Multiple Myeloma: What are the Optimal Therapies in...
Transcript of Multiple Myeloma: What are the Optimal Therapies in...
Multiple Myeloma: What are the Optimal Therapies in 2016?
12th Annual California Cancer Consortium Conference
Aaron Rosenberg MD, MSAssistant Professor of Medicine
University of California, Davis School of MedicineUniversity of California, Davis Comprehensive Cancer Center
17th Annual Advances in OncologySeptember 30-October 1, 2016
Sacramento, CA
Aaron Rosenberg, M.D.Multiple Myeloma: What are the Optimal
Therapies in 2016?
No relevant financial relationships in the past twelve months by presenter or spouse/partner.
The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.
UC Davis Comprehensive Cancer Center
Disclosures
• No Financial Disclosures• I will discuss some off-label therapies within
the context of recently reported data• Some slides have been provided by Celgene
UC Davis Comprehensive Cancer Center
Outline
• Current “Standard” Approaches• Review newly approved agents:
– Ixazomib– Daratumumab– Elotuzumab– Panobinostat
• New tactics?– PDL-1– CAR T-cells
UC Davis Comprehensive Cancer Center
Unabated Progress in Survival
http://seer.cancer.gov/faststats accessed 4/22/16Kyle RA, Rajkumar VS, Blood 2008; 111 (6): 2962
1969: Melphalan/Prednisone
1947: Urethane
1958: Melphalan
1983: 1st Autologous Stem Cell Transplants
1999: Thalidomide
2003: Bortezomib
1962: Single Agent Steroids
2006: Lenalidomide
2013: Pomalidomide
2012: Carfilzomib
2010: Zolendronic acid1996: OS Benefit From Autologous Stem Cell Transplant
2015: Panobinostat
2015: Ixazomib
2015: Elotuzumab
2015: Daratumumab
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Front-Line Therapy: RD vs RVD
• SWOG S0777• Randomized phase III trial
– RVD (21 d): R: 25 mg, d1-14; D: 20 mg d 1,2, 4,5, 8,9, 11,12; V: 1.3mg/m2 1,4, 8, 11
– Rd (28 d): R: 25 mg d1-21; D: 40 mg, d 1, 8, 15, 22
• Patients treated until progression, toxicity– 525 patients
• Women and older patients less likely to get RVd
Durie et al, ASH 2015, Abstract #25
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RVd Wins
RVd (n=242) Rd (n=232)Progression Free Survival
43 months 31 months
1-sided log-rank P= 0.007Overall Survival Not Reached 63 months2-sided log rank P = 0.01
Durie et al, ASH 2015, Abstract #25
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ASH 2015: CyBorD now DOA? Author Abstract # Details
Jimenez-Zepeda 1845 • Retrospective cohort study comparing CyBorD vs Rd• Transplant ineligible• Baseline characteristics fairly well balanced• Response: 23% (CyBorD) vs 28% (Rd), CR 32% vs
38%• Median OS: CyBorD 40 months vs Rd 66 month
(p=0.12)
Cornell 396 • CIBMTR Study of post-autologous HSCT patients• CyBorD 12%, RVD 39%• No effect of primary treatment on outcome as a
whole, however PFS improved with RVd (HR 0.68, p=0.04)
Moreau 393 • Prospective, randomized comparison: VTD vs CyBorD
• Primary Endpoints: response rate• CR rates similar, VGPR and PR rates higher in VTD
arm
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Relapsed Myeloma
• What are the options– Carfilzomib + Dex ORR ~ 20-25%– Polmalidomide + Dex ORR ~ 30-35%
• + Biaxin ~50%
– Carlifzomib + Polmalidomide +Dex ORR ~ 50%– Bortezomib + Panabinostat + Dex ORR ~ 30-35%– Carlifzomib + Lenalidomide + Dex ORR ~87%
• PFS 23mo + improved OS vs Rd
Siegal DS et al Blood 2012, Dimopoulus MA et al, ASH 2013, Ab# 408, Rossin A et al ASH 2012, Ab# 8036,
Shah JJ et al ASH 2013, Richardson PG et al Blood 2013, Stewart KA et al NEJM 2015
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Carfilzomib/ Lenalidomide/ Dexamethasone:Effect of Prior Len Exposure
ASPIRE Trial: 20% prior lenalidomide exposure
Wang et al: 73% prior lenalidomide exposure
• ORR 77%, median PFS 15.4 months
• Among lenalidomideexposed:– ORR 70%– PFS 8 months
Stewart KA et al NEJM 2015, Wang et al Blood 2013
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Ixazomib
• Oral proteasome inhibitor• FDA Indication: treatment of multiple
myeloma in combination with lenalidomideand dexamethasone in patients who have received 1 prior therapy
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TOURMALINE-MM1: Design
Randomization1:1
- 28 Day Cycles- Ixazomib 4mg PO d1, 8, 15- Lenalidomide 25mg PO d1-21- Dexamethasone 40mg PO weekly
- 28 Day Cycles- Placebo PO d1, 8, 15- Lenalidomide 25mg PO d1-21- Dexamethasone 40mg PO weekly
Moreau et al, NEJM 2016
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TOURMALINE-MM1: PFS
Moreau et al NEJM 2016
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TOURMALINE-MM1: High Risk Cytogenetics
Moreau et al, NEJM 2016
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Daratumumab
• Anti-CD38 antibody (IgG Kappa)• FDA indication: relapsed/refractory after at
least 3 prior lines of therapy including an imidand a proteosome inhibitor or are double refractory to imids/proteosome inhibitors
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SIRIUS: Study Design/Flow
Lonial et al, Lancet 2016
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SIRIUS: Response Rates
Lonial et al, Lancet 2016
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Sirius: SurvivalMedian PFS: 4 mo12 months OS: 65%Median OS:
Responders: Not reached
Non-Responders: 14 months
Lonial et al, Lancet 2016
Progression Free Survival
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CASTOR Trial
Patients Relapsing after ≥ 1 prior therapy
Bortezomib/ DexamethasoneX 8 cycles
Dartumumab/Bortezomib/ DexamethasoneX 8 cycles
R
Palumbo, NEJM 2016
Indefinite Dartumumab
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Primary Endpoint: PFSOverall Response Rate- Bortez/Dex: 63%- Dara/Bortez/Dex: 82%
Palumbo, NEJM 2016
Phase 1b Trial of DARA, POM and DEX Trial in RRMM: Response
DARA + POM + DEX(N = 75)
n, % 95% CIORR (≥ PR), n (%) 53 (71) 59.0-80.6Best response
sCR 4 (5) 1.5-13.1CR 3 (4) 0.8-11.2VGPR 25 (33) 22.9-45.2PR 21 (28) 18.2-39.6MR 2 (3) 0.3-9.3SD 17 (23) 13.8-33.8PD 0.8-11.2
≥ VGPR 32 (43) 31.3-54.6≥ CR 7 (9) 3.8-18.3
CR, complete response;; DARA, daratumumab; DEX, dexamethasone; MR, minimal response; ORR, overall response rate; PD, progressive disease; POM, pomalidomide; PR, partial response; RRMM, relapsed/refractory multiple myeloma; sCR, stringent complete response, SD, stable disease; VGPR, very good partial response.Chari A, et al. Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. ASH 2015, abstract #508.
• ORR was 71%• ORR in double refractory
pts was 67%• Clinical benefit rate (≥ MR)
was 73%• Median time to first
response was 1.2 months• At median time of 4.2
months– Median time to best
response was 2.8 months– Responses are deepening
over time– 47 of 53 of responders
(89%) had not progressed
ASH 2015 Update, Courtesy of Celgene
UC Davis Comprehensive Cancer Center
Elotuzumab
• Anti-SLAM F7 antibody (IgG)• FDA Indication: in combination with
lenalidomide/dexamethasone for patient relapsing after 1-3 prior therapies
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ELOQUENT-2
Lonial et al, NEJM 2015
Randomization
Lenalidomide 25 mg d1-21Dexamethasone 40 mg weeklyElotuzumab 10mg/kg IV
- weekly for 8 weeks- Every other week
Lenalidomide 25 mg d1-21Dexamethasone 40 mg weekly
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ELOQUENT-2: PFS
Lonial et al, NEJM 2015
ELOQUENT-2 Phase 3 Trial of ERd vs Rd in RRMM: OS
ERd, elotuzumab, lenalidomide, and dexamethasone; HR, hazard ratio; NE, not evaluable; OS, overall survival; Rd, lenalidomide and dexamethasone; RRMM, relapsed/refractory multiple myeloma.Dimopoulos MA, et al. Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/RefractoryMultiple Myeloma: 3-Year Safety and Efficacy Follow-up. ASH 2015, abstract #28.
• Prespecified interim analysis for overall survival indicates a strong trend (P = .0257) with early separation sustained over time for ERd vs Rd
ASH 2015 Update, Courtesy of Celgene
ELOQUENT-2 Trial: ERd vs Rd in RRMM Subsets Overall Survival in Subgroups
a ISS stage II or III, t(4;14)+, or del(17p)+. b ISS stage I or II; t(4;14)−, del(17p)−, or 1q21−; age < 55 yrs. c ≥ 1 cell del(17p)+. BORT, bortezomib; ERd, elotuzumab, lenalidomide, and dexamethasone; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; NE, not estimable; OS, overall survival; Rd, lenalidomide and dexamethasone; RRMM, relapsed/refractory multiple myeloma.Lonial S, et al. ELOQUENT-2 Update: Phase 3 Study of Elotuzumab + Lenalidomide/Dexamethasone vs Lenalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma—Identifying Responders by Subset Analysis. ASCO 2016, abstract #8037. ASCO 2016 Update, Courtesy of Celgene
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Panobinostat
• Pan-histone deacetylase inhibitor• FDA Indication: relapsed/ refractory myeloma
after at least two prior therapies, including bortezomib
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Re-Analysis of PANORAMA-1
Richardson et al, Blood 2016
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Relapsed MM – Fit Patients
Carfilzomib/Rev/Dex(KRd)
Clinical Trials
Fit? Yes Personalize to Patient
and Situation
No
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What do I Mean Personalize?!My take on existing/available treatments
Patient Factors Therapeutic Choice
All Patients CLINICAL TRIALTolerating therapy, wants an all-oral regimen
Biaxin/Pomalidomide/Dex
Needs a break from infusion center/ intolerant of imids
Daratumumab
Pom refractory Cytotoxic (Bendamustine, Doxil) based regimen
High risk cytogenetics:del(17p), t(4;14)
Wants an all oral regimen
Triplet therapyIxazomib based therapy
No prior/remote Lenalidomide exposure
Elo-Len-Dex
Physically fit, no prior cardiac disease, multiply refractory
Panobinostat/Bortezomib/Dex
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Drug Specific Management Issues and Challenges
ixazomib • Nausea/vomiting and diarrhea, esp during first 3-4 cycles• Approved for use with lenalidomide
daratumumab • Long infusions during first treatments• Infusion reactions in ~50% of patients• Monoclonal Antibody (IgG Kappa) Interferes with
SPEP/Immunofixation
elotuzumab • No single agent activity – needs to be paired with imid• Pairing with bortezomib has not been approved• Infusion reactions uncommon (10%)• GI and liver toxicity seen• Monoclonal Antibody (IgG Kappa) Interferes with
SPEP/Immunofixation
panobinostat • 30% stopped treatment due to AE• Arrhythmia• diarrhea• Hepatotoxicity
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NEW AGENTS COMING DOWN THE PIPELINE
UC Davis Comprehensive Cancer Center
New Drugs/ treatments in Development (curated list)
• PD1 inhibitors (in combtination)– Pembrolizumab– MPDL3280A
• Anti-CD 38 antibodies– Isatuximab
• Proteosome inhibitors– Oprozomib– Marizomib
• Anti-BCL2– Venetoclax
• CAR-T Cells
UC Davis Comprehensive Cancer Center
Pembrolizumab
• Keynote-23 presented at ASCO 2016– Pem 200 mg every other week– Lenalidomide 26mg– Dex 40 mg weekly– Toxicity included tumor lysis syndrome (despite 96%
prior lenalidomide exposure)– ORR: 50% overall, 38% in lenalidomide refractory
• Two Phase III Trials Ongoing:– Keynote 183 (relapse/refractory) – Keynote 185 (newly diagnosed)
UC Davis Comprehensive Cancer Center
Pembrolizumab + Pom/DexASH abstract 506
ASH Abstract 506, Badros et alSlide Courtesy of Dr. Badros
Day 1 Day 7 Day 14 Day 21
Pembrolizumab 200 mg IV 1st 6 patients treated on day 1 only
x x
Pomalidomide 4 mg orally
Dexamethasone 40 mg Orally20 mg for patients > 70 yr. old
x x x x
- Cycles are repeated every 28 days for responding/stable pts
- After 24 months; responding patients can continue pomalidomide and dexamethasone alone until progression.
Baseline Patients’ DemographicsCharacteristic N=33
Age – yrMedian (Range) 65 (42-81)
Sex – no. (%)MaleFemale
24 (73%)9 (27%)
Race – no (%)CaucasiansAfrican AmericansOthers (Hispanic, Asian)
17 (52%)13 (39%)3 (9%)
Isotype – no.(%)IgGIgALight chain
18 (55%)7 (21%)8 (24%)
LDH – Median (range) 415 (148- 4800)
Cytogenetics – no. (%)High risk [del 17p, t(4:14) and/or t(14:16)]del 13q1q+
14 (42%)16 (48%)23 (70%)
ASH Abstract 506, Badros et al, Slide Courtesy of Dr. Badros
Best Response to Treatment (IMWG Criteria)Evaluable Pts (n=27)
AllN=27
Double refractoryN=20
High risk cytogeneticsN=12
ORR (≥ PR), %sCRCRVGPRPR
104
11
0029
0015
Stable Disease 8 (30%) 6 (30%) 5 (42%)
Progressive disease 3 (10%) 3 (15%) 1 (8%)
60% 55% 50%
ASH Abstract 506, Badros et al, Slide Courtesy of Dr. Badros
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CAR-T Cells: anti-CD19
Garfall et al NEJM 2015
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CAR-T Cells: Anti BCMA
• Phase I Dose Escalation• At highest dose level, both patients
responded, including 1 stringent complete response
Ali et al, ASH 2015 abstract LBA-1