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Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute

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1 Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute
New Paradigms, New Treatments in Relapsed/Refractory Disease: An Update Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Harvard Medical School

2 Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead Scientific Founder: Acetylon, Oncopep

3 Integration of Novel Therapy Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapy Eight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse

4 There is a well defined and recognized unmet need in multiple myeloma treatment
Frontline Treatment Relapsed Relapsed or Intolerant Expected survival (m) 20-50 Sensitivity to therapy Sensitive Treatment limitations/ comorbidities Peripheral neuropathy (~15% at diagnosis) 14-16 Less Sensitive/Resistant >80% incidence of peripheral neuropathy Compromised marrow reserve Cytopenia 6-10 Resistant Intolerant to or ineligible for available therapy Elderly population ( risk for heart, lung, renal, liver dysfunction, diabetes) Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition. Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156. For Planning Purpose Only Not Reviewed by Legal or Regulatory


6 Overview of Phase III Trials with Len and Bortezomib in Relapsed/Refractory MM
Regimen Trial ORR, % CR or nCR, % ≥ VGPR, % DOR, Mos TTP or PFS, Mos Median OS, Mos Len + dex MM-009[1] 61 24 NE 16 11 35[5] MM-010[2] 60 25 17 Bortezomib APEX[3] 43 8 6 30 Vdox MMY-3001[4] 44 13 27 10 9 1. Weber DM, et al. N Engl J Med. 2007;357: Dimopoulos M, et al. N Engl J Med. 2007;357: Richardson PG, et al. Blood. 2007;110: Orlowski RZ, et al. J Clin Oncol. 2007;25: Weber D, et al. Blood. 2007;110:Abstract 412. 6

7 Palumbo et al. ASH 2010 abstr 620.

8 SC vs IV Bortezomib for Relapsed/Refractory Myeloma
Moreau et al, ASH 2010 abstr 312 EQUIVALENT EFFICACY Peripheral Neuropathy Bortezomib IV (N=74) Bortezomib SC (N=148) P- value* Any PN event, % 53 38 0.04 Grade 2, % 41 24 0.01 Grade 3, % 16 6 0.03 Risk factors for PN, % Grade 1 PN at baseline 28 23 Diabetes at baseline 11 13 Exposure to prior neurotoxic agents 85 86 *P-values are based on 2-sided Fisher’s exact test

9 Bortezomib, Lenalidomide and Dex Therapy
Lenalidomide induces caspase 8 mediated apoptosis of MM cells in BM in vitro and in vivo; Dex (caspase 9) enhances response Synergistic MM cell toxicity of lenalidomide (caspase 8) with Bortezomib (caspase 9>8) in vitro and in vivo (dual apoptotic signaling) Phase I-II trials show that majority (58%) of patients refractory to either agent alone respond to the combination Phase I-II trials show 100% response with 74% CR/VGPR and 52% CR/nCR when used as initial therapy, including molecular responses. Richardson et al. JCO 2009; 27: Richardson et al. Blood 2010; 116: 9

10 Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor
Novel chemical class with highly selective and irreversible proteasome binding Improved antitumor activity with consecutive day dosing No neurotoxicity in animals Durable responses in relapsed and relapsed/ refractory MM w/o neuropathy Carfilzomib lenalidomide Dex versus lenalidomide Dex phase III trial for new drug approval Epoxyketone Tetrapeptide Demo et al. Cancer Res 2007; 67:6383 Kirk et al., Blood 2008, 112: Siegal et al. Blood 2012:120:2817.

11 Category (XX) 4/15/2017 Benefit of Carfilzomib in Relapsed/Refractory MM: Meaningful ORR, DOR and OS Response Category Total N = 266, n (%) 1 (0.4) VGPR 13 (4.9) PR 47 (17.7) MR CR SD 81 (30.5) PD 69 (25.9) Not evaluable 21 (7.9) ORR = 22.9% (95% CI: 18.0, 28.5) CBR = 35.7% (95% CI: 30.0, 41.8) Duration of response Median DOR = 7.8 months (95% CI: 5.6, 9.2) Overall Survival Median OS = 15.4 months (95% CI: 12.5, 19.0) DRAFT

12 Jakubowiak A. et al., Blood, 2012; 120: 1801-8.
CRd in Relapsed and Upfront MM Wang et al ASCO 2011; Jakubowiak et al ASH 2011 Response to CRd therapy was high, with an ORR of 78% 41% VGPR or better CRd well-tolerated with durable responses ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled. Remarkable extent and frequency of response to CRd upfront (100% ORR, 80% CR,nCR after 12 cycles) Jakubowiak A. et al., Blood, 2012; 120: 12 12

13 Carfilzomib in Relapsed/Refractory MM
Study Ph BTZ status n Median prior tx lines CFZ dose Mode of admin ORR PX A11 II Relapsed and refractory 266 5 20/27 mg/m2 2-10 min IV infusion 24% PX I/II Relapsed and/or 20 4.5 20/56 mg/m2 30-min IV infusion 60% Siegel et al. Blood. 2012;120(14): Papadopoulos KP, et al. Blood. 2011;118(21):Abstract and poster 2930.

14 Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory MM
CFZ dose of 20/56 mg/m2 administered as a 30-minute IV infusion resulted in high response rates in our BTZ treated/refractory population. Response rates were comparable to those seen in PX CFZ dose of 20/56 mg/m2 was associated with more frequent cardiac and pulmonary toxicities, particularly HTN and pulmonary edema/CHF. Possible contribution from “supportive” measures? CFZ dose of 20/56 mg/m2 continues to be explored in ongoing Phase II/III studies. Lendvai et al, ASH 2012 Abstr 947

15 Pomalidomide in Myeloma
C MM cells IL-6 TNF IL-1 B A Bone Marrow Stromal Cells ICAM-1 Bone Marrow Vessels NFAT IL-2 IFN  PKC IL-2 NK Cells NK-T Cells VEGF bFGF PI3K CD28 CD8+ T Cells Dendritic Cells D E Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004 Hayashi T et al. Brit J Hematol 128: 192, 2005 Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001

16 Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma
POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids POM + LoDEX, 34%; POM alone, 15% Response was durable with POM regardless of the addition of LoDEX POM + LoDEX, 8.3 months ; POM alone, 8.8 months POM is generally well tolerated, with low rates of discontinuations due to AEs Age had no impact on ORR, DoR, or safety Jagannath S, et al. ASH 2012 abstract 450.

17 Pom/Dex is well tolerated
Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma (345 patients) Pom/Dex has high response rates even in heavily pretreated relapsed myeloma Pom/Dex is well tolerated Toxicity and efficacy are similar between the 2mg and 4mg dose levels The strongest predictors of response include the number and type of prior regimens. The strongest predictors of TTP and survival include the number and type of prior regimens, LDH, and B2M. Lacy et al. ASH 2013 Abstr 201.

18 A Phase III Clinical Trial of Pomalidomide with Low-dose Dex vs
A Phase III Clinical Trial of Pomalidomide with Low-dose Dex vs. High-dose Dex in Relapsed/Refractory MM POM + LoDEX significantly improved PFS and OS Median PFS: 3.6 vs 1.8 months HR = 0.45; P < .001 Median OS: not reached vs 7.8 months HR = 0.53; P < .001 Equal benefit in pts refractory to both LEN and BORT POM + LoDEX was generally well tolerated POM + LoDEX should be considered as a new treatment option for these pts Dimopoulos et al. ASH 2013 LBA6

19 MM-005: A Phase 1 Trial of Pomalidomide, Bortezomib, and Low-dose Dexamethasone in Relapsed or Relapsed/Refractory MM POM + BORT + LoDEX (PVD) well tolerated cohort 5 as the MTD/MPD POM 4 mg; BORT 1.3 mg/m2; DEX 10/20 mg Responses in RR MM across all cohorts ORR: 73%, VGPR: 27%, SD: 27% Responses were rapid; majority are ongoing Efficacy even with adverse cytogenetics Phase III Trial Pom Bort Dex vs Bort Dex for full approval Richardson et al. ASH 2013 Abstr 727.

20 Carfilzomib Pomalidomide Dexamethasone (Car-Pom-d) in Relapsed/Refractory MM
MTD was Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg, and dexamethasone 40 mg There are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicity The combination of Car-Pom–d is highly active in this heavily pretreated, refractory patient population The combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status ≥ VGPR 13% ≥ ORR 50% ≥ CBR 67% PFS (median) 7.4 months OS 1 year Shah et al. ASH 2012 Abstr 74.

21 Current and Future Directions
Development of immune therapies Development of novel agents targeting the MM cell in the BM microenvironment 3. Development of rationally-based combination therapies 4. Utilization of genomics for improved classification and personalized therapy Myeloma will be a chronic illness, with sustained CR in a significant fraction of patients.

22 MAb-Based Therapeutic Targeting of Myeloma
Antibody-dependent Cellular cytotoxicity (ADCC) Apoptosis/growth arrest via targeting signaling pathways Complement-dependent Cytotoxicity (CDC) Effector cells: MM FcR MM C1q MM CDC ADCC Daratumumab (CD38) huN901-DM1 (CD56) nBT062-maytansinoid (CD138) 1339 (IL-6) BHQ880 (DKK1) RAP-011 (activin A) Daratumumab (CD38) Lucatumumab or Dacetuzumab (CD40) Elotuzumab (CS1) Daratumumab (CD38) XmAb 5592 (HM1.24) Tai & Anderson Bone Marrow Research 2011

23 Phase 2 Elotuzumab Lenalidomide Low-dose Dex in Relapsed/ Refractory MM
Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM 82% for all pts (91% in pts who had received only 1 prior therapy) 92% for pts treated with elotuzumab 10 mg/kg Median PFS was 33 mos for patients receiving elotuzumab mg/kg The combination was generally well tolerated Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%), thrombocytopenia (16%), and lymphopenia (16%) Premedication regimen decreased incidence and mitigated severity of infusion reactions* Richardson et al. ASH 2012, Lonial et al. ASCO 2013 23

Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit 4 patients achieving PR (13%) 6 patients achieving MR (19%) 5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide dexamethasone Plesner et al. ASH 2012 Abstr 73.

25 Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM
Well tolerated, no autoimmunity Induced tumor reactive lymphocytes in a majority of patients Induced humoral responses to novel antigens (SEREX analysis) Disease stabilization in 70% of patients DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models Vasir et al. Brit J Hematol 2005; 129: Rosenblatt et al. Blood 2011; 117:

26 Background: MM/DC Vaccination following Autologous PBSCT for Myeloma
Rosenblatt et al., CCR 2013

27 PD-L1 Plays an Important Role in Dampening the Anti-tumor Immune Response
cancer cell PD-L1 lymphocyte IFNg-mediated up-regulation of tumor PD-L1 PD-L1/PD-1-mediated Inhibition of tumor cell killing receptor Presence of intratumoral T-cells may lead to adaptive immune resistance Priming and Activation of T cells PD-L1 expression in the tumor microenvironment can inhibit anti-tumor T cell activity: PD-L1 expression by tumor infiltrating immune cells PD-L1 expression by cancer cells Immune cell modulation of T cells Stromal PD-L1 modulation of T cells PD-L2 mediated inhibition of TH-2 T cells Chen DS, Irving BA, Hodi FS. Clin Cancer Res. 2012;18:6580.

28 Combination Immunotherapy Posttransplant
Anti PD-1 Ab administration in the early post-autologous transplant period is well tolerated Anti-PD1 results in the expansion of tumor reactive lymphocytes in the post-transplant period that persist at 6 months This provides a promising platform for combination with a tumor vaccine We have inititated enrollment into cohort 2, in which patients receive an autologous DC/myeloma fusion vaccine 1 week prior to each dose of Anti-PD-1Ab Avigan et al.

29 Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
b 5, 5i 1, 1i 2, 2i ATPases/ Cdc48 Potential Therapeutic Targets 26S PROTEASOME ATP ADP UB enzymes E1, E2 and E3-UB-Ligases Ub Poly-ubiquitinated proteins (proteasome substrates) Free for re-cycling Six Protease activities Degraded protein Immunoproteasome Proteasome: Present and Future Therapies Deubiquitylating Enzymes (DUBs) Bortezomib, Carfilzomib, CEP-18770 ONYX-0912 MLN 2238 NPI-0052: 5, 1, 2 5 PR-924 P5091 target USP-7 29

30 P5091 Specifically Target USP-7 and does not Alter Proteasome Activity
USP-7 Knockout Proteasome Activity Assay P5091 (µM) Velcade (nM) Chauhan et al. Cancer Cell 2012;22:

31 P5091 Overcomes Bortezomib-Resistance in MM Cells
Chauhan et al. Cancer Cell 2012; 22:

32 MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib-Resistance
24h 48h Chauhan et al., Clin Cancer Res, 2011; 17:

33 Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study
Single-agent oral MLN9708 MTD mg/m2 on a weekly (days 1, 8, and 15 every 28 days) schedule Oral MLN9708 generally well tolerated hematologic and gastrointestinal events generally manageable, low rate of discontinuations Infrequent PN, only 1 grade 3 PN Pharmacokinetic profile supports weekly oral dosing Relapsed and/or refractory MM patients (median 4 prior lines of therapy) ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post Bortezomib Kumar ASCO 2013

34 MLN9708 in Relapsed and/or Refractory MM: Expansion Cohorts of a Phase 1 Dose-Escalation study
46 pts evaluable for response 21 in dose-escalation cohorts 30 in expansion cohorts (including 6 from dose-escalation cohorts) 6 pts have achieved ≥PR 1 CR, confirmed by bone marrow (PI-naïve expansion cohort) 5 PRs (1 each at 1.2 and 2.23 mg/m2 in dose-escalation cohorts; 1 in RRMM and 2 in bortezomib-relapsed expansion cohorts) 1 pt achieved MR (bortezomib-relapsed expansion cohort; 40% M-protein reduction) All 7 pts remain in response, with duration of disease control of up to 15.9 months 28 pts have achieved SD 14 in dose-escalation cohorts 9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts Durable, with disease stabilization for up to 12.9 months Richardson et al. ASH 2011

35 In Vitro Anti-MM Activity of Oral
Chymotryptic Inhibitor ONX 0912 (Opromazib) Myeloma Cell Lines Patient Tumor Cells Phase I clinical trials ongoing Chauhan et al. Blood. 2010;116:490614

36 Marizomib: A Non-Peptide Proteasome Inhibitor Induces Rapid, Broad and Prolonged Inhibition
Marizomib (NPI-0052) H N O C 3 l Exhibits high levels of proteasome inhibition without toxicities associated with bortezomib Active in bortezomib and IMiD resistant myeloma preclinically Chauhan et al., Cancer Cell 2005; 8:

37 Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**) All Pts EBMT ≥ SD 11/20 55% MR + PR 3/20 15% Uniform Criteria 12/21 57% PR + VGPR 4/21 19% Pts Refractory to Bortezomib EBMT ≥ SD 8/12 67% MR + PR 2/12 17% Uniform Criteria PR + VGPR Median Duration of Response (all Pts) = 133 days (~ 5 mos) Pts Exposed to Bortezomib EBMT ≥ SD 11/19 58% MR + PR 3/19 16% Uniform Criteria PR + VGPR Pts Refractory to Lenalidomide EBMT ≥ SD 8/13 62% MR + PR 3/13 23% Uniform Criteria 9/14 64% PR + VGPR 4/14 29% Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**. Refractory defined as having PD during or within 60 days of last regimen. *As of 05 Dec 11 Richardson et al. ASH 2011

38 Functional Sequelae of Btk Inhibition by PCI-32765 in the MM BM milieu
Stem Cell MM PCI32765 TRAP5b SDF-1 IL-8 Activin A APRIL MIP-1 MIP-1 TGF1 RANTES BAFF PCI32765 Colony formation Btk activation by IL-6, SDF-1 Tumor microenvironment Adhesion Migration Homing IL-6 SDF-1 MIP-1 MIP-1 M-CSF MCP-1 MIP-1, MIP-1, IL-8, TGF1 RANTES, BAFF, TRAF2, CXCR4, LAT, PLC2, MYD88, NFATc1 Bone resorption PCI-32765 M-CSF, IL-6, MCP-1 RANK M-CSF fms Stromal cells Osteoclast precursors Osteoclast Tai et al. Blood2012; 120:

39 BET Bromodomain Inhibition Suppresses c-myc Expression and Function and Triggers Anti-MM Activity
Delmore JE., Issa GC, et al. Cell 2011; 146:904.

40 Additional Targeted Therapies in Development
KSP inhibitors (Array 520) AKT inhibitor (GSK agent) Nuclear transport inhibitors (KPT) CDK inhibitors

41 Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Development of Rationally-based Combination Therapies (HDAC and Proteasome Inhibitors) Protein Ub protein aggregates (toxic) Ub Ub Ub Ub 26S proteasome HDAC6 Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912 Ub Panibinostat, Vorinostat, ACY1215 HDAC6 dynein Ub Lysosome Aggresome HDAC6 Ub Ub dynein Microtubule Autophagy Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:

42 PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)
VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MM The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM Significant improvement in response rate ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001) PFS and TTP were prolonged in the combination arm compared with bortezomib alone PFS hazard ratio reduction of 23% (P=0.01); months (6.9–8.4) versus 6.83 months (5.7–7.7) Diarrhea, fatigue, and thrombocytopenia limited tolerability Dimopoulos et al. ASH 2011, Lancet Oncology, in press 42 42

43 Bench to Bedside Translation of HDAC 6 Selective Inhibitor ACY 1215
Orally bioavailable, highly potent, selective inhibitor of HDAC 6 synthesized in fall 2009 Synergistic MM cytotoxicity with Bortezomib in vitro and in vivo Favorable PK/PD, toxicity profile Phase Ia/Ib/II clinical trials of ACY1215, alone and with Bortezomib and with lenalidomide/dexamethasone, ongoing; trials with pomalidomide and carfilzomib this year. Santo et al. Blood 2012;119:

44 Mutations in Myeloma 19 Patients Each With Newly Diagnosed and Relapsed MM
Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1, EIF3B, XBP1, LRRK2 NF-kB signaling: 10 point mutations, 4 additional structural re-arrangements affecting coding Confers bortezomib sensitivity Histone methylating enzymes: WHSC1, UTX, MLL BRAF: 4% activating : Single patient MM response Andrulis et al Cancer Discovery 2013; 3: PSMB5 b5 proteasome subunit mutation confers proteasome inhibitor resistance in laboratory, not identified in clinic Lichter et al Blood 2012: 120: Chapman et al. Nature 2011; 471:

45 (Munshi et al, ASH 2011 Abstract 276)
Whole Genome Sequencing Identifies Acquisition of New Changes in MM: 71 Patient Study (Munshi et al, ASH 2011 Abstract 276) New mutations in late sample Early mutationnot in late sample Early Tumor Late Tumor Early Tumor Late Tumor EARLY LATE

46 Relapsed Refractory Myeloma
Lenalidomide dexamethasone, bortezomib, and pegylated doxorubicin are approved regimens for relapsed MM. Pomalidomide/dex and carfilzomib are newly FDA approved options. There are many promising protocols of novel immune and targeted agents which show promise, alone and in combination. 4. Genomic analyses are both defining the basis for evolution underlying relapse and identifying new targets.

47 United Nations Against Myeloma: Bench to Bedside Research Team
Kenneth Anderson Nikhil Munshi Paul Richardson Robert Schlossman Irene Ghobrial Steven Treon Jacob Laubach Deborah Doss Kathleen Colson Mary McKenney Kim Noonan Tina Flaherty Kathleen Finn Muriel Gannon Stacey Chuma Janet Kunsman Diane Warren Carolyn Revta Andrea Freeman Alexis Fields Andrea Kolligian John Feather Farzana Masood Nora Loughney Heather Goddard Tiffany Poon Nicole Stavitzski Ranjit Banwait Shawna Corman Meghan Marie Leahy Caitlin O’Gallagher Christina Tripsas Karin Anderson Shannon Viera Katherine Redman Amber Walsh Samir Amin Wanling Xie Parantu Shah Holly Bartel Lisa Popitz Jeffrey Sorrell Teru Hideshima Constantine Mitsiades Dharminder Chauhan Noopur Raje Yu-Tzu Tai Ruben Carrasco James Bradner Gullu Gorgun Jooeun Bae Francesca Cottini Michele Cea Antonia Cagnetta Teresa Calimeri Edie Weller Ajita Singh Ze Tian Diana Cirstea Yiguo Hu Naoya Mimura Jiro Minami Sun-Yung Kong Weihua Song Douglas McMillin Catriona Hayes Steffen Klippel Jana Jakubikova Panisinee Lawasut Niels van de Donk Eugen Dhimolea Jake Delmore Hannah Jacobs Masood Shammas Mariateresa Fulciniti Jianhong Lin Jagannath Pal Samantha Pozzi Loredana Santo Claire Fabre Anuj Mahindra Rao Prabhala Puru Nanjappa Michael Sellito Avani Vaishnav Greece USA Japan Taiwan UK Canada Turkey India Germany Australia Italy Austria Ireland Israel China

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