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Disclosures Consulting fees from: Bristol-Myers Squibb, Celgene, - - PDF document

Nov 11, 2022 291 likes •506 views

Induction Therapy: Have a Plan Sagar Lonial, MD Professor, Winship Cancer Institute Director of Translational Research, B-cell Malignancy Program Disclosures Consulting fees from: Bristol-Myers Squibb, Celgene, Millennium, Novartis,

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Induction Therapy: Have a Plan

Sagar Lonial, MD Professor, Winship Cancer Institute Director of Translational Research, B-cell Malignancy Program

Disclosures

  • Consulting fees from:
  • Bristol-Myers Squibb, Celgene, Millennium,

Novartis, Sanofi, and Onyx

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Topics

  • When to treat? Smoldering vs Symptomatic
  • Risk stratification
  • Choice of Induction regimen
  • Role of HDT
  • Role of consolidation/maintenance

Criteria for Diagnosis of Myeloma

MGUS

  • < 3 g M spike
  • < 10% plasma cells

AND

SMM

  • ≥ 3 g M spike
  • ≥ 10% plasma cells

Active MM

  • ≥ 10% plasma cells
  • M spike +

AND

No anemia, bone lesions, normal calcium, and kidney function

MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma. Kyle et al, 2009.

Anemia, bone lesions, high calcium, or abnormal kidney function

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Kyle R et al. N Engl J Med 2007;356:2582-2590

Smoldering Multiple Myeloma

27% will convert in 15 years Roughly 2% per year

Free Light is Useful for Risk Assessment in AMM

Dispenzeri et al Blood 2008

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Lenalidomide

25 mg/daily during 21d every 28 d

Dexamethasone

20 mg D1-D4 and D12-D15 every 28 d

Therapeutic abstention

Induction

Nine 4-week cycles

Maintenance

Lenalidomide

10 mg/daily during 21 d every month*

Therapeutic abstention

Schedule of therapy (n:126 pts)

Treatment arm (n = 60) Control arm (n = 66)

* Low-dose Dex will be added at the moment of biological progression Ammendment on August 2011: Stop treatment at 2 years of treatment

PFS for Early treatment

Mateos et al, NEJM 2013

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OS from study entry

Mateos et al, NEJM 2013

Challenges to Adoption

  • Not clear these patients were truly

smoldering (bone disease)

  • Method for identifying these patients not

standardized (minimal overlap methods)

  • New definition of Smoldering coming from the

IMWG soon

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Freelight Ratio >100 predicts risk

Larsen et al, Leukemia 2013

Plasma cells can predict for Progression

Kastritis et al, Leukemia 2013

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ECOG/SWOG: Phase III – Asymptomatic Myeloma*(PI: SL)

Lenalidomide vs. observation

ECOG/SWOG: Phase III – Asymptomatic Myeloma*(PI: SL)

Lenalidomide vs. observation

Observation Observation Lenalidomide Lenalidomide CR/PR/ Stable CR/PR/ Stable Prog. anytime Prog. anytime Continue therapy till prog. or toxicity Continue therapy till prog. or toxicity Off Rx Off Rx R A N D O M IZ A TI O N

Control/standard arm No Dex to isolate the effect of len

Overall Survival - Multiple Myeloma Patients (1980-1992)

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The Good News

  • Outcomes for patients are clearly improved
  • The use of HDT or melphaln based novel agent inductions have

doubled median survival for nearly all patients

Kumar SK, et al. Blood. 2008

PETHEMA Cure with old Drugs

Martinez-Lopez et al, Blood 2011

Functional cure?

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What is the Current state of the Art?

  • Induction for younger patients

– 3 drug induction followed by auto transplant in first response (Cavo et al) – Maintenance therapy post auto transplant (Attal, McCarthy, Palumbo) – Maximize duration of first response (Palumbo) – Goals of treatment now include trying to achieve MRD negativity (San Miguel/Paiva)

Trial Regimens n ≥ VGPR, % After Induction After First ASCT After Maintenance Cavo[1] VTD x 3 TD 241 239 62 28 79 58 IFM 2005-01[2] VD x 4 VAD 223 218 37.7 15.1 54.3 37.2 HOVON-65/ GMMG-HD4[3] PAD x 3 VAD 371 373 42 14 62 36 PETHEMA/GEM[4] TV T a2-IFN 74 CR rate improved by 23% (TV), 11% (T), 19% (a2-IFN) PETHEMA/GEM[5] VTD TD VMBCP/VBAD/B 130 127 129 60 29 36 E4A03[6] RD Rd 445 422 50 40

  • 1. Cavo M, et al. Lancet. 2011;376:2075-2085. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629.
  • 3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. ASH 2011. Abstract 3962. 5.

Rosiñol L, et al. Blood. 2012;120:1589-1596. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients

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Regimens Phase (N) ≥ VGPR, % Survival Bortezomib/lenalidomide/ Dexamethasone (RVD)[5] I/II (n = 66) 67 (after induction) 18-mo PFS: 75% (with or without ASCT) Carfilzomib/lenalidomide/ Dexamethasone (CRD)[2,3,4] I/II (n = 53) 87 (after induction)[3] 88 (after induction)[4] rapid /deep responses improved with time 12-mo PFS: 97%[2] 24-mo PFS: 92%[2] Carfilzomib/thalidomide/ Dexamethasone (CTD)[1] II (n = 70) 64 (after induction) 71 (after ASCT) 84 (after consolidation) Bortezomib/cyclophosphamide/ dexamethasone (CyBorD)[6] II (n = 63) 60 (ITT) 67 (if completed all 4 cycles) Similar activity with weekly

  • r twice weekly dosing

Ixazomib/lenalidomide/ dexamethasone[7] I/II (n = 62) 70 (after induction)

  • 1. Sonneveld P, et al. ASH 2013 (abstract 688). 2. Jakubowiak A, et al. Blood. 2012;120:1801-9. 3.

Jasielec J, et al. ASH 2013 (abstract 3220). 4. Korde N, et al. ASH. 2013 (abstract 538). 5. Richardson, PG et al. Blood. 2010;116:679. 6. Reeder CB, et al. Blood. 2010;115:3416-3417. 7. Richardson PG, et al. ASH 2013. Abstract 535.

Early Phase Studies: Novel Regimens for Induction for Transplantation-Eligible Pts

Role and Timing of HDT

  • Optimal induction is a Key
  • Is the role of HDT waning?
  • Does timing matter?
  • What is the impact of MRD
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Getting to Minimal Residual Disease (MRD): New Definitions for CR

S.S. Patient 1×1012 Stringent CR Molecular/Flow CR ?Cure?

Disease burden

Newly diagnosed 1×108 1×104 0.0

Antibodies Maintenance Therapy

CR MRD

Distribution of high risk features

Flowchart for patients

RVD induction (222 pts) Early ASCT (138 pts) HDT‐ASCT

Lenalidomide maintenance (60 pts) Bortezomib maintenance (6 pts) RVD maintenance (15 pts) Observation (57 pts)

Delayed ASCT (84 pts)

Lenalidomide maintenance (65 pts)

HDT‐ASCT at relapse (28 pts)

RVD maintenance (3 pts) Observation (16 pts)

Nooka et al ASCO 2013

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Progression Free Survival – entire cohort

Nooka et al ASCO 2013

Overall Survival – entire cohort

Nooka et al ASCO 2013

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402 patients (younger than 65 years) randomized from 62 centers  Patients: Symptomatic disease, organ damage, measurable disease

Treatment schedule

Rd*

four 28-day courses R: 25 mg/d, days 1-21 d: 40 mg/d, days 1,8,15,22

MPR

six 28-day courses M: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4 R: 10 mg/d, days 1-21

MEL200

two courses M: 200 mg/m2 day -2 Stem cell support day 0

NO MAINTENANCE MAINTENANCE

28-day courses until relapse R: 10 mg/day, days 1-21

R A N D O M I Z A T I O N 1° R A N D O M I Z A T I O N 2° *Thromboprophylaxis randomization: aspirin vs low molecular weight heparin R, lenalidomide; d, low-dose dexamethasone; M, melphalan; P, prednisone; MEL200, melphalan 200 mg/m2

MPR vs MEL200

MPR

six 28-day courses M: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4 R: 10 mg/d, days 1-21

MEL200

two courses M: 200 mg/m2 day -2 Stem cell support day 0 R A N D O M I Z A T I O N 1°

M, melphalan; P, prednisone; R, lenalidomide; MEL200, melphalan 200 mg/m2

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MPR vs MEL200

Progression-free survival

Median PFS MPR 24 months MEL200 38 months

HR 1.69 P <.0001

70 25 50 75 100 10 20 30 40 50 60 25 50 75 100 Months 10 20 30 40 50 60 70

5-year OS MPR 62% MEL200 71%

HR 1.25 P =.27

Overall survival

Months

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2

Difference in Outcomes is accounted for by MRD negativity

R maintenance vs No maintenance

R, lenalidomide

R A N D O M I Z A T I O N 2°

NO MAINTENANCE MAINTENANCE

28-day courses until relapse R: 10 mg/day, days 1-21

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R maintenance vs No maintenance

Median PFS R maint. 37 months No maint. 26 months

HR 0.52 P <.0001

Months

5-year OS R maint. 75% No maint. 58%

HR 0.62 P =.02

Months

25 50 75 100 10 20 30 40 50 60 70 25 50 75 100

  • s

10 20 30 40 50 60 70

R, lenalidomide

Progression-free survival Overall survival 48% reduced risk of progression 38% reduced risk of death

25 50 75 100 10 20 30 40 50 60 70

MEL200-R MEL200 MPR-R MPR Months

100 10 20 30 40 50 60 70 25 50 75

MEL200-R MEL200 MPR-R MPR Months

Progression-free survival Overall survival

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

MPR vs MEL200 vs MPR-R vs MEL200-R

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Phase III Maintenance Studies – Transplant Eligible Patients

Trial N Regimen Outcomes IFM 2005-02[1] 614 Maintenance lenalidomide vs placebo following first or second ASCT 4-yr PFS: 60% vs 33% CALGB 100104[2] 460 Maintenance lenalidomide vs placebo after ASCT Median TTP: 46 vs 27 mos RV-MM-PI-209[3] 402 MPR + maintenance lenalidomide vs MPR vs MEL200 + maintenance lenalidomide vs MEL200 Median PFS (R vs no R): 37 vs 26 mos 5-Yr OS (R vs no R): 75 vs 58 mos HOVON-65[4] 827 VAD vs PAD followed by HD melphalan and ASCT, then thalidomide or bortezomib as maintenance Median PFS: 28 vs 35 mos CR/nCR: 15% vs 31% Nordic MSG 15[5] 370 Bortezomib x 21 wks vs no maintenance ≥ nCR: 45% vs 35%

  • 1. Attal M, et al. N Engl J Med. 2012;366:1782-1791. 2. McCarthy PL, et al. N Engl J Med. 2012;366:1770-
  • 1781. 4. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 5. Mellqvist UH, et al. Blood.

2013;121:4647-4654.

Progression Free Survival from IFM pilot

Roussel et al, JCO 2014

RVD Induction HDT RVD consolidation Len maintenance

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OS for RVD induction at Emory With Risk Adapted Maintenance

Nooka et al, Leukemia 2013 N= 256 patients all received RVD all risks groups included and early and delayed transplant.

Risk‐Adapted Maintenance, 2014 Update

Standard risk Lenalidomide maintenance Patients progressing on lenalidomide, then transplant Patients with t(4;14) Bortezomib maintenance High risk RVD maintenance1

RVD: lenalidomide‐bortezomib‐dexamethasone.

  • 1. Nooka AK et al. Leukemia. 2014;28:690‐693.

Reflects current practice at Emory

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Emory OS by Genetics

Nooka et al, Leukemia 2013 N= 256 all patients received RVD High risk all received 3 drug maintenance Minimal exposure to alkylators

Conclusions

  • How you approach induction is important
  • Role of HDT continues to be there, especially

for high and intermediate risk patients

  • Maintenance and maximal prolongation of

first remission is critical for long term survival

  • Initial and long term planning for treatment of

MM is the first step for improved outcomes.

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Thanks to:

Jonathan Kaufman Charise Gleason Danni Cassabourne Melanie Watson Donald Harvey Renee Smith Colleen Lewis Amelia Langston L.T. Heffner Ebeneezer David Claire Torre S-Y Sun Jing Chen Fadlo Khuri Leon Bernal Larry Boise IMS

Golfers Against Cancer T.J. Martell Foundation

And Many Others who are part of the B-cell Team