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Multiple Myeloma Update from the XI th International Myeloma Workshop (IMW)

Multiple Myeloma Update from the XI th International Myeloma Workshop (IMW). Welcome and Introduction. Featuring:. Sagar Lonial, MD Winship Cancer Institute Emory University Atlanta, GA. Meletios A.K. Dimopoulos, MD National and Kapodistrian University of Athens Athens, Greece.

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Multiple Myeloma Update from the XI th International Myeloma Workshop (IMW)

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  1. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Welcome and Introduction Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

  2. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Genetics Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  3. 1.00 0.75 0.50 0.25 0.00 0 100 200 300 400 500 600 700 GeneticsIFM 99-02 study Patients <66 Years No t(4;14), no del(17p), low 2m Other Overall Survival T(4;14) or del(17p), and high 2m Time (d) Avet-Loiseau H, et al, IMW 2007, Abstract S1.5.

  4. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Genetics Discussion Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

  5. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Upfront Therapy Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  6. Melphalan/prednisone/thalidomide (MPT) vs melphalan/prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial) Hulin C, et al, IMW 2007, Abstract S11.8.

  7. 1 0.75 MP Placebo Median OS = 27.7 mo [24.6 – 34.9] Y/N=54/100 0.50 0.25 0 0 10 20 30 40 50 60 Melphalan/prednisone/thalidomide (MPT) vs melphalan/prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial) (cont) Overall survival by treatment (n=200) MPT Median OS = 45.3 mo [33.3 – Unreached] Y/N=39/100 Proportion Time from Randomization (mo) Log-rank P=0.05 Median follow-up time = 24 months Hulin C, et al, IMW 2007, Abstract S11.8.

  8. Melphalan/prednisone/lenalidomide (MPR) Above responses were obtained with the maximum tolerated dose (MTD) of lenalidomide 10 mg/day for 21 days, melphalan 0.18 mg/kg for 4 days, and prednisone 2 mg/kg for 4 days monthly. Palumbo A, et al, IMW 2007, Abstract PO-717.

  9. Long-term follow-up of bortezomib/ adriamycin/dexamethasone (PAD) Popat R, et al, IMW 2007, Abstract PO-725.

  10. Bortezomib plus melphalan/prednisone vs melphalan/prednisoneVISTA trial design • Eligibility Criteria • Previously untreated MM • Not eligible for HDT/SCT • Presence of measurable disease • Karnofsky performance status score ≥60% Melphalan/Prednisone • Key endpoints • Time to progression • Survival Randomization1:1 n=680 Bortezomib/Melphalan/Prednisone Completed accrual Information from clinicaltrials.gov and investor.millennium.com.

  11. Phase I/II trial of lenalidomide/bortezomib/dexamethasone MTD not yet achieved. Richardson PG, et al, IMW 2007, Abstract PO-715; June 28, 2007 Press release from Millennium Pharmaceuticals.

  12. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Upfront Therapy Discussion Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

  13. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Transplantation Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  14. MR PR VGPR CR Non-evaluable Progression Stable Alternating bortezomib and dexamethasone as induction regimen in younger MM patients Best Response Ever Achieved (n=40) End of Induction Treatment (n=40) ORR: 82.5% ORR: 77.5% Rosinol L, et al, IMW 2007, Abstract S7b.1.

  15. 20 40 60 Alternating bortezomib and dexamethasone as induction regimen in younger MM patients (cont) Thrombocytopenia Neutropenia Peripheral Neuropathy Skin Grade 1 Gastrointestinal Grade 2 Grade 3 Fatigue Liver 0 80 100 Percent Rosinol L, et al, IMW 2007, Abstract S7b.1.

  16. Tandem autologous vs autologous followed by mini-allogeneic transplants Three trials • French group (IFM 99-03 and IFM 99-04) • No difference in EFS • OS: 59 months for auto-auto vs 35 months for auto-allo (P=0.016) • Spanish group • No difference in EFS or OS • CR rate: 11% in auto-auto group vs 33% in auto-allo group (P=0.02) • US group • No difference in OS or PFS at 2 years • At 4 years, groups appeared to separate but no statistical differences except • Relapse rate: 39% in auto-auto group vs 58% in the auto-allo group (P=0.05) Moreau P, et al, IMW 2007, Abstract S7b.2; Rosinol L, et al, IMW 2007, Abstract PO-809; Sahebi F, et al, IMW 2007, Abstract PO-810.

  17. Single vs tandem transplant *P=0.001 Bjorkstrand B, et al, IMW 2007, Abstract S7b.4.

  18. Maintenance therapy after stem cell transplantation • The role of thalidomide? • The role of bortezomib or lenalidomide?

  19. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Transplantation Discussion Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

  20. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Treating Relapsed/Refractory Disease Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  21. Lenalidomide/dexamethasone vs placebo/dexamethasone (MM-010 study) Anagnostopoulos A, et al, IMW 2007, Abstract PO-661.

  22. Pegylated liposomal doxorubicin (PLD) and bortezomib vs bortezomib alone *According to IMWG 2006 criteria. Nagler A, et al, IMW 2007, Abstract PO-625.

  23. 0 100 200 300 400 500 600 700 Pegylated liposomal doxorubicin (PLD) and bortezomib vs bortezomib alone (cont) Overall survivalMedian follow-up time: 14 mo 100 PLD + Bortezomib 80 60 Percent of Subjects Alive (%) Bortezomib 40 20 0 Time (d) Nagler A, et al, IMW 2007, Abstract PO-625.

  24. Treating Relapsed/Refractory Disease Discussion Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Featuring: Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Moderator: Thomas J. Burke

  25. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Novel Agents Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  26. Tanespimycin + bortezomib in relapsed/refractory MM • Tanespimycin (17-AAG/KOS-953) disrupts heat shock protein 90 (hsp90), a molecular chaperone that transports proteins critical for MM growth, survival, and drug resistance • Phase I dose escalation study in 49 patients • 7th dose level reached so far • Combination treatment was well tolerated • Combination treatment resulted in inhibition of hsp90 and proteasome activity Richardson PG, et al, IMW 2007, Abstract PO-615.

  27. Perifosine (KRX-0401) • Oral, signal transduction modulator • Inhibits Akt and activates Jnk • Current trials • Phase I/II trial with bortezomib in patients with relapsed/refractory MM • Phase I and phase II trials with lenalidomide and dexamethasone in patients with relapsed/refractory MM Richardson PG, et al, IMW 2007, Abstract PO-608; Jakubowiak A, et al, IMW 2007, Abstract PO-606; Richardson PG, et al, IMW 2007, Abstract PO-607.

  28. Carfilzomib (PR-171) • Carfilzomib is a novel irreversible proteasome inhibitor • Promotes >80% proteasome inhibition in the blood • Dose-limiting toxicities • Myelosuppression: cyclic reversible thrombocytopenia and neutropenia • A “first dose effect” has occurred at doses ≥20 mg/m2 and heralds rapid decline in M protein • Objective responses have been observed at doses of carfilzomib ranging from 11 mg/m2 to 27 mg/m2 • Rapid onset of response (<1 month) • Responses are durable (4 to >9.5 months) • Responses noted in bortezomib and IMiD failures • Stable disease for >1 year Alsina M, et al, IMW 2007, Abstract PO-611.

  29. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Novel Agents Discussion Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

  30. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Complications of Disease and Treatment Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece

  31. Osteonecrosis of the jaw (ONJ) • Occurs as a result of long-term bisphosphonate treatment, frequently in MM patients • ONJ may occur more frequently in patients treated with zoledronate and pamidronate • Lesions should be biopsied to assess potential MM involvement • Osteoblast and osteoclast genes and proteins are significantly downregulated in patients with ONJ • Antibiotic prophylaxis before/after dental procedures appears to decrease the incidence of ONJ Montefusco V, et al, IMW 2007, Abstract PO-1115; Cafro AM, et al, IMW 2007, Abstract PO-1116; Tacchetti P, et al, IMW 2007, Abstract PO-1117; Raje N, et al, IMW 2007, Abstract PO-1118; Gil R, et al, IMW 2007, Abstract PO-1119.

  32. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Complications of Disease and Treatment Discussion Featuring: Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Moderator: Thomas J. Burke

  33. Multiple Myeloma Update from the XIth International Myeloma Workshop (IMW) Closing Remarks Featuring: Sagar Lonial, MD Winship Cancer InstituteEmory UniversityAtlanta, GA Meletios A.K. Dimopoulos, MD National and Kapodistrian University of AthensAthens, Greece Moderator: Thomas J. Burke

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