1 / 21

Maintenance Therapy in Multiple Myeloma

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. Maintenance Therapy in Myeloma.

david-manning
Download Presentation

Maintenance Therapy in Multiple Myeloma

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

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 > 2nd 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 a-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. Thalidomide: Maintenance Therapy after Autologous Stem Cell Transplant vs PAM or none • 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 * CR + VGPR rates.

  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. Pamidronate With or Without Thalidomide as Post-transplantation Maintenance Therapy • Intergroupe Francophone du Myeloma (IFM) 99 02 • Large, randomized, prospective study No maintenance therapy (n = 200) VAD regimen 3-4 cycles Melphalan 140 mg/m2 and autologous stem-cell transplant Melphalan 200 mg/m2 and second autologous stem-cell transplant Pts with untreated Stage I - III MM < 65 yrs old (N = 780) Pts who did not progress after 2 mos (n = 597) Pamidronate (90 mg/mo) (n = 196) Pamidronate (90 mg/mo) + Thalidomide (100 mg/day) (n = 201) VAD; vincristine, doxorubicin, and dexamethasone Survival benefit in the combination PAM + Thal arm and not in the single agent PAM arm Attal M et al Blood 2006; 108: 3289.

  8. MRC Myeloma IX: Trial Design for Monthly IV Zoledronic Acid vs Daily Oral Clodronate for Newly Diagnosed MM Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy(n = 981) RANDOMIZATION N = 1,960 Patients with newly diagnosed MM (stage I, II, III) Treatment continued at least until disease progression Clodronate (1600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) • Endpoints (ZOL vs CLO) • Primary: PFS, OS, and ORR • Secondary: Time to first SRE, SRE incidence, and safety 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 CLOa • ZOL significantly reduced the relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P = .0118) Riskreduction P value 0.842 OS .0118 16% 0.883 PFS 12% .0179 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 Hazard ratio (ZOL versus CLO) In favor of CLO In favor of ZOL a Cox model adjusted for chemotherapy, and minimization factors. Morgan G, et al. Lancet. 2010;376:1989-1999.

  10. Bortezomib as Maintenance Therapy VMPT-VT vs VMP: Study Design VMPT (n=254) Induction: 9 courses Weekly BORT (4 doses; 1.3 mg/m2) Melphalan 9 mg/m2 Prednisone 60 mg/m2 once daily on days 1-4 of each course Thalidomide 50 mg/day continuously • Endpoints: • Primary: PFS • Secondary: RR, OS, and grade ≥3 AEs VT (n=254) Maintenance: 2 years BORT 1.3 mg/m2 or maximum dose tolerated q2w Thalidomide 50 mg/day continuously RANDOMIZE NDMM (N=511) SCT-ineligible Measurable disease Karnofsky PS ≥60% VMP (n=257) 9 courses Weekly BORT (4 doses; 1.3 mg/m2) Melphalan 9 mg/m2 Prednisone 60 mg/m2 once daily on days 1-4 of each course No Maintenance Therapy (N=257) Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).

  11. VMPT-VT vs VMP: PFS and Time to Next Therapy (TTNT) Median follow-up 54 months TTNT HR: 0.52 (95% CI, 0.42-0.66); P<0.0001 PFS HR: 0.58 (95% CI, 0.47-0.71); P<0.0001 1.00 1.00 0.75 0.75 Patients, % Patients, % VMPT-VT VMPT-VT 0.50 0.50 VMP VMP 0.25 0.25 0.00 0.00 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 Time, Months Time, Months TTNT=time to next therapy. Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).

  12. VMPT-VT vs VMP: Overall Survival Induction Maintenance 1.00 Proportion of Patients 0.75 VMPT-VT 0.50 VMP 0.25 HR: 0.74 (95% CI, 0.55-0.99); P=0.04 0.00 0 10 20 30 40 50 60 70 80 Time, Months Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).

  13. Impact of Maintenance Therapy: VMPT-VT vs VMP 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 Grade 3/4 AE’s during maintenance Palumbo et al. ASH 2010 (Abstract 620)

  14. HOVON-65/GMMG-HD4: Study Design PAD × 3 cycles BORT 1.3 mg/m2days 1, 4, 8, 11 doxorubicin 9 mg/m2days 1-4 dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=371) Multicenter, International, Phase III Trial • Primary endpoint: PFS • Secondary endpoints: response, OS, toxicity Stem cell collection and transplantation* BORT 1.3 mg/m2 every 2 weeks Patients 18-65 years of age with newly diagnosed stage II/III MM (N=744) 2 years VAD × 3 cycles Vincristine 0.4 mg days 1-4 Doxorubicin 9 mg/m2days 1-4 Dexamethasone 40 mg days 1-4, 9-12, 17-20 (n=373) Stem cell collection and transplantation* Thalidomide 50 mg/day *ASCT + melphalan 200 mg/m2; 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 OS PFS 100 100 PFS, % OS, % 80 80 60 60 PAD VAD PAD VAD P=0.002 P=0.07 40 40 20 20 Time, Months Time, Months Improved PFS and OS in pts w/ del 17p13 and those w/ creatinine > 2 mg/dL 0 0 0 12 60 24 36 48 48 60 0 24 36 12 Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955

  16. Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM1,2 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/m2 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 Response: 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

  17. Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy for Previously Untreated MM1,2 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 Induction Randomization step 1 Induction (max. 6 cycles) • One 6-wk cycle, bortezomib 2x wkly • Five 5-wk cycles,bortezomib 1x wkly VMP vs VTP Maintenance Randomization step 2 Maintenance (up to 3 yrs) Bortezomib: 1.3 mg/m2 (d 1, 4, 8, 11), every 3 mos + Thal: 50 mg daily (VT) or Pred: 50 mg every 48 hrs (VP) vs vs VT VP VT 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 PFS OS VMP 3-yr OS 74% VMP 34 mos VTP 3-yr OS 65% VTP 25 mos p=0.1 p=0.3 Mateos et al. Lancet Oncol 2010; 11(10): 934-941

  20. Summary • 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

  21. In Our Clinical Practice • 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

More Related