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A Multicenter Prospective Randomized Study Testing Non-Inferiority

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									 Multiple Myeloma Update from the
 XIth International Myeloma Workshop (IMW)



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



                Genetics
                     Featuring:
         Sagar Lonial, MD    Meletios A.K. Dimopoulos, MD
  Winship Cancer Institute   National and Kapodistrian
        Emory University     University of Athens
              Atlanta, GA    Athens, Greece
                                  Genetics
                                  IFM 99-02 study
                                                 Patients <66 Years
                       1.00
                                                                      No t(4;14), no del(17p),
                                                                                     low 2m
    Overall Survival




                       0.75


                                                             Other
                       0.50



                       0.25
                                            T(4;14) or del(17p), and high 2m


                       0.00
                              0      100   200       300       400     500      600      700
                                                           Time (d)
Avet-Loiseau H, et al, IMW 2007, Abstract S1.5.
Multiple Myeloma Update from the
XIth International Myeloma Workshop (IMW)

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



       Upfront Therapy
                     Featuring:
         Sagar Lonial, MD    Meletios A.K. Dimopoulos, MD
  Winship Cancer Institute   National and Kapodistrian
        Emory University     University of Athens
              Atlanta, GA    Athens, Greece
                Melphalan/prednisone/thalidomide (MPT)
                vs melphalan/prednisone (MP) in patients
                aged ≥75 years (IFM 01-01 trial)

    Best response at                         MP           MPT
    12 months, %                            n=100        n=100
    At least PR (50%)                        31              61

    At least VGPR (90%)                       8              23

    CR                                        1              7
                                                  P<0.0001


Hulin C, et al, IMW 2007, Abstract S11.8.
                       Melphalan/prednisone/thalidomide (MPT)
                       vs melphalan/prednisone (MP) in patients
                       aged ≥75 years (IFM 01-01 trial) (cont)
                             Overall survival by treatment (n=200)
                  1
                                                              MPT
                                                           Median OS = 45.3 mo
   Proportion




                0.75                                       [33.3 – Unreached] Y/N=39/100

                0.50
                              MP Placebo
                0.25       Median OS = 27.7 mo
                           [24.6 – 34.9] Y/N=54/100
                  0
                       0         10         20        30         40       50        60
                                      Time from Randomization (mo)

                                            Log-rank P=0.05
                                   Median follow-up time = 24 months

Hulin C, et al, IMW 2007, Abstract S11.8.
             Melphalan/prednisone/lenalidomide (MPR)

                     Best response, %                               n=54

                     PR                                             81.4

                     VGPR                                           47.6

                     CR                                             23.8

      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.
               Long-term follow-up of bortezomib/
               adriamycin/dexamethasone (PAD)

                                             PAD 1 trial   PAD 2 trial
    Best response, %                           n=21          n=19
    Overall response rate                        95            89
         CR                                      24            11
         nCR                                     5             5
         VGPR                                    33            26
         PR                                      33            47


Popat R, et al, IMW 2007, Abstract PO-725.
            Bortezomib plus melphalan/prednisone
            vs melphalan/prednisone
            VISTA trial design


 Eligibility Criteria
 • Previously
  untreated MM                                            Melphalan/
                                                          Prednisone
 • Not eligible for                                                       Key endpoints
  HDT/SCT                       Randomization
                                     1:1                                Time to progression
 • Presence of
  measurable                                                                 Survival
  disease                            n=680
                                                          Bortezomib/
 • Karnofsky                                              Melphalan/
  performance                                             Prednisone
  status score ≥60%


                                                   Completed accrual

Information from clinicaltrials.gov and investor.millennium.com.
               Phase I/II trial of
               lenalidomide/bortezomib/dexamethasone


           Best response, n                                                      15

           ORR                                                                  100


           CR                                                                    20

             MTD not yet achieved.




Richardson PG, et al, IMW 2007, Abstract PO-715; June 28, 2007 Press release from Millennium Pharmaceuticals.
Multiple Myeloma Update from the
XIth International Myeloma Workshop (IMW)

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



        Transplantation
                     Featuring:
         Sagar Lonial, MD    Meletios A.K. Dimopoulos, MD
  Winship Cancer Institute   National and Kapodistrian
        Emory University     University of Athens
              Atlanta, GA    Athens, Greece
                Alternating bortezomib and
                dexamethasone as induction
                regimen in younger MM patients
              Best Response Ever Achieved                   End of Induction Treatment
                        (n=40)                                        (n=40)
                           8%                                             3%
                                              17%                                      17%
                    8%                                           17%

                 3%
                                                            3%
              12%

                                                           13%

                 10%                                                                     39%
                                                42%
                                                                  8%

                           ORR: 82.5%                                  ORR: 77.5%

                MR        PR       VGPR         CR    Non-evaluable      Progression         Stable

Rosinol L, et al, IMW 2007, Abstract S7b.1.
                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        20       40    60       80        100
                                                   Percent
Rosinol L, et al, IMW 2007, Abstract S7b.1.
               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.
                Single vs tandem transplant

                                                  Single   Tandem
                Response, %                       n=384     n=101
                CR or VGPR*                        40        60
                Probability of 5-year EFS*         25        14
                5-year OS rate                     50        50
                *P=0.001




Bjorkstrand B, et al, IMW 2007, Abstract S7b.4.
Maintenance therapy after stem cell
transplantation

• The role of thalidomide?
• The role of bortezomib or
  lenalidomide?
Multiple Myeloma Update from the
XIth International Myeloma Workshop (IMW)

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



Treating Relapsed/Refractory Disease

                         Featuring:
             Sagar Lonial, MD    Meletios A.K. Dimopoulos, MD
      Winship Cancer Institute   National and Kapodistrian
            Emory University     University of Athens
                  Atlanta, GA    Athens, Greece
               Lenalidomide/dexamethasone vs
               placebo/dexamethasone (MM-010 study)

                             Lenalidomide/   Placebo/
   Response                 dexamethasone dexamethasone P value

   TTP, mo                             11.3            4.7   0.001

   PR, %                                59             24    0.001




Anagnostopoulos A, et al, IMW 2007, Abstract PO-661.
              Pegylated liposomal doxorubicin (PLD) and
              bortezomib vs bortezomib alone
                                                     PLD +
     Response rates,                    Bortezomib bortezomib
     %                                    n=310      n=303    P value
     Total
                                              44       52       0.05
     (CR + nCR + PR)
     CR + nCR                                 13       17

     PR                                       31       35

     CR + VGPR*                               20       30      0.007
*According to IMWG 2006 criteria.
Nagler A, et al, IMW 2007, Abstract PO-625.
                                          Pegylated liposomal doxorubicin (PLD) and
                                          bortezomib vs bortezomib alone (cont)
                                                                 Overall survival
    Percent of Subjects Alive (%)




                                    100
                                                           Median follow-up time: 14 mo

                                     80                                                      PLD + Bortezomib


                                     60

                                                            PLD +
                                                                                                   Bortezomib
                                     40                   Bortezomib    Bortezomib
                                              Censored       82%            75%
                                                Died         18%            25%
                                     20
                                                 HR (95% CI) 1.41 (1.002, 1.97)
                                                           P<0.05
                                      0
                                          0       100         200         300         400    500     600        700
                                                                                  Time (d)
Nagler A, et al, IMW 2007, Abstract PO-625.
    Multiple Myeloma Update from the
    XIth International Myeloma Workshop (IMW)


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



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

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



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


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



      Closing Remarks
                     Featuring:
         Sagar Lonial, MD    Meletios A.K. Dimopoulos, MD
  Winship Cancer Institute   National and Kapodistrian
        Emory University     University of Athens
              Atlanta, GA    Athens, Greece
                      Moderator:
                  Thomas J. Burke

								
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