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

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?

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

10 Improving Response Rates with Combination Therapies
10

11 Frontline Therapy Transplant Ineligible Patients
Increasing Options

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

13 First Trial: MPT vs Rd vs Rd Continuous
Plenary

14 Active treatment + PFS follow-up phase
FIRST: Lenalidomide/Dexamethasone vs MPT in NDDM SCT-Ineligible Patients[1] Active treatment + PFS follow-up phase Phase III N = 1623 Randomization 1:1:1 Arm A Continuous Rd Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 PD or unacceptable toxicity subsequent anti-MM Tx PD, OS, and Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex mg Days 1, 8, 15, 22/28 Arm B Rd18 Mel + Pred + Thal 12 cycles[2] (72 wks) Melphalan 0.25 mg/kg Days 1-4/42 Prednisone mg/kg Days 1-4/42 Thalidomide mg Days 1-42/42 Arm C MPT 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. 1. Facon T, et al. ASH Abstract Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009;27:

15 FIRST Trial: Progression-Free Survival
100 80 60 40 20 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 = ) Rd vs Rd18: 0.70 (P = ) Rd18 vs MPT: 1.03 (P = ) Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 Mos 1. Facon T, et al. ASH Abstract 2. Reproduced with permission.

16 Integrating Approved Newer Agents into Frontline Regimens
Transplant Eligible

17 Carfilzomib, Lenalidomide, dexamethasone (CRd) Treatment Schema
Induction CRd Maintenance Lenalidomide (off protocol) Transplant-eligible and ineligible patients LEN Cycles 25+ CRd Cycles 1–4 CRd Cycles 5–8 CRd Cycles 9–24 Until disease progression or unacceptable toxicity Transplant-eligible ≥PR ASCT Stem cell collection Cycles 1–8 CFZ mg/m2 Days 1–2, 8–9, 15–161 LEN 25 mg Days 1–21 DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8 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 Jakubowiak AJ, et al. Blood. 2012;120(9):

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 Progression-free Survival
CRd – Survival Progression-free Survival Overall Survival 24-month rate 98% 24-month rate 94% N=53 Median follow-up of 25 months (range 5-37) Patients receive 8 cycles of CRd Induction then 16 cycles of CRd maintenance then LEN maintenance until progression Jakubowiak et al, ASCO 2013

20 CRd - Time to Response Jakubowiak et al, ASCO 2013
Median Time to Response, mo 0.9 3.7 6.7 11.0 13.1 Jakubowiak et al, ASCO 2013

21 Integrating Approved Newer Agents into Frontline Regimens
Transplant Ineligible Patients

22 Carfilzomib, Melphalan, Prednisone (CMP)
PFS 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) CR 6% VGPR 50% PR % SD 9% PD 0 Median PFS = 22 months OS 93.9% >VGPR 56% >PR 91% OS= 87% Median follow-up = 12 months Moreau et al, ASCO 2013, Courtesy P. Moreau

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

24 Yet to be Approved New Agents with Potential

25 Ixazomib (weekly), Lenalidomide, dexamethasone Patients treated at RP2D (2.23 mg/m2 / 4.0 mg)
ORR 94% ORR 95% ORR 90% ≥VGPR 49% ≥VGPR 58% ≥VGPR 58% % Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPR 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 Efficacy: Best Response Phase II (Study 1703)
Elotuzumab 10 mg/kg Elotuzumab 20 mg/kg Total Patients, n 36 37 73 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) <PR, n (%) 3 (8) 9 (24) 12 (16) Overall median time to response: 1 mo (range, ); 1 new and 3 deepening responses were observed since the previous data cut (October, 2011)1 Overall median time to best response: 2.5 mo (range, ) Median duration of objective response: 15 mo 1. Lonial S et al. Blood 2011;Abstract 303 28

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
Phase Treatment Primary Endpoint MM Patient Population ELOQUENT - 1 III RD +/– Elotuzumab PFS Previously Untreated ELOQUENT - 2 Relapsed or Refractory

31 Daratumumab Phase I/II Maximal Change in Paraprotein
* Data at baseline below limits for measurable disease Results are before database lock ≤1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg

32 % Change in Paraprotein
SAR650984: Maximal Change in Paraprotein Myeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher 150 1 mg/kg Q2W 3 mg/kg Q2W 125 5 mg/kg Q2W 10 mg/kg Q2W 100 10 mg/kg QW 20 mg/kg Q2W 75 50 25 % Change in Paraprotein -25 -50 -75 -100 One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable

33 Stem Cell Transplantation

34 Conventional Chemotherapy vs ASCT RANDOMIZED STUDIES Median OS
Patients (n) Age Median Follow Up Conventional Chemotherapy ASCT IFM90[1] 200 <65 7 y 44 57 MAG91[2] 190 55-65 56 m 50 55 MRC7[3] 403 42 m 42 PETHEMA[4]* 164 64 72 *in patients responding to conventional chemotherapy 1. 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.

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

36 Not as Simple as We Thought
Maintenance Therapy Not as Simple as We Thought

37 Post-Transplant Lenalidomide Maintenance CALGB 100104
Updated OS Includes pts crossing over Updated TTP Estimated HR=0.51 (95% CI = 0.39 to 0.66), 146 events on placebo 104 events on lenalidomide Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003 ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months. Cut-off date January 7, 2013 McCarthy, IMW Kyoto, April 2013

38 CALGB 100104: Event-Free Survival & SPM
Hematologic SPM: 8 (LEN; 3.5%) vs. 1 (PBO; 0.4%) Solid-tumor SPM: 10 (LEN; 4.3%) vs. 5 (PBO; 2.2%) 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:

39 IFM 2005-02: Progression-Free Survival
ASCT: autologous stem cell transplant; β2-M: β2-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 2005-02: 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 2005-02: Event-Free Survival & SPM*
Hematologic SPM: 13 (LEN) vs. 5 (placebo) (18 v 7) Solid tumor SPM: 10 (LEN) vs. 4 (placebo) (13 v 11) * 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:

44

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

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
MPR-R significantly extended median PFS vs. MP and MPR 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:

48 MM-015: Overall Survival The number of deaths is low and comparable across treatment groups 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:

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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