Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Welcome and Introduction Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring: Moderator: Richard Lutes, MD

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Upfront Therapy Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring:

Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03) Rajkumar SV, et al, ASCO 2007, Abstract LBA Overall survival (mo) Probability Log-rank P= Rd RD ABAB Subjects, nEvents, n (%)Censored, n (%) Median survival (95% CI) A Len/High-dose Dex (RD)22341 (18)182 (82)NA (23.56, NA) B Len/Low-dose Dex (Rd)22213 (6)209 (94)NA (NA, NA)

Rajkumar SV, et al, ASCO 2007, Abstract LBA year survival rateNEvents Survival Probability (95% CI) Len-High Dex (RD) (0.82, 0.92) Len-Low Dex (Rd) (0.94, 0.99) Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)

Toxicity, % Len/ High-dose Dex n=217 Len/ Low-dose Dex n=216P value Any non-Hem toxicity (Grade ≥3) <0.001 Toxicity of any type (Grade ≥4) Early Deaths (<4 months) Rajkumar SV, et al, ASCO 2007, Abstract LBA8025. Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)

Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM trial) Best response at 12 months, % MP n=100 MPT n=100 At least PR (50%)3161 At least VGPR (90%)823 Complete remission17 P< hulin c, et al, ASCO 2007, Abstract 8001.

Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM trial) hulin c, et al, ASCO 2007, Abstract Time from randomization (mo) Log-rank P=0.05 Median follow-up time = 24 months MPT Median OS = 45.3 mo [33.3 – Unreached] Y/N=39/100 MP Placebo Median OS = 27.7 mo [24.6 – 34.9] Y/N=54/100 Proportion Overall survival by treatment (n=200)

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Upfront Therapy Discussion Discussion Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring: Moderator: Richard Lutes, MD

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting TransplantationTransplantation Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring:

TTIII plus bortezomib Barlogie B, et al, ASCO 2007, Abstract Months from Start of Induction PR nCR CR Percent of patients (%)

TTIII plus bortezomib Barlogie B, et al, ASCO 2007, Abstract Endpoint at 24 months% Overall survival87 Event-free survival84 CR91 nCR80 PR60 Treatment-related mortality5 Post-relapse survival34

Alternating bortezomib and dexamethasone as induction regimen in younger MM patients Rosinol L, et al, ASCO 2007, Abstract End of Induction Treatment (n=40) Best Response Ever Achieved (n=40) ORR: 77.5%ORR: 82.5% MRPRVGPRCRNon-evaluableProgressionStable

Alternating bortezomib and dexamethasone as induction regimen in younger MM patients Rosinol L, et al, ASCO 2007, Abstract Liver Gastrointestinal Peripheral Neuropathy Thrombocytopenia Percent Neutropenia Skin Grade 1 Grade 2 Grade Fatigue

Characteristics of patients relapsing after autologous stem cell transplant Characteristics, % Early relapse n=94 Late relapse n=338P value Male NS PCLI ≥1% <0.001 β 2 -microglobulin >3.5 mg/dL NS Bone disease NS Refractory at transplant Durie-Salmon: Stage II NS Stage III NS >1 induction regimen Abnormal karyotype3414.8< Circulating PC at collection Mahmood ST, et al, ASCO 2007, Abstract 8022.

Mel-based autotransplants for MM Retrospective analysis of 2836 transplant patients identified 5 factors that could influence outcomes –Type of treatment (tandem transplant or not) –Presence of cytogenetic abnormality –High β 2 -microglobulin –Low albumin –Low platelet counts Retrospective analysis of 2836 transplant patients identified 5 factors that could influence outcomes –Type of treatment (tandem transplant or not) –Presence of cytogenetic abnormality –High β 2 -microglobulin –Low albumin –Low platelet counts Pineda-Roman M, et al, ASCO 2007, Abstract 8043.

Reduced intensity conditioning 32 patients with relapsed/refractory MM –19 patients with HLA-identical sibling donor 5 patients had disease progression 4 patients in complete remission 5 patients in PR or VGPR –13 patients with no HLA-identical donor 11 patients had disease progression –Overall, 6 patients died from treatment-related mortality (incidence, 33%) 32 patients with relapsed/refractory MM –19 patients with HLA-identical sibling donor 5 patients had disease progression 4 patients in complete remission 5 patients in PR or VGPR –13 patients with no HLA-identical donor 11 patients had disease progression –Overall, 6 patients died from treatment-related mortality (incidence, 33%) Mohty M, et al, ASCO 2007, Abstract 8045.

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting TransplantationDiscussionTransplantationDiscussion Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring: Moderator: Richard Lutes, MD

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Treating Relapsed/Refractory Disease Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring:

Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alone Response rates, % Bortezomib n=310 PLD + bortezomib n=303P value Total (CR + nCR + PR) CR + nCR1317 PR3135 CR + VGPR* *According to IMWG 2006 criteria. Harousseau JL, et al, ASCO 2007, Abstract 8002.

Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alone Harousseau JL, et al, ASCO 2007, Abstract PLD + Bortezomib Censored Died 82% 18% 75% 25% HR (95% CI) 1.41 (1.002, 1.97) P < Time (d) Percent of Subjects Alive (%) PLD + Bortezomib Bortezomib Overall survival Median follow-up time: 14 mo

Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib Time to progression PLD + bortezomib (vs bortezomib) IMiD exposed PLD + bortezomib (vs bortezomib) IMiD naive Heterogeneity test* Median, d 270 (vs 205)295 (vs 189) Hazard ratio (95% CI) Log-rank P value) 1.62 (1.08, 2.41) P= (1.42, 2.84) P< P=0.446 *Treatment by subgroup (IMiD exposed, IMiD naïve) interaction test from the Cox model. Sonneveld P, et al, ASCO 2007, Abstract 8023.

Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib *According to IMWG criteria. Sonneveld P, et al, ASCO 2007, Abstract PLD + Bortezomib IMiD exposed n=123 PLD + Bortezomib IMiD naïve n=180 Time to progression, % OR (CR + PR)4847 CR45 PR4442 nCR99 CR + VGPR*3127 Duration of response (CR + PR), days

Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT) Palumbo AP, et al, ASCO 2007, Abstract Months P=0.02 ≥ PR < PR Age: 65 yearsResponse: PR rate Proportion of Patients 1 Months P=0.19 <65 years ≥65 years Proportion of Patients

Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT) Palumbo AP, et al, ASCO 2007, Abstract Months P=0.98 Del (13) No Deletion  2 -microglobulin Deletion (13) Proportion of Patients 1 Months P=0.06  2 m <3.5 mg/dL  2 m >3.5 mg/dL Proportion of Patients

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Novel Agents Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring:

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 7 th dose level reached so far –Combination treatment was well tolerated –Combination treatment resulted in inhibition of hsp90 and proteasome activity 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 7 th dose level reached so far –Combination treatment was well tolerated –Combination treatment resulted in inhibition of hsp90 and proteasome activity Richardson PG, et al, ASCO 2007, Abstract 3532.

Phase I evaluation of carfilzomib (PR-171) in hematologic malignancies 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/m 2 and heralds rapid decline in M-protein Objective responses have been observed at doses of carfilzomib ranging from 11 mg/m 2 to 27 mg/m 2 –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 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/m 2 and heralds rapid decline in M-protein Objective responses have been observed at doses of carfilzomib ranging from 11 mg/m 2 to 27 mg/m 2 –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 Stewart KA, et al, ASCO 2007, Abstract 8003.

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Novel Agents Discussion Discussion Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring: Moderator: Richard Lutes, MD

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Final Thoughts Nikhil Munshi, MD Dana-Farber Cancer Institute Boston, MA S. Vincent Rajkumar, MD Mayo Clinic Rochester, MN Featuring: Moderator: Richard Lutes, MD