multiple myeloma highlights: 2016 ash annual meeting ... · 5 slides multiple myeloma highlights:...

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SLIDESMultiple Myeloma Highlights:

2016 ASH Annual Meeting Patient Webinar

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Multiple Myeloma Highlights: 2016 ASH Annual Meeting Patient Webinar

January 11, 2017

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Welcome and Introductions

Anne Quinn Young, MPHSenior Vice President, Marketing & Communications

Multiple Myeloma Research Foundation

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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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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 induction, consolidation, and maintenance therapies before and 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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• 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.

MMRF CoMMpassSM Study

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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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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); MM, multiple myeloma; Revlimid (lenalidomide), and dexamethasone; Rd, Revlimid (lenalidomide) and dexamethasome; SMM, smoldering multiple myeloma.

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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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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; OS overall survival; PFS, progression-free survival; 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, but safety and

efficacy remain open questions

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Summary



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Relapsed/Refractory Multiple Myeloma



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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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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


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


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.


to VEL

DARA + VEL + DEX (DVd)

VEL + DEX (Vd)


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 PFS and 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; OS, overall survival; PFS, progression-free survival.

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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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Venclexta® (Venetoclax) + Velcade(Bortezomib)

• Venclexta® (Venetoclax; 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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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

Venclexta Results

DEX, dexamethasone; ORR, objective response rate; RRMM, relapsed/refractory multiple myeloma; VEL, Velcade(bortezomib); VEN, Venclexta (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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• 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 REV 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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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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• 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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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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Summary



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Question & Answer



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



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Resources for You!

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