s. vincent rajkumar professor of medicine mayo clinic€¦ · rajkumar sv. 2019 §car-ts...
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![Page 1: S. Vincent Rajkumar Professor of Medicine Mayo Clinic€¦ · Rajkumar SV. 2019 §CAR-Ts §Belantamab mafodotin (GSK2857916) §AMG 420/ AMG701 §Isatuximab §Iberdomide (CC-220) §Venetoclax](https://reader034.vdocuments.site/reader034/viewer/2022050522/5fa61e5c4dfbf542367cc9fb/html5/thumbnails/1.jpg)
Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center
Treatment of Multiple Myeloma in Transplant Ineligible Patients
S. Vincent RajkumarProfessor of Medicine
Mayo Clinic
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
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Disclosures
No conflicts to disclose
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The Last Decade
§ New Lab tests§ New Imaging
§ New Criteria(MDE)
Diagnosis
§ PET§ MRD
(NGF, NGS)
§ New Response Criteria (MRD)
Response
§ FISH§ GEP§ Molecular
methods
§ New Staging (RISS)
Prognosis
§ Carfilzomib§ Pomalidomide§ Panobinostat§ Ixazomib§ Elotuzumab§ Daratumumab
§ New Drugs§ (Abs)
Treatments
Rajkumar SV © 2019
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Risk Stratification of Myeloma
§ t(4;14) (FGFR3,MMSET)
§ t(14;16) (C-MAF)§ t(14;20) (MAF-B)
§ Trisomies* § t(11;14) (CCND1)§ t(6;14) (CCND3)
*~10% have both trisomies and IgH translocationsKumar S, et al. Blood. 2012;119:2100-2105
Disease Aggressiveness
Rajkumar SV © 2018
del 17p, p53 mutations, gain 1q
Dise
ase
Aggr
essi
vene
ss
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INITIAL THERAPY
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FIRST Trial: MPT vs Rd18 vs Rd till progressionKaplan–Meier Estimates of Progression-free Survival and Overall Survival
Benboubker L et al. N Engl J Med 2014;371:906-917.
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SWOG VRd vs RdEight 21-day Cycles of VRd
Bortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1-14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12
Six 28-day Cycles of Rd
Lenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22
RandomizationN = 525
Newly diagnosed MM
Stratification:• ISS (I, II, III)• Intent to
transplant @ progression (yes/no)
9
After induction; Both arms recevied Rd Maintenance Until PD, Toxicity or Withdrawal
Durie BGM, et al. ASH 2015
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Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X) Copyright © 2017 Elsevier Ltd Terms and Conditions
S0777 Trial: VRd vs Rd Progression-free Survival
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Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X) Copyright © 2017 Elsevier Ltd Terms and Conditions
S0777 Trial: VRd vs Rd Overall Survival
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Age >75
• SWOG S0777 trial VRd vs Rd• PFS and OS Age <65, 65–75, >75 years • VRd was superior in Age >75 years
• Median PFS 39 vs 20 months • Median OS 63 vs 31 months (P<0.05)
Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X)
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FRAILTY
• Factors– 3-drug vs 2-drug induction– Duration of therapy
important, even in elderly
http://www.myelomafrailtyscorecalculator.net
Palumbo. Blood. 2015;125:2068.
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Ran
dom
izat
ion
Inte
rmed
iate
Fit
(1:1
) Induction
*9x Rd
*Rd Continuous
Maintenance
RV-MM-PI-0752 Trial
Larocca, et al. Blood 2018 132:305
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Initial Treatment of Myeloma
Not Transplant Candidate
VRd x 9 months;Len maintenanceuntil progression
Frail PatientsRd x 1 year;
Len maintenance until progression
Rajkumar SV © 2019
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Key Questions
• Can we improve on the VRd triplet?• Carfilzomib based (eg., KRd)• Monoclonal Antibody based (eg., DRd)
• Should we use a quadruplet?• Cost• Toxicity
Rajkumar SV © 2019
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T Facon et al. N Engl J Med 2019;380:2104-2115.
MAIA TRIAL: DRd vs VRd
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M Mateos et al. N Engl J Med 2018;378:518-528.
Dara-VMP followed by Dara versus VMP (ALCYONE TRIAL)
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CLARION: KMP vs VMP: Overall Survival
0Months
KMPVMP
KMP(n=478)
107 (22.4)NE
VMP(n=477)95 (19.9)
NE
1.08 (0.82–1.43)Nominal 1-sided P=0.71
Death – n (%)Median OS – monthsHR for KMP vs VMP (95% CI)
12 18 24 366 30
478477
410411
367363
270264
1110
433428
127114
42
0
1.0
0.8
0.6
0.4
0.2
0Prop
ortio
n Su
rviv
ing
Number at risk:KMPVMP
• At the data cutoff date for the primary analysis of PFS (Jul 15, 2016), the HR for OS was 1.21
• In an updated evaluation of OS (Nov 4, 2016), the HR for OS was 1.08
Median follow-up time: 27.1 months for KMP and 26.3 months for VMPFacon T. IMW 2017
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eastern cooperative oncology group
VRd vs KRd
Accrual complete
E1A11: Phase III – Newly Diagnosed Myeloma*(PI: Shaji Kumar)KRd vs VRd
VRd x 12 cycles
KRd x 12 cycles
LenalidomideX 2 years
LenalidomideUntil prog
Continue therapytill prog. or toxicity
Continue therapytill prog. or toxicity
RANDOMIZATION
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Newly Diagnosed MM: TOURMALINE MM2
Placebo-Rd x 18 cycles
Ixa-Rd x 18 cycles
Ixa-RUntil prog
Placebo-RUntil prog
Continue therapytill prog. or toxicity
Continue therapytill prog. or toxicity
RANDOMIZATION
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Metrics
• Control Arm• VRd vs Rd• DRd vs Rd• ERd vs Rd• IRd vs Rd
• Adjudication• Number of
RCTs?• Hazard ratio?• Absolute length
of PFS?• Cost?• Convenience?• Endpoint?
Rajkumar SV © 2019
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Myeloma: Frontline Treatment
Not Transplant Candidate
VRd x 8-12 cyclesLen maintenance
orDRd until progression
Frail PatientsRd x 1 year;
Len maintenance until progression
*Based on S0777, MAIA, CASSIOPEIA Rajkumar SV © 2019
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Newly Diagnosed MyelomaTransplant Ineligible
High Risk MM in USA
?Quadruplet
Len not available
VTd
Acute renal failure
VCD
PCLEMD
?Quadruplet
OtherSituations
IRd
Rajkumar SV © 2019
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Active Drugs in Multiple Myeloma
§ Alkylators§ Steroids§ Interferon§ Anthracyclines
Old Drugs
§ Carfilzomib§ Pomalidomide§ Panobinostat
§ Ixazomib§ Daratumumab§ Elotuzumab§ Selinexor
Recently ApprovedDrugs (2013-2015)
§ Bortezomib§ Thalidomide§ Lenalidomide§ Liposomal
doxorubicin
Older Drugs(2003-2007)
Rajkumar SV. 2019
§CAR-Ts§Belantamab mafodotin (GSK2857916)§AMG 420/ AMG701§Isatuximab§Iberdomide (CC-220)§Venetoclax§Filanesib§LGH 447§Dinaciclib§Oprozomib§Marizomib
Future Drugs
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R
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T
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A
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D
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A
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Arm A:KRd Cycles 1-9 MRD Analysis1
Arm B:Dara + KRdCycles 1-9
Arm C: KRd Cycles 1-9
Arm D: Dara +
Lenalidomide Cycles 10-33
Arm E: Lenalidomide Cycles 10-33
Observation until disease progression
Observation until disease progression
Step 1: InductionStep 2: Consolidation and Maintenance
Stratification• R-ISS Stage at Diagnosis: 1 vs 2 vs 3• MRD Status: Positive vs Negative
1. All patients will be randomly assigned regardless of biomarker status.
Accrual Goal: 1450 patients
EQUATE TRIAL