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Should Alkylators be used Upfront in Transplant- Ineligible Patients? NO!! Lymphoma-Myeloma October 2013 Scottsdale, Arizona Rochester, Minnesota Jacksonville,

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Presentation on theme: "Should Alkylators be used Upfront in Transplant- Ineligible Patients? NO!! Lymphoma-Myeloma October 2013 Scottsdale, Arizona Rochester, Minnesota Jacksonville,"— Presentation transcript:

1 Should Alkylators be used Upfront in Transplant- Ineligible Patients? NO!! Lymphoma-Myeloma October 2013 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

2 Objectives 1. Review the emerging data regarding replacing “MP” as backbone in upfront therapy 2. Provide practical advice as to initiating therapy in older patients with myeloma 3. Unequivocally defeat my friend Antonio in this debate 4. Concede that cyclophosphamide may be an exception to this general rule

3 Summary Points – Why Melphalan is no longer standard of initial care in elderly patients 1. Novel agents are equivalent if not superior to MP+novel agent 2. MP+ results in greater short term toxicity 3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity 4. Melphalan can lead to increased second primary malignancies

4 mSMART 2.0: Classification of Active MM  FISH  Del 17p  t(14;16)  t(14;20)  GEP  High risk signature All others including:  Hyperdiploid  t(11;14)  t(6;14)  FISH  t(4;14)*  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% High-Risk 20%Intermediate-Risk 20% Standard-Risk 60% 3 years 4-5 years 8-10 years Mikhael et al Mayo Clinic Proceedings April 2013

5 mSMART – Off-Study Transplant Ineligible Observation Intermediate RiskStandard Risk* MP + weekly Bortezomib or weekly CyBorD Bortezomib maintenance Rd Mikhael et al Mayo Clinic Proceedings April 2013 High Risk VRd

6 Argument #1 Novel agents are equivalent if not superior to MP+novel agent

7 MPT 1 N = 129 VMP 2 N = 337 MPR 3 N = 153 MPR-R 4 N = 152 VTP 5 N = 130 CR16%30%11%16%27% > VGPR29%Not reported33%32%37% > PR69%71%68%77%81% PFS21.8 moTTP: 24.0 mo14 mo31 mo23 mo Median follow- up 31.8 mo36.7 mo25 mo 22 mo 1 Palumbo A, et al. Blood. 2008;112: ; 2 Mateos MV, et al. Blood. 2009;114(22). Abstract 3859; 3,4 Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5 Mateos MV, et al. Blood. 2009;114(22). Abstract 3. MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone. Newly Diagnosed, Patients SCT Ineligible

8 Primary Study Schema RANDOMIZATIONRANDOMIZATION 445 patients RD x 4 cycles Rd x 4 cycles Less than PR CR/PR Thal + Dex x 4 cycles Patients can go off and proceed to SCT CR/PR/stable Rajkumar et al lenalidomide plus RD versus lenalidomide plus Rd in newly diagnosed MM

9 BEST RESPONSE: > PR* RD [n]Rd [n] Odds Ratio Fisher's Exact Overall81.3% [214]70.2% [208]1.85p=0.009 < % [103]66.0% [103]3.02p=0.002 > % [111]74.3% [105]1.19p=0.634 > % [71]73.8% [65]1.04p=1.000 > % [36]70.4% [27]1.47p=0.566 * Same observations with VGPR except age > % vs 47.7%

10 Results Second Interim Analysis RD vs. Rd Rajkumar et al, RDRd CR + PR79%68% 1 year OS87%96% Grade 3 or worse AE 52%35% RD did not result in superior TTP, PFS, or OS compared to Rd OS at 1-year was significantly better with Rd than RD, resulting in early closure of the trial

11 Overall Survival-ITT Age > 65 yrs Age > 65 Age > 70Age < 65 Age > 75 Status RD N=223(%) Rd N=220(%) Total* N=443 Treatment End by Mandatory Crossover Yes195(87.4)169(76.8)364 No28(12.6)51(23.2)79

12 Survival Rate by Age N12 month survival probability (95%CI) 24 month survival probability (95%CI) Age <65 Len-High Dex ( )0.86 ( ) Len-Low Dex ( )0.92 ( ) Age ≥65 Len-High Dex ( )0.72 ( ) Len-Low Dex ( )0.85 ( )

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16 Larocca A, et al. Gr. Emat. Milano 2012

17 Conclusion #1 MP is not necessary Lenalidomide-dexamethasone and bortezomib-dexamethasone are effective and viable options

18 Argument #2 MP+ results in greater short term toxicity

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24 Conclusion #2 3 drug regimens that include melphalan are more toxic (and not necessarily more effective) Dose reduction is critical in the elderly

25 Argument #3 As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

26 CP Multiple Myeloma n=2,981 Proportion surviving Time from diagnosis (months) Kumar et al: Blood 111:2516, 2008 Diagnosis after 1996 Diagnosis during/ before 1996 P<0.001 Survival, med 44.8 mo Survival, med 44.8 mo Survival, med 29.9 mo Survival, med 29.9 mo

27 Multiple Myeloma Mayo Patients % 66% P < S. Kumar, 2012

28 Argument #4 Melphalan can lead to increased second primary malignancies

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33 The “NEW” CyBorD All three drugs given weekly Cyclophosphamide 300mg/m2 PO Bortezomib 1.5 mg/m2 IV or SQ Dexamethasone 40mg PO We consider one cycle a 4 week course No “week off” Less neuropathy, more convenience, equal efficacy Always give viral prophylaxis Comment – I see CyBorD as a slight modification to VMP

34 Summary Points – Why Melphalan is no longer standard of initial care in elderly patients 1. Novel agents are equivalent if not superior to MP+novel agent 2. MP+ results in greater short term toxicity 3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity 4. Melphalan can lead to increased second primary malignancies

35 Quote – ASCO 2013 – Dr. Antonio Palumbo “Gli Americani avevano ragione: non dobbiamo usare melphalan come terapia iniziale nei pazienti anziani” “The Americans were right – we should not use melphalan upfront in elderly patients”


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