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Imedex 2-27-14 Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma –Transplant eligible vs transplant ineligible –Doublets vs triplets.

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Presentation on theme: "Imedex 2-27-14 Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma –Transplant eligible vs transplant ineligible –Doublets vs triplets."— Presentation transcript:

1 Imedex Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma –Transplant eligible vs transplant ineligible –Doublets vs triplets –Integrating Novel Agents into Frontline Therapy Carfilzomib Elotuzumab Pomalidomide Oral PI’s –Maintenance

2 Myeloma Survival by Decade

3 Current OS and High Risk Myeloma A good risk stratification system should allow identification of this ~25% patients

4 Current Paradigm of Initial Treatment

5 The Concept of Dividing Myeloma Patients into Transplant Eligible vs Transplant Ineligible Arguments for making this distinction: –The use of melphalan impedes the ability to collect PBSC’s –Older patients cannot tolerate more aggressive regimens –Older patients don’t need to achieve a deeper response since they don’t have as long to live anyway Arguments against making this distinction: –More and more we have been able to collect stem cells after melphalan –There are data that older patients benefit just as much from deeper responses and would appreciate the added longevity (I would) –Most US oncologists don’t use melphalan-based regimens anyway (prefer Vd and Rd)

6 Should CR be Our Goal in All Patients

7 Martinez-Lopez et al Blood. 2011;118(3): Prognostic effect of Patients in CR vs those in (nCR or VGPR or PR) vs those with (SD or PD) after HDT/ASCT

8 In non-transplant candidates, achievement of CR is also associated with improved PFS and OS Gay F et al. Blood. 2011;117:3025. Shouldn’t the achievement of deeper response be also a goal in non-transplant candidates? PFS

9 Frontline Therapy Transplant Eligible Patients Are Triplets the Standard of Care?

10 Improving Response Rates with Combination Therapies

11 Frontline Therapy Transplant Ineligible Patients Increasing Options

12 Initial Treatment of Transplant - Ineligible Candidates Continue initial therapy? Initial therapy Maintenance? Duration? MP-based regimens MPT > MP VMP > MP VMP = VTP MPR-R>MPR=MP VMPT> VMP Duration?

13 First Trial: MPT vs Rd vs Rd Continuous Plenary

14 FIRST: Lenalidomide/Dexamethasone vs MPT in NDDM SCT-Ineligible Patients [1] Randomization 1:1:1 Arm B Rd18 Arm C MPT Len + LoDex18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Mel + Pred + Thal 12 cycles [2] (72 wks) Melphalan0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42 PD, OS, and subsequent anti-MM Tx PD or unacceptable toxicity Active treatment + PFS follow-up phase Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal [3] 100 mg Days 1- 42/42; Mel [3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage. Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Arm A Continuous Rd 1. Facon T, et al. ASH Abstract Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009;27: Phase III N = 1623

15 FIRST Trial: Progression-Free Survival Median PFS Rd (n = 535)25.5 mos Rd18 (n = 541)20.7 mos MPT (n = 547)21.2 mos HR: Rd vs MPT: 0.72 (P =.00006) Rd vs Rd18: 0.70 (P =.00001) Rd18 vs MPT: 1.03 (P =.70349) Mos Patients (%) wks 1. Facon T, et al. ASH Abstract 2. Reproduced with permission.

16 Integrating Approved Newer Agents into Frontline Regimens Transplant Eligible

17 Cycles 1–8 CFZ mg/m 2 Days 1–2, 8–9, 15–16 1 LEN 25 mg Days 1–21 DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8 Carfilzomib, Lenalidomide, dexamethasone (CRd) Treatment Schema Jakubowiak AJ, et al. Blood. 2012;120(9): Stem cell collection ≥PR CRd Cycles 9–24 CRd Induction CRd Maintenance CRd Cycles 1–4CRd Cycles 5–8 ASCT LEN Cycles 25+ Lenalidomide (off protocol) Transplant-eligible Transplant- eligible and - -ineligible patients Until disease progression or unacceptable toxicity Cycles 9–24 CFZ on Days 1–2 and 15–16 only CFZ, LEN, DEX at last best tolerated doses Cycles 25+ LEN at last best tolerated dose

18 CRd - Best Response (n=53)* *ITT, including patients who discontinued treatment early (eg, proceed to transplant) † iCR is an estimate of MRD-negative disease (10 color flow), based on percentage of patients in sCR evaluated for MRD at 12 months (18 of 19) and at 22 months (22 of 24) † Jakubowiak et al, ASCO 2013

19 CRd – Survival N=53 Median follow-up of 25 months (range 5-37) Jakubowiak et al, ASCO month rate 98% 24-month rate 94% Progression-free Survival Overall Survival Patients receive 8 cycles of CRd Induction then 16 cycles of CRd maintenance then LEN maintenance until progression

20 CRd - Time to Response Median Time to Response, mo Jakubowiak et al, ASCO 2013

21 Integrating Approved Newer Agents into Frontline Regimens Transplant Ineligible Patients

22 Carfilzomib, Melphalan, Prednisone (CMP) MTD defined at CFZ 36 mg/m2 Patients receive 9 cycles then stop treatment 68 patients have been enrolled in Phase 1 +2 Median age 72 years (61 – 86) High risk 17% After a median of 7 cycles (1 – 9) CR6% VGPR 50% PR 35% SD9% PD0 Moreau et al, ASCO 2013, Courtesy P. Moreau >VGPR 56% 93.9% PFS OS Median follow-up = 12 months >PR 91% Median PFS = 22 months OS= 87%

23 Carfilzomib, Cyclophosphamide, dex (CCd) Time to Event Palumbo et al, ASH 2012, Courtesy A. Palumbo Patients receive 9 cycles of CCD then CFZ maintenance until progression

24 Yet to be Approved New Agents with Potential

25 Ixazomib (weekly), Lenalidomide, dexamethasone Patients treated at RP2D (2.23 mg/m 2 / 4.0 mg) % ≥VGPR 58% ≥VGPR 49% ≥VGPR 58%  Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPR ORR 94%ORR 95% ORR 90% Kumar et al, ASH 2012, Courtesy S. Kumar

26 Oprozomib (ONX 0912) Oprozomib (OPZ, formerly ONX 0912) is a structural analog of carfilzomib (CFZ) –It is an orally bioavailable, next-generation PI –Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor Being evaluated in hematologic malignancies and solid tumors Savona MR, et al. Blood. 2012;120. Abstract 203.

27 Monoclonal antibodies Anti CS 1 –Elotuzumab Anti CD 38 –Daratumumab –SAR

28 Elotuzumab 10 mg/kg Elotuzumab 20 mg/kgTotal Patients, n ORR (≥PR), n (%) 33 (92)28 (76)61 (84) CR/stringent CR, n (%) 5 (14)4 (11)9 (12) VGPR, n (%) 17 (47)13 (35)30 (41) PR, n (%) 11 (31)11 (30)22 (30)

29 Progression-free Survival from the Phase II Cohort 10 mg/kg (n=36): 33 mos (95% CI: NA) 20 mg/kg (n=37): 18.6 mos (95% CI: ) Total (n=73): 25.8 mos (95% CI: ) In the 10 mg/kg cohort, median PFS was 33 months In the 20 mg/kg cohort, the median PFS was 18 months Lonial et al, ASCO 2013

30 Ongoing Studies with Elotuzumab PhaseTreatmentPrimary Endpoint MM Patient Population ELOQUENT - 1III RD +/– Elotuzumab PFS Previously Untreated ELOQUENT - 2III RD +/– Elotuzumab PFS Relapsed or Refractory

31 Daratumumab Phase I/II Maximal Change in Paraprotein ≤1 mg/kg2 mg/kg4 mg/kg8 mg/kg16 mg/kg Data at baseline below limits for measurable disease Results are before database lock *

32 SAR650984: Maximal Change in Paraprotein Myeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable 5 mg/kg Q2W 10 mg/kg Q2W 10 mg/kg QW 20 mg/kg Q2W 3 mg/kg Q2W 1 mg/kg Q2W -100 % Change in Paraprotein

33 Stem Cell Transplantation

34 Conventional Chemotherapy vs ASCT RANDOMIZED STUDIES Median OS Patients (n)Age Median Follow Up Conventional ChemotherapyASCT IFM90 [1] 200<657 y4457 MAG91 [2] m5055 MRC7 [3] 403<6542 m4255 PETHEMA [4]* 164<6542 m Attal M et al. N Engl J Med. 1996;335: Fermand JP et al. J Clin Oncol. 2005;23: Child A et al. N Engl J Med. 2003;348: Blade J et al. Blood. 2005;106:3755. *in patients responding to conventional chemotherapy

35 Len-Bz-Dex × 3 Len-Bz-Dex ×5 Len ×12m (IFM) Len until relpase (US Stem collection Len-Bz-Dex × 3 ASCT Len ×12m (IFM) Len until relapse (US) Stem collection Len-Bz-Dex ×2 ASCT at relapse NCI Clinical Trial Identifier NCT The Debate…ASCT: Up-Front or at Relapse

36 Maintenance Therapy Not as Simple as We Thought

37 ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months. 146 events on placebo 104 events on lenalidomide Post-Transplant Lenalidomide Maintenance CALGB Estimated HR=0.51 (95% CI = 0.39 to 0.66), McCarthy, IMW Kyoto, April 2013 Updated TTP Updated OS Includes pts crossing over Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= Cut-off date January 7, 2013

38 CALGB : Event-Free Survival & SPM ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; EFS: event-free survival; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy. McCarthy PL. N Engl J Med. 2012;366: –Hematologic SPM: 8 (LEN; 3.5%) vs. 1 (PBO; 0.4%) –Solid-tumor SPM: 10 (LEN; 4.3%) vs. 5 (PBO; 2.2%)

39 IFM : Progression-Free Survival ASCT: autologous stem cell transplant; β 2 -M: β 2 -microglobulin; del: deletion; HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; PBO: placebo; PFS: progression-free survival; VGPR: very good partial response. Attal M. N Engl J Med. 2012;366:

40 IFM : Overall Survival With a median follow-up of 45 months, no differences in OS has been observed across treatment arms –4 year OS (post-randomization): 73% (LEN) vs. 75% (placebo) IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. Attal M. N Engl J Med. 2012;366:

41

42

43 IFM : Event-Free Survival & SPM* * Data as of Oct 2011, including events during consolidation and maintenance. EFS: event-free survival; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy. Attal M. N Engl J Med. 2012;366: –Hematologic SPM: 13 (LEN) vs. 5 (placebo) (18 v 7) –Solid tumor SPM: 10 (LEN) vs. 4 (placebo) (13 v 11)

44

45 Bortezomib Maintenance HOVON-65/GMMG-HD4 Trial PFS OS Sonneveld et al, J Clin Oncol 2012;30: Bortezomib was used both pre- and post-transplant Benefits mostly in patients with high risk disease

46 MM-015: Study Design Dex: dexamethasone; ISS: International Staging System; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone- lenalidomide followed by lenalidomide maintenance; PBO: placebo; po: orally. Palumbo A. N Engl J Med. 2012;366:

47 MM-015: Progression-Free Survival HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; PFS: progression-free survival. Palumbo A. N Engl J Med. 2012;366: MPR-R significantly extended median PFS vs. MP and MPR

48 MM-015: Overall Survival HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; OS: overall survival. Palumbo A. N Engl J Med. 2012;366: The number of deaths is low and comparable across treatment groups

49 Controversies in Maintenance Therapy Should everyone (anyone) receive it? Should everyone receive the same drug(s)? –Lenalidomide? –VRd for high risk? Who is high risk? What should be the duration of therapy –Is there a way to measure this (MRD)? –Does more therapy result in more SPM’s and less effect? Would some patients be better off with just “consolidation?” At least those of us who work in this area will not be at a loss for new studies.


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