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Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting

Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting. Welcome and Introduction. Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting. Todd Zimmerman, MD The University of Chicago Medical Center

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Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting

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  1. Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting

  2. Welcome and Introduction Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  3. Upfront and Induction TherapyEligible for Transplant Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  4. Upfront and Induction Therapy RVD (Lenalidomide + Bortezomib + Dexamethasone) Phase I/II Trial in Newly Diagnosed Multiple Myeloma (MM) Patients • 57% CR/nCR and 74% VGPR in phase II is very encouraging • Induction regimen that may allow autologous stem cell transplant (ASCT) to be kept in reserve • Favorable tolerability profile (50% Grade 1, 20% Grade 2 neuropathy) Anderson KC et al. 2010 ASCO. Abstract 8016.

  5. Upfront and Induction Therapy vTD (Reduced-Dose Bortezomib + Thalidomide + Dexamethasone) as Induction for ASCT in de novo MM Patients (n=205) • 25% bortezomib dose-reduction protocol (vTD) had superior efficacy and markedly reduced peripheral neuropathy (PN) vs full-dose VD despite addition of thalidomide Moreau P et al. 2010 ASCO. Abstract 8014.

  6. Upfront and Induction Therapy Other ASCT-induction combinations with consistent VGPR ≥70% • Proteasome inhibitor (eg, bortezomib) + immunomodulatory agent (IMiD) • Cyclophosphamide + bortezomib + dexamethasone (CyBorD) • Liposomal doxorubicin + bortezomib + dexamethasone • Liposomal doxorubicin + bortezomib + IMiD Greater attention to toxicities warranted when the following agents are used as cotherapy • Cyclophosphamide • Liposomal doxorubicin Khan ML et al. 2010 ASCO. Abstract 8131; Berenson JR et al. 2010 ASCO. Abstract 8134.

  7. Upfront and Induction Therapy Phase III Trial of Melphalan + Prednisone + Lenalidomide (MPR) vs Melphalan 200 mg/m2 (MEL200) in Newly Diagnosed Patients • Induction: lenalidomide + low-dose dexamethasone used for induction • Stem-cell mobilization: cyclophosphamide + granulocyte-colony stimulating factor (G-CSF) • Consolidation: randomized to MPR or MEL200 (tandem melphalan with ASCT support) • MPR and MEL200 both improved quality of induction response • PFS and OS not significantly different between protocols Palumbo AP et al. 2010 ASCO. Abstract 8015.

  8. Stem Cell Transplant • Phase III Trials Evaluating Benefit of Post-ASCT Maintenance With Lenalidomide • Cancer and Leukemia Group B (CALGB) Trial • N=568 post-ASCT patients • Lenalidomide at day 100 to 110 post-ASCT significantly delays time-to-progression (TTP) vs placebo regardless of β2-M level • Intergroupe Francophone du Myélome (IFM) Trial • N=614 post-ASCT patients • 3-yr PFS was 68% with lenalidomide maintenance vs 35% placebo • PFS advantage regardless of whether patients had CR following ASCT • Conclusions • Disease progression primary cause of post-ASCT treatment failure • Lenalidomide prolongs PFS and delays TTP after ASCT • Lenalidomide has reasonable tolerability profile McCarthy PL et al. 2010 ASCO. Abstract 8017; Attal M et al. 2010 ASCO. Abstract 8018.

  9. Upfront and Induction TherapyNot Eligible for Transplant Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  10. Treatments forTransplant-Ineligible Patients Potential Impact of Novel Combinations • VISTA trial confirmed benefit of VMP (bortezomib + melphalan + prednisone) vs MP • Phase III trial: 4-drug combination of VMP + thalidomide (VMPT) significantly improves PFS and overall response rates (ORR)vs VMP • VMPT patients received VT maintenance (VMPT-VT) • Infusion of bortezomib at weekly intervals (vs 6-week cycles) significantly improved incidence of Grade 3/4 PN Boccadoro M et al. 2010 ASCO. Abstract 8013.

  11. Maintenance Therapy Importance of Maintenance Therapy • Not mandatory but should be considered • Keeping or maintaining remission critical to long-term survival of MM patients • Lenalidomide in maintenance protocols has evidence-based benefit • Individual patient tolerance of treatment side effects a consideration

  12. Treating Relapsed/Refractory DiseaseNovel Agents Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  13. Relapsed/Refractory Disease: Novel Agents Carfilzomib: A Second-Generation Proteasome Inhibitor • Irreversible proteasome inhibition (differs from bortezomib) • Has activity in bortezomib-resistant patients • CR rate may not be equivalent to bortezomib, but optimum dose still to be determined • Occasional renal effects controlled with hydration, low-dose steroids; less neurotoxic than bortezomib • Outcomes of phase II trials may justify accelerated approval • Carfilzomib + lenalidomide + low-dose dexamethasone an active, well-tolerated combination (Abstract 8029) Bensinger W et al. 2010 ASCO. Abstract 8029; Badros AZ et al. 2010 ASCO. Abstract 8128; Lee P et al. 2010 ASCO. Abstract 8147; Wolf JL et al. 2010 ASCO. Abstract 8135; Vij R et al. 2010 ASCO. Abstract 8000.

  14. Relapsed/Refractory Disease: Novel Agents Phase Ib Trial of Carfilzomib + Lenalidomide + Low-Dose Dexamethasone (CRd) in RR Patients Bensinger W et al. 2010 ASCO. Abstract 8029.

  15. Relapsed/Refractory Disease:Novel Agents Pomalidomide: The Newest IMiD • Newest entry in drug class with proven anti-MM activity • Favorable toxicity profile, similar to lenalidomide • May fill niche for patients refractory to lenalidomide or bortezomib • Pomalidomide + dexamethasone had 46% ORR in heavily pretreated patients R/R to lenalidomide + bortezomib • Results corroborated in parallel study at higher oral dose (4 mg/day vs 2 mg/day) Lacy M et al. 2010 ASCO. Abstract 8002.

  16. Relapsed/Refractory Disease:Novel Agents Deacetylase Inhibitors: Vorinostat and Panobinostat • Orally administered therapeutic option for patients with R/R MM • Manageable toxicity profile, no Grade 3/4 PN • Activity seen in patients pretreated with bortezomib and lenalidomide • PAN + BTZ trial: activity with steroid-free regimen (Abstract 8001) Alsina M et al. 2010 ASCO. Abstract TPS308; Jagannath S et al. 2010 ASCO. Abstract 8133; Mateos M et al. 2010 ASCO. Abstract 8030; Richardson PG et al. 2010 ASCO. Abstract 8031; San-Miguel JF et al. 2010 ASCO. Abstract 8001.

  17. Relapsed/Refractory Disease:Novel Agents RAD-001 and Elotuzumab • RAD-001 (everolimus): mTOR Inhibitor • Oral agent evaluated in steroid-sparing protocols • RAD-001 + lenalidomide: 63% (12/19) MR + PR (Abstract 8032) • Single-agent RAD-001: 53% (8/15) PR + SD (Abstract 8137) Elotuzumab: humanized monoclonal antibody (targets CS1 glycoprotein, highly expressed in MM) • Elotuzumab + bortezomib: 60% (17/28 ) ≥ MR (Abstract 8003) • Infusion produced saturation of CS1 sites in bone marrow plasma cells • Elotuzumab + lenalidomide + dexamethasone: 82% (23/28) ORR (Abstract 8020) Jakubowiak AJ et al. 2010 ASCO. Abstract 8003; Lonial S et al. 2010 ASCO. Abstract 8020; Guenther A et al. 2010 ASCO. Abstract 8137; Mahindra AK et al. 2010 ASCO. Abstract 8032.

  18. Novel Agents Zoledronic Acid (ZA): Bone-Sparing Bisphosphonate • Phase III trial (n=1970), ZA vs clodronate (CLO) in newly diagnosed MM patients • Skeletal-related effects (SREs): 27% ZA; 35.3% CLO (P=0.0004) • OS: 50 mos, ZA; 44.5 mos, CLO (P=0.01) • PFS: 19.5 mos, ZA; 17.5 mos, CLO (P=0.018) • ZA has superior SRE prevention efficacy AND significant survival benefits • Survival benefits were independent of SRE prevention • “Practice changing” outcome supports role of bisphosphonate class in MM therapy • Potentially reverses anecdotal trend away from bisphosphonates due to infusion-associated toxicities Morgan G et al. 2010 ASCO. Abstract 8021.

  19. Relapsed/Refractory Disease:Novel Agents Denosumab vs Zoledronic Acid for Prevention of Skeletal-Related Effects • Denosumab: human monoclonal antibody targeting RANK ligand pathway of osteoclast activity; different mechanism of action (MOA) vs bisphosphonates • Phase III trial: denosumab (n=886) vs ZA (n=890) • Time to 1st SRE: 19 mos, denosumab; 14.4 mos ZA (P=0.02) • SRE Incidence: 31.4%, denosumab; 36.3%, ZA • Similar overall adverse event (AE) rates for both groups • Acute-phase AEs within 3 days: 6.9%, denosumab; 14.5%, ZA • Denosumab prolonged time to SRE and had lower rates of AEs including pain Vadhan-Raj S et al. 2010 ASCO. Abstract 9042; von Moos R et al. 2010 ASCO. Abstract 9043.

  20. Genetics and Other Risk Factors Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  21. Genetics Role of Gene Expression Profiling (GEP) • Should not displace ISS staging – simple, bedside system for MM patients • GEP identifies investigational or novel interventions suitable for high-risk patients who respond poorly or only briefly • Focuses on cytogenetic abnormalities, MM-associated gene deletions • Important not to focus therapeutic decisions or expectations on a single biomarker • Data indicate bortezomib can overcome cytogenetics and other unfavorable disease markers Barlogie B et al. 2010 ASCO Abstract 8019; Haessler J et al. 2010 ASCO. Abstract 8123; Qiang Y et al. 2010 ASCO. Abstract 8126; Shaughnessy JD et al. 2010 ASCO. Abstract 8027.

  22. Genetic Profiles Role of Bortezomib in Overcoming High-Risk Genetic Profiles • Bortezomib combinations (eg, RVD) have proven efficacy and tolerable side-effect profile in high-risk patient – Bortezomib + dexamethasone, then MEL200, overcame t(4:14) associated with poor MM outcome in newly diagnosed patients (Abstract 8113) • Phase II study: bortezomib + doxorubicin + dexamethasone in newly diagnosed patients with 1q21 chromosome amplification – ORR comparable in 1q21-positive (7/7) and 1q21-negative (16/17) patients (Abstract 8028) Avet-Loiseau H et al. 2010 ASCO. Abstract 8113; Joshua DE et al. 2010 ASCO. Abstract 8028.

  23. Final Thoughts Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Todd Zimmerman, MD The University of ChicagoMedical Center Chicago, IL Paul G. Richardson, MD Harvard Medical School Dana-Farber Cancer InstituteBoston, MA Moderated by Anne Quinn Young, MPH

  24. Future Issues forMultiple Myeloma Therapy • Can novel therapies enable delaying or avoiding ASCT? • Still recommend stem-cell harvesting • How can novel agents be combined most effectively with ASCT? • Using clinical trial data to derive tailored therapies using novel agents

  25. Multiple Myeloma Update From the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting Closing Remarks Anne Quinn Young, MPHMultiple Myeloma Research FoundationNorwalk, CT www.multiplemyeloma.org

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