Ruben Niesvizky Myeloma Center Myelomacenterorg run9001medcornelledu Multiple Myeloma Natural History of Disease Durie B International Myeloma Foundation Concise review of the disease and treatment options multiple myeloma 20112012 edition ID: 499729
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Slide1
Relapsed and Refractory Myeloma
Ruben Niesvizky
Myeloma CenterMyelomacenter.orgrun9001@med.cornell.eduSlide2
Multiple Myeloma: Natural History of Disease
Durie B; International Myeloma Foundation.
Concise review of the disease and treatment options: multiple myeloma. 2011/2012 edition;
Kumar SK, et al.
Mayo
Clin
Proc
. 2004;79:867-74.
M-Protein Level
MGUS or Indolent
Myeloma
Active
Myeloma
Remission
Relapse
Frontline
Therapy
Second- or Third-Line Therapy
Remission duration decreases with each line of therapy
//
//
Asymptomatic
Symptomatic
Relapsing
RefractorySlide3
OutlineApproach to the patient with RRMM:Evidence based Factors to be considered in selecting therapyProteasome inhibitorsInmunomodulatory
AgentsHDAC inhibitorsAlkylating agentsSlide4
Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period
Aggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior
IMiD, bortezomib-based therapy)Slide5
Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period
Aggressiveness of relapseRelapsed or relapsed and refractory disease“
High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)Slide6
Response Duration Decreases With Successive Therapies578 patients; median age 65 years (follow up 55 months)Overall survivalOne year 72%Two years 55%Three years 22%
84% died within five years
Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.Slide7
APEX: Bortezomib
Early or Late Relapse
Bortezomib1 prior therapy
n = 132
> 1 prior therapy
n = 200 Median TTP (months)7.04.9 CR (%) 10%*7%† CR + PR (%) 51%*37%† Median Duration of Response (months)8.17.8 1-year Survival
89%
73%
*
Evaluable patients, response to bortezomib after 1 prior therapy: n = 128
†
Evaluable patients, response to bortezomib after >1 prior therapy: n = 187
Sonneveld P, et al. Haematologica. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium Pharmaceuticals, Inc.Slide8
Time to Progression Overall Survival
2
nd Line (LenDex)Median 17.1 months≥ 3th line(LenDex
)Median 10.6 months
2
nd Line (LenDex)Median 42 months ≥ 3th line(LenDex)Median 35.8 monthImproved Outcomes with the Early Use of LenDex : TTP and OSStadmauer EA et al. Eur J Haematol 2009; 82:426-32Slide9
Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period
Aggressiveness of relapseRelapsed or relapsed and refractory disease“
High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)Slide10
Kumar SK, et al.
Bone Marrow Transplant
. 2008;42:413-420.Time to Progression After SCT Correlates With OS After Initial RelapseSlide11
Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapy
Plateau phase=quiescent period Aggressiveness of relapseRelapsed or relapsed and refractory disease“
High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)Slide12
Frontline vs Relapsed Refractory
Response to Therapy Survival Outcomes
Toxicities and Co-morbiditiesToxicities and Co-morbiditiesResponse to Therapy Survival OutcomesTreatment Naive
Relapsed and Refractory
High risk features Genomic instabilitySlide13
Relapsed /Refractory
Outcomes in Relapsed and Refractory Multiple Myeloma
Adapted from:
Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.Jagannath
S.
Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156. Relapsed FrontlineTreatmentExpectedsurvival (months)20-50Sensitivity totherapySensitiveTreatment limitations/comorbiditiesPeripheral neuropathy (~15% at diagnosis)14-16Less Sensitive/Resistant>80% incidence of peripheral neuropathyCompromised marrow reserveCytopenia
6-10
Resistant
Intolerant to or
ineligible for available therapy
Elderly population
(
risk for heart, lung, renal, liver dysfunction, diabetes)Slide14
Nature of RelapseHow did the patient present?80% share clinical features with presentationHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapse
Extra medullar diseaseSlide15Slide16
Nature of RelapseHow did the patient present?80% share clinical features with presentation35% relapse both light chain and intact Ig
49.6% intact Ig10% free light chain onlySlide17
Survival according to paraprotein and FLC secretion at first relapse.
Brioli A et al. Blood 2014;123:3414-3419
©2014 by American Society of HematologySlide18
Survival from relapse according to
paraprotein
and FLC secretion at relapse for patients with
IgG
and IgA
paraproteins. Brioli A et al. Blood 2014;123:3414-3419©2014 by American Society of HematologySlide19
Nature of RelapseHow did the patient present?80% share clinical features with presentation
35% relapse both light chain and intact Ig49.6% intact Ig
10% free light chain onlyHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapseExtra medullar diseaseSlide20Slide21
Progression-free survival according to the presence of
extramedullary
(EM) involvement at diagnosis.
Varettoni M et al. Ann Oncol 2009;21:325-330
© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgSlide22
Outcome according to baseline PET/CT.
Zamagni E et al. Blood 2011;118:5989-5995
©2011 by American Society of HematologySlide23
Patient Heterogeneity Slide24
Clinical Considerations for Relapsed/Refractory DiseaseToxicity considerationsPeripheral neuropathyThrombotic risk
MyelosuppressionImpact of prior therapies (eg, SCT, other cumulative toxicity)Slide25
ANY PROGRESS?
Kumar et al. Blood. 2008
Brenner et al. Blood. 2008
Overall survival in 6-year intervals from time of diagnosis
Time (months)
Proportion of patients
0
0.2
0.4
0.6
0.8
1.0
0
20
40
60
80
100
120
140
2001
–
2006
1995
–
2000
2001
–
2006
1989
–
1994
1983
–
1988
1977
–
1982
1971
–
1976Slide26Slide27
Kumar et al: Leukemia Nov 2013
> 65 años
< 65 añosSlide28
Bortezomib
Carflizomib
Ixazomib
Oprozomib
Proteosome
InhibitorsSlide29
Proteasome InhibitorsOutcomes Correlate with Depth of ResponseSlide30
Quality of Response: Survival
Niesvizky et al.,
Br J Haematol. 2008 Oct;143(1):46-53
Slide31
Proteasome InhibitorsBenefits of RetreatmentSlide32
Bortezomib Retreatment
– A Retrospective Multicenter Survey
Retrospectively collected data- multicenter non-interventional survey of pts who received bortezomib for a second time (retreatment) Patients: 65 pts,19 centers; median age 65 yrsHrusovsky I, et al. ASH 2007, abstract #2720Results:
49 evaluable (modified ITT)
Bortezomib mg/m
2InitialRe-treatment1.394%86%1.02%12%other8%4%+ Dex39%61%
Median 4 prior therapies
Retreatment
Initial
bortezomib
Diagnosis
52 mos
Mean of 5 cycles
Mean of 4 cycles
6 pts received additional therapy
Best Response
months
Patients (n)
Treatment Outcomes
Safety:
AE occurring in > 2 patients
Retreatment
Median
% Patients
Treatment receivedSlide33
Petrucci
et al, Br J Haem
2013,160,649-659Slide34
Petrucci
et al, Br J Haem
2013,160,649-659Slide35
Proteasome InhibitorsCarflilzomibSlide36
Carfilzomib IV on days 1, 2, 8, 9, 15 and 16 every 28 days
20 mg/m
2 in Cycle 1 and 27 mg/m2 from Cycle 2 and beyond (maximum 12 cycles)Study 003-A1: Open-Label Phase 2b Study of Single-Agent Carfilzomib in Relapsed and Refractory Multiple Myeloma (R/R MM)
Primary endpoint: ORR IMWG response criteria (IRC assessed)
Secondary endpoints
CBR (ORR+ MR), DOR, OS, PFS, TTP, safetySiegel D, et al. Blood. 2012;120:2817-25.Study Population (N=266)Relapsed from ≥2 prior lines of therapyMust include bortezomibMust include thalidomide or lenalidomideRefractory to last regimenCBR = clinical benefit rate; DOR = duration of response; IMWG = International Myeloma Working Group; IRC = Independent Review Committee; MR = minimal response; ORR = overall response rate; OS = overall survival; PFS = progression-free survivalSlide37
Single-Agent Carfilzomib: Response Rates
*IRC-determined; 11 patients had unconfirmed response
Percentage of PatientsORR = 24%
CBR =
37%
DCR = 69%TTR: 1.9 mo (≥PR) and 1.0 mo (≥MR)DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)Subset analyses of higher risk populations showed similar response rates(e.g., unfavorable cytogenetics, baseline peripheral neuropathy)Siegel D, et al. Blood. 2012;120:2817-25.N = 257 response-evaluable populationCR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; TTR = time to response; VGPR = very good partial responseSlide38
Single-Agent Carfilzomib: PFS, OSSiegel D, et al. Blood
. 2012;120:2817-25.
Proportion alive and without progression MonthsMedian PFS = 3.7 mo (95% CI 2.8–4.6)
1.0
0.8
0.60.40.20.00391218
6
15
Proportion surviving
Months
Median OS = 15.6
mo
(95% CI 13.0–19.2)0
312
21271.0
0.80.60.40.2
0.015
6
9
18
24
N = 257 response-evaluable populationSlide39
39Slide40
Phase II Trial of Carfilzomib Plus Len/Dex in R/R MM (1-3 prior lines of therapy)
Response (N = 52
pts receiving maximal planned dose)n (%)
ORR
Stringent CR
CRVGPRPRSD40 (77)2 (4)1 (2)19 (37)18 (35)3 (6)Median duration of response, mos (range)22.1 (9.5-38.0)Wang M, et al. Blood. 2013;122:3122-3128.Week 1Week 2Week 3Week 4: rest
Carfilzomib
20/27 mg/m
2
IV*
Dexamethasone
40 mg/d PO
Lenalidomide d1-d21
25 mg/d PO
D1/D2
D8/D9
D15/D16
D1
D8
D15
D22
*20 mg/m
2
cycle 1 days 1 and 2 only,
27 mg/m
2
thereafterSlide41
Phase III ASPIRE Trial: Carfilzomib + Len/Dex vs Len/Dex
in R/R MM (ongoing)
Study Population (N=780)Measurable disease1-3 prior regimensRelapse or PDResponse to ≥1 prior regimenExclusion factors:Bortezomib-refractory
Len/dex-refractoryPrior carfilzomib
CRdCarfilzomib27 mg/m2 IV day 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1, 2 of cycle 1 only)Lenalidomide25 mg Days 1-21Dexamethasone40 mg once weeklyRdLenalidomide25 mg Days 1-21Dexamethasone40 mg once weeklyStratify: Prior bortezomib, prior lenalidomide, β2 microglobulin levelPrimary endpoint: PFSAvailable at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed April 29, 2014.28-day cyclesPress release-PFS 26.3 vs 17.6 HR 0.69: Slide42
Phase 1b Study of High-Dose Carfilzomib + Dexamethasone in R/R MMBadros A, et al. ASH 2012. Abstract 4036.
Study population: N=22 (expanded 007 cohort)
Median prior regimens: 4Regimen: (28-day cycles)Carfilzomib 20/45 or 20/56 mg/m2 30-min IV D1,2,8,9,15,16Dexamethasone 20 mgD1,2,8,9,15,16 then 40 mg D22Endpoint
CFZ20/45CFZ20/56Total
ORR, %
575055CR, %000VGPR, %145025PR, %43030DORNRNRPFS, months5.46.0Treatment-emergent Grade ≥3 AE, %CFZ20/45CFZ20/56TotalHematologicThrombocytopeniaAnemiaLymphopenia292914502525362718NonhematologicHypertensionHypophosphatemiaPneumonia141470013999SafetyEfficacyCFZ = carfilzomibSlide43
Phase III ENDEAVOR: Carfilzomib + Dex vs Bortezomib/Dex in R/R MM1
ClinicalTrials.gov. Available at:
http://clinicaltrials.gov/ct2/show/NCT01568866. Accessed March 26, 2014.Vij R, et al. Blood. 2012;119:5661-5670.Study Population (N=888)
Measurable diseaseResponsive to at least 1 prior therapy
Relapsed
following 1-3 prior treatment regimensECOG PS 0-2CdCarfilzomib20/56 mg/m2 IV D1,2, 8, 9, 15, 16Dexamethasone20 mg PO or IV D1, 2, 8, 9, 15, 16, 22, 2328-day cycleVdBortezomib1.3 mg/m2 IV or SC D1, 4, 8, & 11Dexamethasone20 mg PO or IV D1, 2, 4, 5, 8, 9, 11, 1221-day cycleTreat until PD or unacceptable toxicityStratify: Prior PI, prior lines of therapy, ISS, bortezomib IV vs. SCPrimary endpoint: PFSNote use of higher carfilzomib dose—based on results from 004 trial, which suggested dose-response relationship of carfilzomib2Slide44
Novel PIs Under Investigation in R/R MM
Agent
StatusIxazomibTwo phase I studies showed activity of single-agent
ixazomib[2,3]
Oprozomib
Phase 1 dose-escalation study showed some activity in patients with heavily pretreated hematologic malignancies, including MM[4]Richardson PG, et al. ASH 2011. Abstract 302.Lonial S, et al. ASCO 2012. Abstract 8017.Kumar S, et al. ASCO 2013. Abstract 8514.Savona MR, et al. ASH 2012. Abstract 203.Slide45
Ixazomib: Oral Proteasome InhibitorSlide46
Ixazomib treatment duration and response.
Kumar S K et al. Blood 2014;124:1047-1055
©2014 by American Society of HematologySlide47
Proteasome InhibitorsOprozomibSlide48Slide49Slide50Slide51Slide52
OPomDex Study Design (Phase 1b)Slide53
Bortezomib
Carflizomib
Ixazomib
Oprozomib
Ub
Ub
Ub
Ub
Ub
Substrates
+
Thalidomide
Lenalidomide
Pomalidomide
Proteosome
Inhibitors
Immunomodulating
AgentsSlide54
Immunomodulating AgentsSlide55
Pomalidomide in Relapsed/Refractory Multiple Myeloma
POM + LoDEX
achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4Study
Phase
N
TreatmentPopulationMedian Prior Tx (Range)≥ PRLacy4260POM: 2 mg(28/28-day cycle)Dex: 40 mg/week1-3 prior Tx, relapsed/refractory2 (1-3)65%
2
34
POM:
2 mg
(28/28-day cycle)
Dex
: 40 mg/week
LEN-refractory4 (1-14)
32%
2
35POM: 2 mg (28/28-day cycle)DEX:
40 mg/weekLEN- and BORT- refractory
6 (3-9)26%
2
60
POM:
4 mg
(28/28-day cycle)
Dex
:
40 mg/week
1-3 prior
Tx
, LEN-refractory
2 (1-3)
37%
2
35
POM:
4 mg
(28/28-day cycle)
DEX:
40 mg/week
LEN- and BORT- refractory
6 (2-11)
29%
55
3. Lacy MQ et al.
Blood
. 2011;118:2970.
4. Lacy MQ et al.
Blood.
2011;118: Abstract 3963.
1. Lacy MQ et al.
J Clin Oncol.
2009;27:5008.
2. Lacy MQ et al.
Leukemia.
2010;24:1934.Slide56
Pomalidomide
Pts
, n
Median No. Prior Regimens
Refractory
to Recent Therapy (%)ORR (%)Pomalidomide ± dex119151002534Pomalidomide, dex2706NR2629Pomalidomide, dex3845
85
34
35Pomalidomide, cyclophosphamide, prednisone
4
32
NR (1 to 3)
44*59Pomalidomide
, dex, clarithromycin5
46NR (at least 3)
NR60
*Len specifically
4. Palumbo A et al.
Blood
. 2011;118. Abstract 632.Mark TM et al. Blood
. 2011;118. Abstract 635.
1. Vij R et al.
J Clin Oncol. 2012;30. Abstract 8016. 2. Lacy MQ et al.
Blood. 2011;118:2970.3. Leleu X et al. Blood. 2011;118. Abstract 812.Slide57
ClaPd:
Study Design
A single-center, phase 2 study of Clarithromycin combined with Pomalidomide + Low Dose Dexamethasone in RRMMp.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.
1 2 8 9 15 16 21 22 28
Day
Dex 40mg PODex 40mg PODex 40mg PODex 40mg POPomalidomide 4 mg POClarithromycin 500mg PO BIDSlide58
Clarithromycin???Slide59
Results
98 patients completed at least 1 cycle of
ClaPD.median number of cycles received was 6 (range 1–25)median study follow-up was 9.6 months (range 1.0–25.6)In responding patients, median time to PR was 1 cycle (range 1–7).Median time to best response was 2 cycles (range 1-14).
Best
Response (IMWG Criteria)
n (%)Overall(N = 98)ORR (≥ PR)56 (57)CBR (≥ MR)65 (66)sCR6 (6) VGPR 17 (17)PR33 (34)MR9 (9)SD 23 (23)PD 10 (10)IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.Slide60
Treatment History With Len/
Bort Did Not Influence Response to ClaPD
Best Response (IMWG Criteria)
n (%)
Overall
(N = 98)Lenalidomiderefractory(N = 83)BortezomibRefractory (N = 82)Lenalidomide and bortezomib refractory(N = 72)ORR (≥ PR)56 (57)47 (63)46 (56)39 (54)CBR (≥ MR)65 (66)56 (67)54 (65)(65)sCR6 (6) 6 (7)5 (6)5 (7)VGPR 17 (17)13 (16)13 (16)9 (13)PR33 (34)
28 (34)
28 (34)
25 (35)
MR9 (9)8 (10)
8 (10)
8 (11)
SD 23 (23) 18 (22)
19 (23)16 (22)PD 10 (10)
8 (12)9 (11)9 (13)
IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.Slide61
ResultsOS by cytogenetic risk
OS by double-refractory
state 0 200 400 600 800Time (days)Number of patients at risk Relapsed 41 26 16 10 0
Refractory 54 33 18 9 01.00
Survival (%)
0.750.500.250 0 200 400 600 800Time (days)1.00Survival (%)0.750.500.250Number of patients at risk Relapsed 26 18 13 6 0Refractory 74 44 23 14 0Not double-refractoryDouble-refractoryStandard riskHigh risk
Adverse
cytogenetics
did not appear to influence risk of death
as of last study follow-up.
HR 1.05, 95%CI (0.49,2.26),
P
= 0.888
A history of being double-refractory, however, approached a significant effect on survival time.
HR 2.67, 95%CI (0.93,7.69),
P
= 0.068Slide62
IFM 2010-02: Study design
N = 50
RRMM
Exposed to Len
del 17p and/or t(4;14)
Measurable diseaseECOG 0–2PNn > 1 x109/LPlat ≥ 75 x109/LHb ≥ 8 g/dLCrCl ≥30 mL/minPomalidomide4 mg/day, po, days 1–21 (of 28 d cycle)Dexamethasone40 mg, po, days 1, 8, 15, 22 Aspirin/LMWHonce daily, continuouslyUntil progressionSafety analysis by DMC after 15 patients recruited End-pointsPrimary: TTPSecondary: Safety, Response rate (CBR), DoR, OS, PFS, EFS, cytogenetic groupsMedian follow-up: 8.2 monthsn (%)n (%)
Progression
25 (69)
Death other cause
1 (3)
Toxicity
9 (25)
Sponsor decision
1 (3)
At data cut-off, 36 patients (72%) had discontinued trialSlide63
O/N
Median
95% CI
ITT population
33 / 50
2.9[2.7;5.0]8-month TTP, %22del17p12 / 22*7.3[2.7;14.7]8-month TTP, %41
t
(4;14
)
24 / 32*
2.8
[1.9;4.0]
8-month
TTP, %12.4
del17p
t(4;14)
ITT
IFM 2010-02: Time To Progression (ITT)Slide64
O/N
Median
95% CI
ITT population
26 / 50
12[4.9;15.5]8-month OS, %55del17p12 / 22*12[2.4;-]8-month OS, %58
t
(4;14
)
16 / 32*
9.2
[4.6;-]
8-month
OS, %50
IFM 2010-02: Overall SurvivalSlide65
Shah JJ, et al. Blood. 2013;122:690.
Phase I/II: Carfilzomib/Pomalidomide/
LoDEX (Car-Pom-d) in R/R MMCarfilzomib*20/27 mg/m2 (D1-2, 8-9, 15-16)
Pomalidomide*4 mg (D1-21)Dexamethasone*
40 mg weekly (20 mg after cycle 4)
*Dosing based on MTD established in phase 1Primary endpoint: ORR Secondary endpoints:DOR, TTP, PFS, time to next therapy, OSStudy Population (N=79)Relapsed and/or refractory measurable MMLenalidomide-refractory28-day cycles (cycles 1-6)CarfilzomibD1-2, 15-16 PomalidomideunchangedDexamethasoneunchangedMaintenance(cycles 7+)Treatment continued until PD or unacceptable toxicityAll patients received antiviral treatment and aspirin 81 mg or low molecular weight heparinSlide66
Car-POM-d in R/R MM: Efficacy
Cytogenetic Risk (by mSMART)
Response,
%
High
(n = 18)Intermediate (n = 19)Standard (n = 38)All Pts(N = 79)ORR78537470VGPR22263227PR56264243
Median PFS: 9.7
mos; median DOR: 17.7 months; median OS not reached
No significant difference in PFS or OS based on cytogenetics80% of pts with del(17p) were alive at 12 mos; 58% were progression-free
Shah JJ, et al.
Blood. 2013;122:690.Slide67
Bortezomib
Carflizomib
Ixazomib
Oprozomib
Ub
Ub
Ub
Ub
Ub
Substrates
+
Thalidomide
Lenalidomide
Pomalidomide
Romidepsin
Vorinostat
Panobinostat
Proteosome
Inhibitors
Immunomodulating
Agents
HDAC inhibitorsSlide68Slide69
Phase 2 trial of the histone deacetylase inhibitor romidepsin
for the treatment of refractory multiple myeloma
Niesvizky et al, CancerVolume 117, Issue 2, pages 336-342, 22 SEP 2010Slide70
Description
Regimen
NORR (> PR), %
HDAC Inhibitors
Romidepsin
+ bortezomib + dex[4]2560Vorinostat + bortezomib[5]14317Bortezomib + panobinostat + dex[6]5534.5HDAC Inhibitors in RRMMSlide71
Vorinostat Bortezomib
vs Placebo BortezomibDimopoulos et al,
Lancet Oncol. 2013 Oct;14(11):1129-40Vorinostat: Median PFS: 7·63 months (95% CI 6·87-8·40) Placebo: Median 6·83 months (5·67-7·73) (hazard ratio [HR] 0·77, 95% CI 0·64-0·94;p=0·0100).Slide72
PANORAMA 1: Phase III Trial of Panobinostat + Bortezomib + Dex
Study Population (
N=768)Relapse or relapsed/refractory MMBortezomib-refractory excluded1-3 prior lines of therapyPanobinostat
BortezomibDexamethasone
Placebo
BortezomibDexamethasonePrimary endpoint: PFSStratification based on prior lines of therapy, prior bortezomibRichardson PG, et al. ASCO 2014. Abstract 8510.Slide73
PANORAMA 1: Primary Endpoint Met (PFS)Slide74
Bortezomib
Carflizomib
Ixazomib
Oprozomib
Ub
Ub
Ub
Ub
Ub
Substrates
+
Thalidomide
Lenalidomide
Pomalidomide
Melphalan
Cyclophosphamide
Bendamustin
Romidepsin
Vorinostat
PanobinostatSlide75
Autotransplant for Refractory MM
PFS
OS
N = 66
Median = 11 mo
N = 66Median = 19 moSWOG Trial 8993Vesole DH, et al. J Clin Oncol. 1999;17:2173-2179. Slide76
PBSCT in Relapsed MM
Cook G et al,The Lancet Oncology, Volume 15, Issue 8, Pages 874 - 885, July 2014
TTP median HD Mel 19 months [95% CI 16—25]Cyclophosphamide 11 months [9—12]; hazard ratio 0·36 [95% CI 0·25—0·53]; p<0·0001).Slide77
A Phase 1 Study of Bendamustine and
Melphalan Conditioning for Autologous Stem Cell Transplant with Multiple Myeloma.Slide78
Dose Levels for Bendamustine
Dose Level
On Day 1 Melphalan (100mg/m2)
On Day 2 Melphalan (100mg/m
2
)130 mg/m2260 mg/m2390 mg/m2460 mg/m260 mg/m2
5
90
mg/m
260
mg/m2
6
125 mg/m
2100 mg/m2Slide79
Bortezomib
Carflizomib
Ixazomib
Oprozomib
Ub
Ub
Ub
Ub
Ub
Substrates
+
Thalidomide
Lenalidomide
Pomalidomide
Filanesib
Palbociclib
Melphalan
Cyclophosphamide
Bendamustine
Romidepsin
Vorinostat
Panobinostat
Elotuzumab
Daratumumab
SAR650984Slide80Slide81
The Team and Collaborators
Tomer
Mark MDMorton Coleman, MDRoger Pearse
, MDAdriana Rossi, MD
David
JayabalanKaren Pekle RNPArthur Perry PASusan Matthew, PhD Scott Ely, MD/MPHSelina Chen-Kiang, PhDMonica Guzman, PhDGiorgio Inghirami, MDLinda Tegnestam RNKathleen Pogonowski RNStanley Goldsmith MDMaureen Lane PhDPaul Christos Myelomacenter.org