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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
1
Multiple Myeloma Highlights: 2016 ASH Annual Meeting Patient Webinar
January 11, 2017
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Welcome and Introductions
Anne Quinn Young, MPHVice President, Development and Strategic Partnerships
Multiple Myeloma Research Foundation
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
3
David Siegel, MD, PhDJohn Theurer Cancer Center of
Hackensack University Medical CenterHackensack, NJ
Sagar Lonial, MD, FACPWinship Cancer Institute
of Emory University Atlanta, GA
Faculty
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Sagar Lonial, MD, FACPWinship Cancer Institute of
Emory University Atlanta, GA
CoMMpassSM, Smoldering Myeloma, Induction, and Stem Cell Transplants
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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Overall Trends in 2016
• MMRF CoMMpassSM Study to accelerate precision medicine
• Possible benefits of early treatment for high-risk smoldering MM (83% PR+)
• Role of consolidation and maintenance therapies after autologous stem cell transplant (ASCT) in newly diagnosed MM (NDMM)
• DarzalexTM (daratumumab) for early relapsed/refractory multiple myeloma (RRMM)
• Novel therapies for highly pretreated RRMM
– Keytruda® (pembrolizumab)
– selinexor
– chimeric antigen receptor T cells (CAR T cells), especially those directed against B-cell maturation antigen (BCMA)
PR+, partial response or better
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MMRF CoMMpassSM Study
• Longitudinal observational study with 1,000 patients+ worldwide
• Largest genomics data set of any cancer
• Database is publicly available for all researchers to access
• Next-generation RNA sequencing technologies can help identify high-risk MM patients
• MMRF’s CoMMpass-based research provides insight into cancer genomes with unprecedented detail
MM, multiple myeloma
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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MMRF CoMMpassSM Study
• A total of 19 studies1–19 were presented using data from the MMRF CoMMpassSM Study, covering such topics as:
– Best methods of genetic sequencing
– Specific chromosomal mutations found in MM
– Role of patient race in treatment patterns
– Outcomes in patients ineligible for clinical trials
– Individual genetic differences affecting a patient’s response to certain medications
1. Neri P et al. Blood 2016;128(22):120. 2. Miller A et al. Blood 2016;128(22):193. 3. Keats JJ et al. Blood 2016;128(22):194. 4. Misund K et al. Blood2016;128(22):355. 5. Lagana A et al. Blood 2016;128(22):357. 6. Miller C et al. Blood 2016;128(22):374. 7. Perumal D et al. Blood 2016;128(22):802. 8. D’Agostino M et al. Blood 2016;128(22):2079. 9. Scott AD et al. Blood 2016;128(22):2084. 10. Drusbosky L et al. Blood 2016;128(22):2099. 11. Gupta VA et al. Blood 2016;128(22):2108. 12. Fiala MA et al. Blood 2016;128(22):2349. 13. Fiala MA et al. Blood 2016;128(22):2350. 14. Benard BA et al. Blood2016;128(22):3279. 15. Lagana A et al. Blood 2016;128(22):3285. 16. Gruber F et al. Blood 2016;128(22):4406. 17. Connolly C et al. Blood 2016;128(22):4423. 18. Paulus A et al. Blood 2016;128(22):4432. 19. Necamp J et al. Blood 2016;128(22):4502.
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Smoldering Multiple Myeloma
• How do we identify smoldering MM (SMM)? – Calcium, renal, anemia, bone lesions (CRAB) criteria– Plasma cell infiltration– Free light chain assay– PET/CT imaging
• Who is at high risk for progression to symptomatic MM?
CT, computed tomography; MM, multiple myeloma; PET, positron-emission tomography.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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EmplicitiTM for High-Risk SMM
• EmplicitiTM (elotuzumab) – an anti-SLAMF7 monoclonal antibody
• Study goal:
– In high-risk SMM, can we delay or prevent progression to overt MM using early treatment with Empliciti (EM), Revlimid® (lenalidomide; REV), and dexamethasone (DEX) (combination called ERd), compared with REV and DEX (Rd)?1
• Rationale:
– Demonstrated benefits of Rd vs. no treatment in the SMM population2
– Demonstrated benefits of EM and REV in RRMM population3
1. Ghobrial IM et al. Blood 2016;128(22):976. 2. Mateos M et al. N Engl J Med 2013;369:438-447. 3. Lonial S et al. N Engl J Med 2015;373(7):621-31.
RRMM, relapsed/refractory multiple myeloma; SMM, smoldering multiple myeloma.
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Conclusion: There may be a shift towards redefining High risk SMM as MM
Empliciti for High-Risk SMM (cont.)
• Study is ongoing, but early results of ERd are encouraging– 82.6% had a partial response or better
– Safe and well tolerated in patients with high-risk SMM
• Long-term follow up is needed to determine whether ERd is better than observation or Rd alone in this population
1. Ghobrial IM et al. Blood 2016;128(22):976.
ERd, Empliciti (elotuzumab), Revlimid (lenalidomide), and dexamethasone; Rd, Revlimid (lenalidomide) and dexamethasome; SMM, smoldering multiple myeloma.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
11
Research Questions About NDMM
• Upfront ASCT is the standard of care in NDMM, but many patients relapse, even with complete response to ASCT
• Can ASCT outcomes be improved with:
– Double or “tandem” ASCT?
– Triplet therapy using an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) for induction (before transplant)?
– IMiD- and PI-based triplet therapy for consolidation (after transplant)
– Triplet therapy for BOTH induction and consolidation ?
ASCT, autologous stem cell transplant; NDMM, newly diagnosed multiple myeloma.
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Triplet Induction Therapy Before ASCT
1. Kazandjian D et al. Blood 2016;128(22):4527.
Conclusion: KRd-R induction/maintenance produced deep complete responses (CR) regardless of age or genetic risks
• Phase 2 study update: induction therapy with KRd followed by ASCT and 2 years of REV maintenance (KRd-R)
• Excellent results:
– Overall response rate (ORR) was 98%
– Progression-free survival (PFS) at 48 months was 82%
– Overall survival (OS) at 58 months was 86%
ASCT, autologous stem cell transplant; KRd, Kyprolis (carfilzomib), Revlimid (lenalidomide), and dexamethasone; KRd-R, Kyprolis(carfilzomib), Revlimid (lenalidomide), and dexamethasone followed by Revlimid maintenance; REV, Revlimid (lenalidomide).
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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Single ASCT vs. Double ASCT vs. Single Plus Consolidaton in NDMM
• StaMINA Phase 3 Trial – 3 study groups:
– Single ASCT with REV maintenance
– Double ASCT with REV maintenance
– Single ASCT followed by consolidation with bortezomib (Velcade®; VEL), REV, and DEX (VRd) and then REV maintenance
• Results: PFS and OS were very similar in all 3 groups
ASCT; autologous stem cell transplant; NDMM, newly diagnosed multiple myeloma; REV, Revlimid (lenalidomide).
1. Stadtmauer EA et al. Blood 2016;128(22):LBA-1.
Conclusion: Addition of VRd consolidation or a second ASCT was not superior to a single ASCT
followed by REV maintenance
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Triplet Therapy Before and After Transplantation (IFM Studies)
CR/sCR, complete response/stringent complete response; IRd, Ninlaro (ixazomib), Revlimid (lenalidomide), and dexamethasone; I, Ninlaro (ixazomib); KRd, Kyprolis (carfilzomib), Revlimid (lenalidomide), and dexamethasone; R, Revlimid (lenalidomide); VGPR, very good partial response.
Moreau1 Roussel2
Triplet therapy for both induction and consolidation
IRd KRd
Maintenance I R
Response rates (after consolidation)
VGPR or better 80% 92.5%
CR/sCR 44% 69%
1. Moreau P et al. Blood 2016;128(22):674. www.clinicaltrials.gov NCT01936532. 2. Roussel M et al. Blood 2016;128(22):1142.
Conclusion: IRd and KRd triplet therapy before and after transplant produced very good responses, Safety and
efficacy remain open questions
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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Relapsed/Refractory Multiple Myeloma
David Siegel, MD, PhDJohn Theurer Cancer Center of
Hackensack University Medical CenterHackensack, NJ
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CASTOR and POLLUX trials:DarzalexTM (Daratumumab) for RRMM
• 2016 approval based on CASTOR1 and POLLUX2 trials
– twin multicenter, phase 3, randomized, open-label controlled trials of DarzalexTM (daratumumab; DARA) for patients with RRMM and a median of 2 prior lines of therapy
• Initial results were presented at ASCO and EHA meetings in June 2016
– DARA resulted in >60% reduction in risk of disease progression or death in both studies
• New information: presentations at ASH 2016 examined different endpoints and broke down results within certain subgroups
1. Palumbo A et al. New Engl J Med 2016;375(8):754-766. 2. Dimopoulos MA et al. New Engl J Med 2016;375(14):1319-1331.
ASCO, American Society of Clinical Oncology; EHA, European Hematology Association; RRMM, relapsed/refractory multiple myeloma.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
17
Study Design of CASTOR and POLLUX
1. Palumbo A et al. New Engl J Med 2016;375(8):754-766. 2. Dimopoulos MA et al. New Engl J Med 2016;375(14):1319-1331.
• RRMM• ≥1 prior therapy• Not refractory
to LEN
• RRMM• ≥1 prior therapy• Not refractory
to LEN
DARA + REV + DEX (DRd)
DARA + REV + DEX (DRd)
REV + DEX (Rd)REV + DEX (Rd)
Endpoints:• PFS• OS, ORR, CR, VGPR• MRD• Time to progression• Time to response• Duration of response
Endpoints:• PFS• OS, ORR, CR, VGPR• MRD• Time to progression• Time to response• Duration of response
CR, complete response; DARA, Darzalex (daratumumab); DEX, dexamethasone; REV, Revlimid (lenalidomide); MRD, minimal residual disease; PFS, progression-free survival; ORR, overall response rate; OS, overall survival; RRMM, relapsed/refractory multiple myeloma; VEL, Velcade (bortezomib); VGPR, very good partial response.
• RRMM• ≥1 prior therapy• Not refractory
to VEL
DARA + VEL + DEX (DVd)
VEL + DEX (Vd)
Endpoints:• PFS• OS, ORR, CR, VGPR• MRD• Time to progression• Time to response• Duration of response
CASTOR
POLLUX
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Minimal Residual Disease and DARA
• Minimal residual disease (MRD) – more sensitive than traditional definitions of clinical response1,2
• MRD-negativity is associated with longer progression-free survival (PFS) and overall survival (OS) in NDMM patients1,2
– MRD may become a primary endpoint for clinical studies
• Results: DARA induced MRD negativity in over 3 times as many patients as standard of care regimens
1. Munshi NC et al. JAMA Oncol 2017;3(1):28-35. 2. Landgren O et al. Bone Marrow Transplant 2016;52(12):1565-8.
DARA, Darzalex (daratumumab); NDMM, newly diagnosed multiple myeloma.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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Conclusion: DARA was superior to the standard of care in all subgroups analyzed
DARA Outcomes by Subgroups
1. Mateos MV et al. Blood 2016;128(22):1150. 2. Usmani SZ et al. Blood 2016;128(22):1151.
• Two additional studies1,2 grouped the CASTOR and POLLUX results into subgroups of patients based on several factors, including:
– Number of prior lines of therapy (1 vs. 2–3)– High-risk cytogenetics– Refractoriness to prior lines– Treatment-free interval (time since last therapy)
DARA, Darzalex (daratumumab).
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Venetoclax + Velcade (Bortezomib)
• Venetoclax (Venclexta; VEN) – formerly known as ABT-199
– A BCL-2 inhibitor that is FDA approved for use in chronic lymphocytic leukemia
• Rationale: BCL-2 and MCL-1 both promote MM cell survival
– VEL inhibits MCL-1, while VEN inhibits BCL-2 – When used together, VEN enhances the efficacy of VEL
• Goal: MMRC phase 1b dose-escalation study of VEN + VEL + DEX in patients with RRMM to determine safety, efficacy, and optimal dose
1. Moreau P et al. Blood 2016;128(22):975. www.clinicaltrials.gov NCT01794507
DEX, dexamethasone; MM, multiple myeloma; RRMM, relapsed/refractory multiple myeloma; VEL (Velcade), bortezomib.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
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Conclusion: VEN + VEL + DEX has an acceptable safety profile and promising efficacy for RRMM, particularly in
patients with a t(11;14) gene mutation
• ORR was 68%, and 40% achieved VGPR or better
• Response rates were higher in those with no prior VEL treatment, those not refractory to VEL, and those with fewer prior lines of therapy
• Responses were better in patients with a t(11;14) gene translocation than in those without the mutation
– Can be used as targeted therapy for the t(11;14) high-risk subgroup
Venetoclax Results
DEX, dexamethasone; ORR, objective response rate; RRMM, relapsed/refractory multiple myeloma; VEL, Velcade(bortezomib); VEN, venetoclax; VGPR, very good partial response.
1. Moreau P et al. Blood 2016;128(22):975. www.clinicaltrials.gov NCT01794507
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• Patients (N = 9) had heavily pretreated RRMM– Median of 8 prior lines of therapy, including proteasome inhibitors (PIs),
immunomodulatory drugs (IMiDs), and ASCT
– Previously exposed to Pomalyst (pomalidomide; POM)
• Acceptable safety profile, with adverse events similar to those seen in other studies of Keytruda (pembrolizumab) and POM
• ORR was 33%; clinical benefit rate (3 PR, 2 MR, 3 SD) was 89%
Keytruda® (Pembrolizumab) + Pomalyst®
(Pomalidmide) + DEX
1. Wilson L et al. Blood 2016;128(22):2119.
ASCT, autologous stem cell transplant; CR, complete response; DEX, dexamethasone; MR, minimal response; PR, partial response; RRMM, relapsed/refractory multiple myeloma; SD, stable disease.
Conclusion: Results are promising; phase 3 studies of Keytruda (pembrolizumab) are now underway
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
23
• In an MMRC phase 1 study,1 selinexor (SEL) was combined with KyprolisTM
(carfilzomib; CFZ) and DEX in patients with RRMM and at least 2 prior treatment regimens
• Even in patients who were CFZ-refractory, response rates were strong:
– MR or better in 73%– PR or better in 64%– VGPR or better in 18%
• Similar results were seen in the phase 1b/2 STOMP2 trial, which used VEL as the PI instead of CFZ
Selinexor and Proteasome Inhibitors
1. Jakubowiak A et al. Blood 2016;128(22):973. 2. Bahlis NJ et al. Blood 2016;128(22):977. www.clinicaltrials.gov NCT02343042
DEX, dexamethasone; MR, minimal response; PI, proteasome inhibitor; PR, partial response; RRMM, relapsed/refractory multiple myeloma; SEL, selinexor; VEL, Velcade (bortezomib); VGPR; very good partial response.
Conclusion: Early clinical evidence suggests that SEL can overcome PI resistance in RRMM
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• The STORM trial used SEL for patients highly refractory to previous combinations
– All patients were at least “quad-refractory” to 2 IMiDs (both VEL and POM) and 2 PIs (both VEL and CFZ)
– Some patients were “penta-refractory” to both IMiDs, both PIs, plus 1 anti-CD38 antibody (DARA or isatuximab)
• ORR was 21% for quad patients and 20% for penta patients
• Clinical benefit rates (MR+) were 32% for all, 29% for quad, and 37% for penta
Selinexor for Highly Refractory MM
1. Vogl DT et al. Blood 2016;128(22):491.
CFZ, Kyprolis (carfilzomib); DARA, Darzalex (daratumumab); IMiD, immunomodulatory drug; MR+, minimal response or better; ORR, overall response rate; PI, proteasome inhibitor; POM, Pomalyst (pomalidomide); REV, Revlimid (lenalidomide); SEL, selinexor; VEL, Velcade (bortezomib).
Conclusion: SEL shows promising anti-tumor activity in the quad- and penta-refractory MM populations, and expansion of this trial is planned
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
25
Anti-BCMA Therapy: Preliminary Results
• B-cell maturation antigen (BCMA) – highly expressed on the surface of myeloma cells
• Ongoing phase 1 study of GSK2857916, a novel anti-BCMA antibody, conducted in 24 patients with RRMM
• Clinical benefit seen at higher doses (1 VGPR, 3 PR, 2 MR)
• Well tolerated with manageable adverse events; eye-related problems were most frequent reason for dose changes
1. Cohen AD et al. Blood 2016;128(22):1148. www.clinicaltrials.gov NCT02064387
MR, minimal response; PR, partial response; RRMM, relapsed/refractory multiple myeloma; VGPR, very good partial response.
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Anti-BCMA CAR T Cells
• Chimeric antigen receptor T cells (CAR T cells) – patient’s own T cells are genetically modified to express chimeric antigen receptors (CARs) directed at MM antigens
– After being genetically altered, cells are infused back into the patient
• BCMA is a promising target for CAR T cell activity
• Current study evaluated anti-BCMA CAR T cell infusion for treatment of advanced MM in heavily pretreated patients
BCMA, B-cell maturation antigen; MM, multiple myeloma.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
27
• Ongoing phase 1 trial studying anti-BCMA CAR T cells alone or with cyclophosphamide
– Patients had advanced RRMM, were IMiD and PI refractory, and had a median of 9 prior lines of therapy
• BCMA levels declined and correlated with depth of response
• Some severe toxicities were seen
• One patient showed anti-BCMA CAR T cell persistence, with ongoing stringent complete response at 7 months and MRD-negative bone marrow
Anti-BCMA CAR T Cells in MM: Design and Results
1. Cohen AD et al. Blood 2016;128(22):1147.
BCMA, B-cell maturation antigen, CAR T cells, chimeric antigen receptor T cells; IMiD, immunomodulatory drug; MM, multiple myeloma; MRD, minimal residual disease; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma.
Conclusion: Anti-BCMA CAR T cells show promising expansion and clinical activity
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Other Promising Studies on BCMA and CAR T cells
• A study in the preclinical evaluation stage is working on creating a treatment based on allogeneic (donor) anti-BCMA CAR T cells1
– CAR T cells that do not need to be custom made from each patient’s own cells could lead to an “off-the-shelf” immunotherapy for MM
• Other researchers showed that REV strengthens the anti-tumor activity of anti-CS1 CAR T cells in mice2
– Human trial planned using REV to enhance CAR T-cell activity
1. Boldajipour B et al. Blood 2016;128(22):381. 2. Wang X et al. Blood 2016;128(22):812.
BCMA, B-cell maturation antigen, CAR T cells, chimeric antigen receptor T cells; MM, multiple myeloma; REV, Revlimid(lenalidomide); RRMM, relapsed/refractory multiple myeloma.
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
29
Antibody (Target) Proteasome inhibitors
B-B4, DL101 (CD138) Marizomib*
Indatuximab (CD38) Oprozomib
Lucatumumab (CD40)
IPH-2101 (KIR) HDAC inhibitors
Atezolizumab (PD-L1)* ACY-2411
Durvalumab (PD-L1) Ricolinostat
Nivolumab (PD-1)
Novel Therapies to Watch For
* Drugs studied in the 1. Ray A et al. Blood 2016;128(22):382.
HDAC, histone deacetylase.
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Novel Therapies to Watch For (cont)
Drug Class Agents
SINE XPO1 antagonists KPT-86021
AKT inhibitor GSK21417952
MEK1/2 inhibitor Trametinib2,3
KSP inhibitors Filanesib (ARRY-520)*4
BTK inhibitors Ibrutinib*, AVL-292
CDK inhibitors PD0332991*, SCH727965, AT7519*
HSP90 inhibitors Ganetespib (STA-9090)*
FGFR3 inhibitor/antibodies TKI258*, MFGR1877S
Mutant B-Raf inhibitor Vemurafenib
1. Cornell RF et al. Blood 2016;128(22):4509. 2. Trudel S et al. Blood 2016;128(22):4526. 3. Qiang YW et al. Blood 2016;128(22):1138. 4. Ocio EM et al. Blood 2016;128(22):4503.
* Drugs studied in the
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
31
Question & Answer
David Siegel, MD, PhDJohn Theurer Cancer Center of
Hackensack University Medical CenterHackensack, NJ
Sagar Lonial, MD, FACPWinship Cancer Institute of
Emory University Atlanta, GA
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Closing Remarks
To learn more about the MMRF, please visit:www.multiplemyeloma.org
Anne Quinn Young, MPHVice President, Development and Strategic Partnerships
Multiple Myeloma Research Foundation
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SLIDESMultiple Myeloma Highlights:
2016 ASH Annual Meeting Patient Webinar
33
Resources for You!
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