Diseases by HCT-CI, Incidence, % Years HCT-CI=1-2 (n=2,813) HCT-CI=0 (n=5,185) HCT-CI3 (n=2,388) p<0.001

34 100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation According to Performance Score and Disease Indication 100 day mortality,% P<0.001

35 Rate of SCT in US according to Age Costa et al ASH 2012 <50 years50-64 years≥ 65 years Figure 1

36 Randomized Phase II LD/HD CD34

37 In my humble opinion High dose melphalan is one of the most active agents in myeloma today –30-40% CR –24 months median remission duration without maintenance –Name another agent with similar single agent activity –It is also cost-effective With stem cell support it can be given safely to older patients with comorbidities. Thus not planning for it’s use upfront is similar to telling a patient I am never going to use bortezomib or lenalidomide during your disease course because “I don’t like it” or I don’t believe in it”. Whether early or late, once twice or more times it remains an active agent that can be extremely effective in all stages of the patients disease journey.

38 POST SCT THERAPIES

39 Tales of Two Cases Case 1 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals –30% plasma cells –Cytogenetic diploid –IgA kappa peak of 3.2 –β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented stringent CR Case 2 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals –30% plasma cells –Cytogenetic t(4;14) –IgA kappa peak of 3.2 –β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dL Both have a 10/10 sibling donor available.

40 Multiple Myeloma meeting eligibility criteria Multiple Myeloma meeting eligibility criteria High-dose melphalan (200 mg/m2) + autologous PBSC transplant High-dose melphalan (200 mg/m2) + autologous PBSC transplant 60 to 120 days No eligible HLA-matched sibling donor No eligible HLA-matched sibling donor Non-myeloablative conditioning TBI 200 cGY allogeneic PBSC transplant Non-myeloablative conditioning TBI 200 cGY allogeneic PBSC transplant High-dose melphalan (200 mg/m2) + autologous PBSC transplant High-dose melphalan (200 mg/m2) + autologous PBSC transplant Observation Thalidomide Dexamethasone x12 months. Thalidomide Dexamethasone x12 months. Biologic assignment* Eligible HLA-matched sibling donor Eligible HLA-matched sibling donor Randomization† PRIMARY ENDPOINT : 3yr Progression Free Survival BMT CTN 0102 Study Schema HLA typing of all patients with siblings *Biologic assignment occurred when HLA-typing results were available after enrollment. † Randomization occurred once patients were assigned to auto-auto

41 1 st Autologous Transplant N=710 1 st Autologous Transplant N=710 No Sibling Donor Auto-Auto N=484 No Sibling Donor Auto-Auto N=484 Sibling Donor Auto-Allo N=226 Sibling Donor Auto-Allo N=226 High Risk N=48 High Risk N=48 Standard Risk N=189 Standard Risk N=189 Standard Risk N=436 Standard Risk N=436 High Risk N=37 High Risk N=37 Main groups compared

42 Monitoring Disease CR Definition Does Matter With Regards to Depth of Remission Rate of molecular CR with HDT is 5% At diagnosis Partial response – 50% reduction in M protein Near complete remission – immunofixation positive only Complete remission – immunofixation negative Nonquantitative ASO-PCR Quantitative ASO-PCR flow cytometry MRD 1 × × × × Number of Myeloma Cells

43 Summary High dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive disease Current therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around years. Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden


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