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Individualizing Treatment in the Era of Novel Agents

Individualizing Treatment in the Era of Novel Agents. Discovery of New Drugs Singular Mechanism of action. Progress in MM Cell Biology Prognostic factors & Myeloma subtypes*. Individualize & Tailor Treatment. * MM sould not be considered a single entity.

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Individualizing Treatment in the Era of Novel Agents

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  1. Individualizing Treatment in the Era of Novel Agents Discovery of New Drugs Singular Mechanism of action Progress in MM Cell Biology Prognostic factors & Myeloma subtypes* Individualize & Tailor Treatment * MM sould not be considered a single entity

  2. Individualizing Treatment in the Era of Novel Agents Stratification Risk Factors Age (< or > 65/70 y) - Cytogenetics - PC proliferation & ISS - Renal function - Response to induction Standard vs High Risk Transplant candidate or non-candidate

  3. Individualizing Treatment in the Era of Novel Agents • The Transplant candidate patient (Young) - Standard Risk - High Risk • The Non- Transplant candidate patient (Elderly)

  4. The Standard risk & transplant candidate patient The Standard Risk & Transplant Candidate : INDUCTION Regimen Patients Response Reference %>PR (%CR + nCR) . Thal-Dx vs Dx 470 63 vs 46 (7.7 vs 2.6) Rajkumar JCO 2008 . TAD vs VAD 400 72 vs 54 (7 vs 3)Lokhorst, Hematol 2008 . T+VAD vs VAD 230 81 vs 66 Zervas ASH 2006 . Vel Dx vs VAD 486 82 vs 67 (20 vs 9) Harousseau ASH 2007 . VTD vs TD256 93 vs75 (36 vs 9) Cavo ASH 2007 . Len-Dx vs Len-dx 485 82 vs 71 (4 vs 2)Rajkumar ASH 2007 . Len-Dx vs Dx19885 vs 71 (22 vs 4) Zonder ASH 2007 • 9 pilot studies on bortezomib combinations: 66-92% ≥ PR (20-32% CR) • BiRD ( Clarithromycin+Len-Dex): 90% ≥ PR (39% CR + nCR) (Niesvizky, Blood 2008)

  5. The Standard risk & transplant candidate patient Does ASCT up-grade the response obtained with Novel Agents? %Complete Responses & nCR Pre-ASCT Post-ASCT (1st) Reference Vel-Dex 21% 35% Harousseau,ASH 2007 VTD 36% 57% Cavo ASH 2007 Vel-Dex (alt) 13% 40% Rosiñol,ASH 2006 (3086) Vel-Dox-Dex 32% 54% Jakubowiak,ASH 2006 (3093) PAD 16% 54% Popat, ASH 2005 V-DTPACE 16% 80% Barlogie,ASH 2005 TAD 4% (32)* 16%(49)*Lokhorst Hematologica 2007 TD (35)* (44)* Macro ASH 2006 * CR+VGPR No problems with stem cell collection or engrafment

  6. The Standard risk & transplant candidate patient Conclusions on Induction Therapy for Standard Risk & Transplant Candidate • VAD is DEAD • Thal-Dex: new gold standard ? …….. Suboptimal • In Thal-based regimens: Higher respose rates (>80%) (and particularly CR rates) could be obtained if Adriamycin or Cyclophosphamide are added. Probably the similar concept can be applied to Len-based regimens • BD or BTD are superior to VAD or TD & CR increases after SCT • No problems with stem cell collection* * Lenalidomide: Decrease in total CD34 cells…….Early collection and with Cyclophosphamide Mazumder et al Leukemia 2007, Kumar et al Leukemia 2007, Paripati et al Leukemia 2008

  7. The Standard risk & transplant candidate patient One or Two ASCT? • One ASCT : Low toxicity, anti-MM activity (+++), low cost. • No Double : - Only patients with <VGPR benefit from 2nd Trx * - Thalidomide (consolidation) converts PR post-Trx into CR** - The CR rate with Novel drugs + one ASCT = Tandem ASCT - Single ASCT + Thal > Double ASCTª * Attal NEJM 2003; ** Attal Blood 2006 & Spencer ASH 2006 ª Abdelkefi Blood 2007; . Auto + Mini-Alo in standard RISK ?: NO until better strategies to reduce GVHD & TRM

  8. ONE or TWO ASCT? • One + Thal* (97pts) Two (98pts) • PF3 at 3 y 85% 57% • OS at 3 y 85% 65% • 100 mg x 6 months • Abdelkefi et al Blood,15:1805 2008,

  9. The Standard risk & transplant candidate patient * Consolidation vs Maintenance treatment * More resistant relapses? The benefit of Thal for patients in CR & those with poor cytogentics is not well established Maintenance treatment* in standard Risk patients • Attal (Blood 2006) Thal > Pamidronate or nothing …………….. > EFS & OS • Spencer ( ASH 2006) Thal + Pred > Prednisone……………….. > EFS & OS • Offidani (ASH 2006) Thal + Dex > IFN / Dex…………………. > EFS & OS • Barlogie (NEJM 2006) Continous Thal……………………….... > EFS but Not OS*

  10. Consolidation with Bortezomib + Thalidomide + Dex • Patients (n=40) with CR or VGPR following ASCT • Treatment (total 4 cycles) • Bortezomib 1.6 mg/m2 once weekly (days 1, 8, 15, 22), then 13-day rest period • Thalidomide 50 mg/day once daily, with increments of 50 mg every 7 days up to 200 mg • Dex 20 mg/day once daily, days 1-4, 8-11 and 15-18, then 17-day rest period • Results • 94% of patients were PCR-positive following ASCT • 27 patients evaluable at end of treatment • PCR-negativity detected in 22% • All PCR-negative patients assessed at 6 months (4 cases) and at 6 and 12 months (2 cases) persisted in MR • Seven relapses/progressions occurred; all among PCR-positive patients • Tumor reduction observed in PCR-positive patients Ladetto et al. ASH 2007 (abstract 530)

  11. The Standard risk & Transplant candidate patient Induction(Vel-D or VTD or TAD or Len-Dex) ASCT (Mel 200) Maintenance(Thal +/- Predn)* * Len or Vel to be explored

  12. The Standard risk & transplant candidate patient Treatment of Relapse following ASCT in Standard Risk patients • Early relapse (< 1 year post ASCT) “Overcome drug resistance” Combination or Alternating non cross-resistant agents VTD-PACE or (Vel-Adria-Dex) & (Thal or Len-Cyclo-Dex) ----> RIC-Allo • Intermediate relapse ( 1-3 years post ASCT) “Prolong survival until curative treatments are developed” Sequential novel agent combinations - Starting with a different drug to that used in maintenance. ( if less < 55 years & suboptimal response ----> RIC-Allo? ) • Late relapse( > 3 years ) Reinduction + 2nd ASCT

  13. Individualizing Treatment in the Era of Novel Agents • The Transplant candidate patient (Young) - Standard Risk - High Risk • The Non- Transplant candidate patient (Elderly)

  14. Individualizing Treatment in the Era of Novel Agents Stratification Risk Factors Age (< or > 65/70 y) • - Poor Cytogenetics.: IgH tr +/-13q, -17p, 1q? • High S-phase (> 2%) & Advanced ISS • - Disease progression under induction • - Renal failure • High Risk Transplant candidate or non-candidate

  15. The High risk & transplant candidate patient The newly diagnosed High risk patient • “New agents appear to overcome the adverse influence of cytogenetic abnormalities” ........ therefore • Induction treatment with novel drugs followed by ASCT could be a useful approach (as for standard risk patients) ..... and • The concept of High risk should be revised.

  16. The High risk & transplant candidate patient • Induction with non cross-resistant agents VTD or(Vel-Adria-Dex) & (Len- Cyclo-Dex) Novel agents: Overcome poor prognosis ASCT+/- RIC-Allo. The High risk* & Transplant Candidate patient • Alternative :Targeted therapies (i.e. FGFR3 Kinase inhibitors) + Standard Treatment ( induction with Novel Agents + AUTO) • Experimental Clinical Trials * Poor cytogenetics : t(4; 14) ; t(14,16); +/-13q ;1p; 17p, Hypodiploid High Proliferative activity (LI / S-phase> 2%) & Advanced stage (ISI III)

  17. The High risk & transplant candidate patient 1,0 0,9 0,8 0,7 Chemosensitive (900) Survival Cumulative Proportion Surviving 0,6 0,5 No Change (50) 0,4 0,3 Progressive disease (31) 0,2 p<0,000 0,1 Years 0,0 0 2 4 6 8 10 12 14 Years The Primary Refractory patient Myeloablative regimens supported by ASCT appeared useful primarily in patients with primary resistant disease ( Alexanian 1994, Vesole 1996, Rajkumar 1996, 2004) Diagnosis Non-responding(81) No Change (50) Progressive disease (31) VBCMP/VBAD (x4) Double SCT Rosinol et al Our proposal : Cocktail of non cross-resistant agents followed by tandem Auto-RIC-Allo.

  18. VAD “old Standard” : doesn’t require dose adjustment • Thalidomide ………………... Little information (feasible) • Lenalidomide ……………….Guidelines* • Bortzomib ………………….. Effective (including dialysis) * Creatinine Clearance > 50 ml / m...................... No dose modification “ “ 30 – 50 ml / m.............. 10 mg / 24 h “ “ < 30 ml / m.............. 15 mg / 48 h Dialysis .............................................................. 15 mg x 3 times/w after dialysis The Patient with Renal Insufficiency • ASCT: Reversibility of Renal failure : 43% TRM: 29% ( Cr >5 mg/dl, Hb < 9 g/dl PS> 3)

  19. Overall Survival according to Renal Function APEX subanalyis: Bortezomib vs Dexamethasone Creatinine clearance (mL/min) Bortezomib 50 (n=62)Bortezomib >50 (n=268) Dex 50 (n=68) Dex >50 (n=255) Bortezomib (censored) 50Bortezomib (censored) >50 Dex (censored) 50 Dex (censored) >50 1.0 0.8 0.6 0.4 0.2 0 Proportion of patients 0 90 180 270 360 450 540 630 720 810 900 990 1080 Time (days) San Miguel et al, Luekemia 2008

  20. Individualizing Treatment in the Era of Novel Agents • The Transplant candidate patient (Young) - Standard Risk - High Risk • The Non- Transplant candidate patient (Elderly)

  21. The Non-transplant candidate patient The newly diagnosed Elderly patient: Induction • TTP/PFS/EFS are highly sensitive to definition and measurements 1. Palumbo et al. Lancet 2006;367:825–831; 2. Facon et al. Lancet 2007;370:1209–1218; 3. Hulin et al. ASH 2007:Abstract 75; 4. Ludwig et al. ASH 2007:Abstract 529; 5. Waage et al. ASH 2007:Abstract 78; 6. San Miguel et al. ASH 2007:Abstract 76

  22. MP-THAL vs MP vs MEL 100 0S PFS Comparison HR P MP / MP-T 1.9 0.0008 MP / MEL 100 1.1 0.55 MEL100 / MP-T 1.7 0.014 Comparison HR P MP / MP-T 2.4 < 0.0001 MP / MEL 100 1.2 0.16 MEL100 / MP-T 2.0 0.0001 MP-T: 54m MEL 100: 39m MP-T: 28m MP: 32 m MEL 100: 19m MP: 17m Facon et al , ASCO 2006

  23. Progression-free survival Overall survival MPT 45.0 mo MPT 21.8 mo Proportion of patients Proportion of patients MP 47.6 mo P = 0.79 MP 14.5 mo P= 0.0004 Months Months MP vs MPT in Newly Diagnosed Elderly MM (≥ 65 years ) Melphalan, 4 mg2 (7 days/28 days) Prednisone, 40 mg2 (7 days/28 days) 6 cycles Thalidomide, 100 mg/day continuously Palumbo Lancet 2006, updated at 2008

  24. MPV vs MP :VISTA trial ,682 patients Time to progression~52% reduced risk of progression on VMP VMP MP VMP MP Median follow-up 16.3 months VMP: not reached (45 deaths) MP: not reached (76 deaths) HR = 0.607, p = 0.0078 VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR = 0.483, p < 0.000001 Number of patients at risk MP: 338 320 301 280 220 157 116 69 29 7 VMP: 344 315 300 290 235 168 115 72 36 4 Number of patients at risk MP: 338 296 241 206 152 86 53 22 5 VMP: 344 295 272 245 185 111 65 31 17 Overall survival~ 40% reduced risk of death on VMP OS @ 2-years 82.6% in VMP vs 69.5% in MP San Miguel et al ASH 2007

  25. VMP CrCl ≥60 mL/min, N = 159, events = 20 VMP CrCl <60 mL/min, N = 185, events = 25 VMP CrCl ≥60 mL/min (N=159): not reached (20 events) VMP CrCl <60 mL/min (N=185): not reached (25 events) VMP CrCl ≥60 mL/min VMP CrCl <60 mL/min VMP CrCl ≥60 mL/min (N=159): 21.7 months (43 events) VMP CrCl <60 mL/min (N=185): not reached (40 events) VMPCrCl does not impact efficacy Response Rates TTP OS San Miguel et al ASH 2007

  26. VMP Cytogenetics (FISH) does not impact efficacy FISH: any (t4-14, t14-16, 17p Del) vs. None TTP OS VMP standard risk VMP high risk VMP standard risk VMP high risk VMP standard risk (N=142): not reached (16 events) VMP high risk (N=26): not reached (3 events) HR = 1.009 (95% CI: 0.278, 3.663) VMP standard risk (N=142): 23.1 months (34 events) VMP high risk (N=26): 19.8 months (7 events) HR = 1.297 (95% CI: 0.55, 3.06) San Miguel et al ASH 2007

  27. Lenalidomide plus melphalan and prednisone (MPR) in newly diagnosed MM Dose-escalating study • N=54 • Median age 71 (57–77) Results • MTD: 0.18 mg/kg melphalan + 10 mg lenalidomide (n=21) • Grade 3/4 AEs at MTD: neutropenia (52.4%), thrombocytopenia (23.8%), febrile neutropenia (9.5%), thromboembolic events (4.8%) Responses data at MTD 1-year EFS: 92% 1-year OS: 100% del13 and t(4;14) did not affect response rate and survival high β2-microglobulin predicted shorter EFS 81% Palumbo et al. JCO 2007;25:4459-65

  28. The Non-transplant candidate patient Preferences for one MP-Combination?* • Consolidate data............................. T- MP, V-MP • Antecedent or Risk of DVT............ V- MP • Antecedent of PN........................... L- MP • Renal Insufficiency........................ V- MP • Distance from Hospital.................. L- MP or T- MP • Poor patient accomplishment....... V- MP • Costs............................................... T- MP * Duration of Treatment : 6 cycles

  29. Phase 3: Lenalidomide + high-dose dex (RD) vs lenalidomide + low-dose dex (Rd) ECOG trial RD (n=223) Rd (n=222) % RD (n=223) Rd (n=222) CR 4% 2% Neutropenia 10 19 VGPR 48% 40% DVT/PE 25 9 ≥PR 82% 71% Infections 16 6 Any ≥ Gr 3 non-hem AE 49 32 TTP 21.7m 22.5m Any ≥ Gr 4 AE 20 9 OS at 12m 88% 96% p=0.003 Early death 5 0.5 OS at 24m 75% 87% p=0.009 • Patients (n=445) (median age: 65 years) • Primary endpoint: RR at 4 months, not designed to evaluate long-term outcomes • Treatment • RD: lenalidomide 25 mg/day days 1–21 every 28 days dex 40 mg days 1–4, 9–12, 17–20 every 28 days • Rd: same lenalidomide dose; dex 40 mg days 1, 8, 15, 22 every 28 days Results • OS for patients ≥65 years: at 12m 84% vs 95% (p=0.01), at 24m 67% vs 82% (p=0.009) for RD vs Rd, respectively • Successful CD34+ collection in 97% of cases Rajkumar et al. ASH 2007 (Abstract 74)

  30. The Non-transplant candidate patient Very elderly Patients (>75 years) • T- MP & V- MP are feasible (L-MP probably) • Modified schemes: - Thalidomide : 100 mg. - Lenalidomide : 10 mg. - Velcade : 1 mg/m2 or weekly schedule Cyclophosphamide ( 50mg / day ) or Low dose Dex

  31. The Non-transplant candidate patient The newly diagnosed Elderly Patient: MAINTENANCE • No data • One year with low dose IMID* + corticosteroids or pulses (one w / 4 w) • * ie, Len: 10 mg or Thal: 50 mg/day, • Risk of more resistant relapse

  32. Conclusions on Treatment options for Elderly patientes with newly diagnosed MM • New treatments approaches in elderly MM result in higher response rate (including high CR) and significant prolongation in PFS and OS (50% increase) as compared to MP • The next goal is to minimize the toxicity mantaining the efficacy. • Areas for investigations: role of maintenance?, optimal sequence of treatment schemes?.

  33. The newly diagnosed Elderly Patient: RELAPSE • First: the general condition of the patient • Candidate for active treatment: • - 1st step…..the alternative drug to that used as induction + (cyclophosphamide & steroids) • - 2nd step…..Experimental trials • No Candidate for active treatment: • - Oral Cyclophosphamide (50mg/day) + Prednisone (30 mg)

  34. Individualizing Treatment in the Era of Novel Agents In vitro proliferation Aggressive growth Stromal independent Progress in MM Cell Biology………..Myeloma subtypes* Inmortalization Non malignant acumulation Malignant Transformation Karyotypic inestability Primary IGH Translocations Delet- Mutat Trisomies Secondary IGH Tr: C-MYC * MM sould not be considered a single entity Discovery of New Drugs …………Singular Mechanism of action Individualize & Tailor Treatment

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