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Maintenance Therapy in Multiple Myeloma The Role of Other Agents (Besides Lenalidomide) James Berenson, MD Institute for Myeloma and Bone Cancer Research.

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Presentation on theme: "Maintenance Therapy in Multiple Myeloma The Role of Other Agents (Besides Lenalidomide) James Berenson, MD Institute for Myeloma and Bone Cancer Research."— Presentation transcript:

1 Maintenance Therapy in Multiple Myeloma The Role of Other Agents (Besides Lenalidomide) James Berenson, MD Institute for Myeloma and Bone Cancer Research Los Angeles, CA

2 Maintenance Therapy in Myeloma  Maintain response achieved following a new treatment with administration of drugs for a prolonged time period  Therapy must be  Convenient  Safe and well tolerated LONGTERM  NOT prevent use or reduce efficacy of other future treatments Goals Reduce the risk of relapse Extend PFS and OS

3 Maintenance Therapy in Myeloma  In what setting- frontline or > 2 nd line  Most of the data is in the frontline setting  How long to “maintain” maintenance therapy  Until relapse or for a fixed length of time  Trials have employed both approaches BUT no randomized trials comparing the two w/i a trial  Which agents  How many to use?  Doses?  Schedule(s)?  Very little data from randomized trials comparing different maintenance regimens as the only randomization

4 Maintenance Therapy in Myeloma: Steroids and  -Interferon 1.  -Interferon: a. 929 patients in 8 trials had prolongation of remission duration and survival by 6 and 5 months Ludwig H. Ann Oncol 1995;467 b. Twist analysis: IFN gained 9.8 months without relapse and 5.8 months survival, but with 4.1 months of toxicity Therefore, benefits must be balanced against toxicity Ludwig H. 1997;1672 2. Prednisone 50 mg qod prolongs overall and event-free survival after VAD induction therapy Berenson J. Blood 2002;99:3163

5 N Initial dose, mg/d Maintenance versus no maintenance CR, %EFS or PFS, %OS, % Attal et al. 1 597 400 w/ PAM 67 vs 55* 3-year EFS 52 vs 36 4-year OS 87 vs 77 Barlogie et al. 2 66840062 vs 43 5-year EFS 56 vs 44 8-year OS 57 vs 44 Spencer et al. 3 243 200 w/ steroid vs steroid alone 63 vs 40*3-year PFS 42 vs 23 3-year OS 86 vs 75 Lokhorst et al. 4 5355024 vs 66* Median 22 m vs 34 m Median 60 m vs 73 m Thalidomide: Maintenance Therapy after Autologous Stem Cell Transplant *CR + VGPR rates. 1.Attal M, et al. Blood. 2006 2. Barlogie B, et al. Blood 2008 3. Spencer A, et al. J clin Oncol. 2009 4. Lokhorst et al. Blood 2010 vs PAM or none

6 Bisphosphonates: Anti-Tumor Effects in MM Direct Induces apoptosis Prevents prenylation of GTPases Indirect Reduces anti-apoptotic and growth factors Anti-angiogenic Decreases angiogenic factors Prevents endothelial cell development Inhibits angioattraction M2 to M1 reversion of TAMs Prevents adhesion of MM cells to stroma Synergizes w/ other anti-MM drugs Immune stimulatory effects- Increases Vg9d2 T cells

7 Intergroupe Francophone du Myeloma (IFM) 99 02 –Large, randomized, prospective study Attal M et al Blood 2006; 108: 3289. VAD regimen 3-4 cycles No maintenance therapy (n = 200) Pts with untreated Stage I - III MM < 65 yrs old (N = 780) Melphalan 140 mg/m 2 and autologous stem-cell transplant Melphalan 200 mg/m 2 and second autologous stem-cell transplant Pamidronate (90 mg/mo) (n = 196) Pamidronate (90 mg/mo) + Thalidomide (100 mg/day) (n = 201) Pts who did not progress after 2 mos (n = 597) VAD; vincristine, doxorubicin, and dexamethasone Pamidronate With or Without Thalidomide as Post-transplantation Maintenance Therapy Survival benefit in the combination PAM + Thal arm and not in the single agent PAM arm

8 MRC Myeloma IX: Trial Design for Monthly IV Zoledronic Acid vs Daily Oral Clodronate for Newly Diagnosed MM Endpoints (ZOL vs CLO) –Primary: PFS, OS, and ORR –Secondary: Time to first SRE, SRE incidence, and safety N = 1,960 Patients with newly diagnosed MM (stage I, II, III) Clodronate (1600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Treatment continued at least until disease progression Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid. a Dose-adjusted for patients with impaired renal function, per the prescribing information. Morgan G, et al. Lancet. 2010;376:1989-1999.

9 MRC Myeloma IX: ZOL Improved OS and PFS vs CLO a a Cox model adjusted for chemotherapy, and minimization factors. Risk reduction Hazard ratio (ZOL versus CLO) 00.2 0.40.60.811.21.41.61.82 P value.0118 0.842 16% In favor of ZOL In favor of CLO OS.017912% 0.883 PFS ZOL significantly reduced the relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P =.0118) Morgan G, et al. Lancet. 2010;376:1989-1999.

10 Bortezomib as Maintenance Therapy VMPT-VT vs VMP: Study Design Endpoints: – Primary: PFS – Secondary: RR, OS, and grade ≥3 AEs Palumbo A, et al. Presented at: ASH. 2012 (abstr 200). VMPT (n=254) Induction: 9 courses Weekly BORT (4 doses; 1.3 mg/m 2 ) Melphalan 9 mg/m 2 Prednisone 60 mg/m 2 once daily on days 1-4 of each course Thalidomide 50 mg/day continuously VMPT (n=254) Induction: 9 courses Weekly BORT (4 doses; 1.3 mg/m 2 ) Melphalan 9 mg/m 2 Prednisone 60 mg/m 2 once daily on days 1-4 of each course Thalidomide 50 mg/day continuously VMP (n=257) 9 courses Weekly BORT (4 doses; 1.3 mg/m 2 ) Melphalan 9 mg/m 2 Prednisone 60 mg/m 2 once daily on days 1-4 of each course VMP (n=257) 9 courses Weekly BORT (4 doses; 1.3 mg/m 2 ) Melphalan 9 mg/m 2 Prednisone 60 mg/m 2 once daily on days 1-4 of each course RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE NDMM (N=511) SCT-ineligible Measurable disease Karnofsky PS ≥60% NDMM (N=511) SCT-ineligible Measurable disease Karnofsky PS ≥60% VT (n=254) Maintenance: 2 years BORT 1.3 mg/m 2 or maximum dose tolerated q2w Thalidomide 50 mg/day continuously VT (n=254) Maintenance: 2 years BORT 1.3 mg/m 2 or maximum dose tolerated q2w Thalidomide 50 mg/day continuously 10 No Maintenance Therapy (N=257) No Maintenance Therapy (N=257)

11 VMPT-VT vs VMP: PFS and Time to Next Therapy (TTNT) 1.00 0.75 0.50 0.25 0.00 01020304050607080 Median PFS, MonthsMedian TTNT, Months VMPT-VT35.346.6 VMP24.827.8 Reduced risk, %42 (of progression)48 (of next therapy) TTNT HR: 0.52 (95% CI, 0.42-0.66); P<0.0001 1.00 0.75 0.50 0.25 0.00 01020304050607080 PFS HR: 0.58 (95% CI, 0.47-0.71); P<0.0001 Time, Months Patients, % Median follow-up 54 months 11 TTNT=time to next therapy. Palumbo A, et al. Presented at: ASH. 2012 (abstr 200). VMPT-VT VMP

12 VMPT-VT vs VMP: Overall Survival Palumbo A, et al. Presented at: ASH. 2012 (abstr 200). Efficacy, %VcMPT-VcTVcMPP Value 5-yr PFS2913<0.0001 5-yr TTNT4119<0.0001 5-yr OS61510.01 3-yr OS from relapse47460.63 VMPT-VT VMP InductionMaintenance 1.00 0.75 0.50 0.25 0.00 01020304050607080 Proportion of Patients Time, Months HR: 0.74 (95% CI, 0.55-0.99); P=0.04 12

13 Impact of Maintenance Therapy: VMPT-VT vs VMP VMPT-VT Hematologic2% DVT1% Sensory neuropathy6% Infection1% Cardiologic1% Discont. due to AE11% Grade 3/4 AE’s during maintenance Landmark analysis after finishing 9 cycles of induction VMPT or VMP 52% reduced risk of progression with VMPT-VT (HR 0.48, P<0.0001) –Irrespective of response (CR or PR) –In pts <75 yrs old, but not ≥75 yrs Prognostic factors: response, age, ISS, cytogenetic abnormalities Palumbo et al. ASH 2010 (Abstract 620)

14 HOVON-65/GMMG-HD4: Study Design Primary endpoint: PFS Secondary endpoints: response, OS, toxicity PAD × 3 cycles BORT 1.3 mg/m 2 days 1, 4, 8, 11 doxorubicin 9 mg/m 2 days 1-4 dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=371) PAD × 3 cycles BORT 1.3 mg/m 2 days 1, 4, 8, 11 doxorubicin 9 mg/m 2 days 1-4 dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=371) VAD × 3 cycles Vincristine 0.4 mg days 1-4 Doxorubicin 9 mg/m 2 days 1-4 Dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=373) VAD × 3 cycles Vincristine 0.4 mg days 1-4 Doxorubicin 9 mg/m 2 days 1-4 Dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=373) BORT 1.3 mg/m 2 every 2 weeks BORT 1.3 mg/m 2 every 2 weeks Stem cell collection and transplantation* Stem cell collection and transplantation* Thalidomide 50 mg/day Thalidomide 50 mg/day Stem cell collection and transplantation* Stem cell collection and transplantation* 2 years Patients 18-65 years of age with newly diagnosed stage II/III MM (N=744) Patients 18-65 years of age with newly diagnosed stage II/III MM (N=744) Multicenter, International, Phase III Trial *ASCT + melphalan 200 mg/m 2 ; allogeneic SCT with no maintenance offered when possible; German patients enrolled through GMMG underwent 2 ASCTs. German centers performed double SCT; Dutch centers performed single SCT. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955

15 HOVON-65/GMMG-HD4: Response, PFS & OS Response VAD Arm: Thalidomide, % (n=414) PAD Arm: BORT, % (n=413) Pand t Value CR ≥ nCR ≥ VGPR ≥ PR 24 34 56 83 36 49 76 90 <0.001 0.002 PFS, % PAD VAD 012 2436 48 60 100 80 60 40 0 20 Time, Months OS, % 0 12 2436 4860 100 80 60 40 0 20 Time, Months PFS OS PAD VAD P=0.002 P=0.07 Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955 Improved PFS and OS in pts w/ del 17p13 and those w/ creatinine > 2 mg/dL

16 Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM 1,2 Endpoints: Primary: PFS; Secondary: response rate, OS, safety Patients: 266 pts <65 yrs of age with previously untreated MM randomized to maintenance therapy; median age 56–58 yrs across arms; 53–59% ISS stage II/III across arms Dose and schedule:  Induction: thalidomide/Dex (6 cycles) vs VTD (6 cycles) vs VBMCP/VBAD (4 cycles) + bortezomib (2 cycles); followed by ASCT with MEL-200; then second randomization to:  Maintenance: 3 arms bortezomib 1.3 mg/m 2 days 1, 4, 8, 11 every 3 mos + thalidomide 100 mg/day (VT) thalidomide 100 mg/day interferon-α2b 3 MU 3 times/week; for 3 yrs Respons e: Rosiñol L, et al. ASH 2012, abstract #334; Induction phase publication: Rosiñol L, et al. Blood 2012;120:1589-1596; Maintenance therapy previous publication: Rosiñol L, et al. ASH 2011, abstract #3962 Maintenance VT (n=89) Maintenance thalidomide (n=87) Maintenance interferon (n=90) Response before maintenance, % CR VGPR PR 53 12 33 49 11 37 53 13 33 Response improvement with maintenance, % CR post-maintenance Increase in CR 74 21 63 15 69 15

17 Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy for Previously Untreated MM 1,2 Outcomes: Median follow-up of 34.9 mos; from onset of maintenance therapy:  PFS: addition of bortezomib to thalidomide (VT) maintenance resulted in significantly longer PFS vs thalidomide or interferon (p=0.0009)  OS: No difference between arms (p=0.47)  Bortezomib-containing (VT) maintenance conferred a significant PFS advantage in pts with low-risk (p=0.002) but not high-risk (p=0.5) cytogenetics Safety:  Gr 3/4 thrombocytopenia for VT vs. thalidomide: 10% vs. 2%; p=0.01  Gr 3/4 neutropenia: Approximately 13% for VT, 16% for thalidomide, and 17% for interferon Rosiñol L, et al. ASH 2012, abstract #334 *p=0.02 vs thalidomide; # p=0.06 vs thalidomide; † discontinued thalidomide but remained on bortezomib

18 Phase III: VMP vs VTP in Newly Diagnosed Elderly Pts with MM (PETHEMA/GEM Study) Pts (n=260), >65 yrs old (median age 73 yrs) Multicenter, two-stage randomized trial VMPVTP vs VTVPVTVP Induction Randomization step 1 Maintenance Randomization step 2 vs Induction (max. 6 cycles) One 6-wk cycle, bortezomib 2x wkly Five 5-wk cycles, bortezomib 1x wkly Maintenance (up to 3 yrs) Bortezomib: 1.3 mg/m 2 (d 1, 4, 8, 11), every 3 mos + Thal: 50 mg daily (VT) or Pred: 50 mg every 48 hrs (VP) Mateos et al. Lancet Oncol 2010; 11(10): 934-941

19 PFS and OS No significant difference in PFS and OS between VMP and VTP groups and not significantly different for VT or VP maintenance p=0.1p=0.3 OSPFS VMP 34 mos VTP 25 mos VMP 3-yr OS 74% VTP 3-yr OS 65% Mateos et al. Lancet Oncol 2010; 11(10): 934-941

20  The role of maintenance therapy with novel agents has not been clearly defined (limitations in trial designs)  Long term use appears to be safe w/ bortezomib and steroids  Better trial designs are required to clarify the role of maintenance therapy in myeloma  Specific drugs  Single agent vs combination  Doses and schedules  Length of therapy- fixed vs to progression  Endpoints- PFS vs OS Summary

21  Maintenance therapy is used for all patients responding in both the frontline and salvage settings  Drugs are continued until progressive disease; however, doses may have to be reduced or discontinued due to toxicity  Drugs are continued that were part of the treatment regimen EXCEPT chemotherapy  New agents are NOT introduced during maintenance (i.e. the devil you know is better (and shown to be effective) than the one you don’t)- if so, this is NEW treatment  Steroids at equivalent dose intensity (160 mg Dex)/month as oral methylprednisolone qod alone or w/ IV Dex qow  Bortezomib 1.3 mg/m2 sc qow  IMiD drugs- Lenalidomide 10 mg for 14 or 21 days depending on regimen; THAL 50-100 mg daily and tapered w/ neuropathy  Zoledronic acid is continued monthly In Our Clinical Practice


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