Robert Z. Orlowski, MD, PhD Associate Professor of Lymphoma/Myeloma and of Experimental Therapeutics Division of Cancer Medicine Director, Myeloma Section The University of Texas M. D. Anderson Cancer Center Houston, Texas Treatment of Patients With Relapsed or Refractory Multiple Myeloma This program is supported by an educational grant from

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Overview  Description of Sample Case  Novel Agents and Combinations in Multiple Myeloma  Considerations for Treatment Selection in Patients with Relapsed/Refractory Multiple Myeloma

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Sample Case: Initial Presentation  A 62-year-old black female presented with several months of right hip pain  Her primary care physician obtained a plain radiographic scan, which showed a 4-cm right hip lytic lesion –A follow-up bone scan showed mildly increased uptake in this region only, without other areas of abnormal signal intensity  A CT-guided biopsy showed CD138+  -restricted plasma cells consistent with a plasmacytoma

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  A complete blood cell count showed mild anemia –Hemoglobin: 10.8 g/dL  An electrolyte panel was normal –No abnormal elevation of calcium or creatinine –The total protein was 9.1 g/dL with an albumin level of 3.6 g/dL  A CT-guided biopsy of the lytic hip lesion showed CD138+  -restricted plasma cells consistent with a plasmacytoma  The patient was referred to a hematologist/oncologist Additional Initial Diagnostic Studies

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Initial Oncologic Studies  A bone survey showed several additional lytic lesions in the skull  Serum protein electrophoresis showed IgG  M-protein level of 2.5 g/dL, with reciprocal suppression of IgM and IgA  Urine protein electrophoresis showed a faint IgG  M- protein, visible only on immunofixation  While the albumin level was normal,  2 -microglobulin was modestly elevated at 4.1 mg/L

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Additional Oncologic Studies  Bone marrow aspiration and biopsy showed infiltration with  -restricted plasma cells, which made up 42% of the cellular marrow elements  Routine cytogenetic studies showed a normal karyotype in 20 examined cells  FISH with a myeloma probe panel revealed a translocation between chromosomes 11 and 14

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  The patient underwent an initial course of palliative radiation therapy to help manage her hip pain  She then began monthly pamidronate and induction therapy with the IMiD thalidomide 200 mg/day and dexamethasone 40 mg once weekly, plus aspirin 81 mg for thromboprophylaxis  After 3 cycles, her M-protein had decreased to 1.2 g/dL, and she was tolerating therapy well Induction Therapy

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  She received 3 additional cycles of induction therapy, which produced a slight further decline in her M-protein to 1.0 g/dL; however, she developed grade 1 numbness and tingling of her toes, which spread to the lower legs  When the thalidomide dose was reduced to 150 mg/day, and then 100 mg/day, her neuropathy receded, but her myeloma progressed—the M-protein rose to 1.8 g/dL, indicating the presence of refractory disease Continued Course

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  Single-agent bortezomib was initiated at the standard dose and schedule of 1.3 mg/m 2 on Days 1, 4, 8, and 11 of a 21-day cycle  After 2 cycles, the M-protein declined to 0.4 g/dL, and 2 cycles later, the immunofixation was negative; she tolerated therapy without neuropathy  2 additional cycles were administered beyond this best response –A bone marrow biopsy showed no clonal plasma cells, and bortezomib was stopped Treatment at First Relapse

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  The patient had mobilization of 8.2 x 10 6 stem cells/kg, which were stored for possible high-dose therapy –Given her CR, and due to family considerations, she chose to delay stem cell transplantation  18 months later, a faint monoclonal protein band reappeared upon immunofixation, and within 3 months, the M-protein had risen to 1.3 g/dL with the appearance of new bony lesions Further Course

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Bortezomib* 1.0 or 1.3 mg/m 2 (± dexamethasone) Up to eight 21-day cycles Patients who responded to previous bortezomib treatment and relapsed after ≥ 6 months (N = 128) Petrucci MT, et al. ASH Abstract *Last tolerated dose in previous bortezomib regimen Primary objective: best response rate Secondary objectives: safety, best confirmed M-protein response, DOR, TTP Phase II RETRIEVE Study

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma RETRIEVE: Responses to Retreatment With Bortezomib  Previous bortezomib results: 27% CR, 73% PR  Retreatment response rates (based on M-protein) Response, %Evaluable Patients Serum (n = 105) Urine (n = 62) CR + PR6160 CR1034 PR5026 CR + PR + MR8379 MR2219 No change1216 PD55 Petrucci MT, et al. ASH Abstract 3690.

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Response to previous bortezomib treatment in patients evaluable for response to retreatment CR (n = 32) PR (n = 92) CR6 (29)5 (29) Single best serum/urine M-protein response to retreatment with bortezomib, n (%) PR7 (33)7 (41) MR3 (14)3 (18) No change/PD5 (24)2 (12) Missing/NA CR 5 (6)16 (36) PR46 (55) 9 (20) MR20 (24) 9 (20) No change/PD13 (15)11 (24) Missing/NA 8 47 SerumUrine Petrucci MT, et al. ASH Abstract RETRIEVE: Outcomes Based on Previous Response

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Time to single best serum M-protein response with bortezomib retreatment Proportion of Responding Patients Achieving Best Serum Response Time to Best Response (Days) CR + PR CR + PR + MR Petrucci MT, et al. ASH Abstract Kinetics of Response

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Pooled Response Analysis ( ) P < Len/DexDex Response Rate (%) CR 15% VGPR 17% CR 2% VGPR 3% PR 28% PR 17% Median DOR: 16 months Median TTP: 13.4 vs 4.6 months Dimopoulos MA, et al. Leukemia. 2009;Jul 23:[E-pub ahead of print].

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Updated OS Results  Median follow-up: 48 months  Median OS: –Len/dex: 38 months –Placebo/dex: 32 months –P =.045  Survival benefit retained despite 48% crossover Dimopoulos MA, et al. Leukemia. 2009;Jul 23:[E-pub ahead of print].

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Efficacy and Previous Thalidomide nORR, %Median TTP, Months Thalidomide naive (2.8 years from diagnosis, 2 previous lines) Previous thalidomide (3.0 years from diagnosis, 3 previous lines) Sensitive Relapsed Refractory Wang M, et al. Blood. 2008;112:

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma PLD/Bortezomib: TTP PLD + bortezomib median TTP: 9.3 months Bortezomib median TTP: 6.5 months P = HR: 1.82 (95% CI: ) Progression Free (%) Orlowski RZ, et al. J Clin Oncol. 2007;25: Reprinted with permission. © 2007 American Society of Clinical Oncology. All rights reserved 0 Time (Days)

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Favoring PLD + Bortezomib Favoring Bortezomib HRs: PLD/Bortezomib vs Bortezomib Subgroup All Patients: Region: Age, years Sex  2 -microglobulin, mg/L Response to prior treatment Baseline ECOG PS Prior stem cell transplantation Prior anthracycline use Prior thalidomide/lenalidomide Cytogenetic abnormality Chromosome 13 deletion USA Non-USA < Male Female 2.5 > 2.5 & ≤ 5.5 > 5.5 Yes No 0 1 Yes No Yes No Yes No Yes N HR % CI ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Orlowski RZ, et al. J Clin Oncol. 2007;25: Reprinted with permission. © 2007 American Society of Clinical Oncology. All rights reserved

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Bortezomib Retains Activity Despite Previous IMiD Exposure  IMiD-exposed patients, –PLD + B –Median TTP: 270 days –Bortezomib alone –Median TTP: 205 days –P =.018 –HR: 1.62 (95% CI: )  IMiD-naive patients receiving PLD + B (n = 192) –TTP: 295 days  IMiD-exposed patients receiving PLD + B (n = 126) –TTP: 270 days  Heterogeneity test: P =.446 Sonneveld P, et al. Cancer. 2008;112:

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma  The case patient received therapy with PLD/bortezomib, and after 4 cycles again achieved CR  2 additional cycles were administered past this best response and salvage therapy was tolerated well without any adverse events  This was followed by high-dose therapy and autologous stem cell rescue, which has to date resulted in continuous CR for 2 years Treatment at Second Relapse

clinicaloptions.com/oncology Practical Applications and Clinical Advances in Multiple Myeloma Conclusions  Increasingly effective treatment options exist for patients with relapsed/refractory multiple myeloma –Bortezomib alone –Bortezomib plus PLD –Lenalidomide plus high-dose dexamethasone  Use of these agents in novel combinations can benefit patients even with previous exposure  Other drugs can be used in combinations with bortezomib and the IMiDs  Future: Novel agents are showing positive preliminary data

More Hematology/Oncology Available Online Medical Meeting Coverage: key data plus Expert Analysis panel discussions exploring clinical implications Treatment Updates: comprehensive programs covering the most important new concepts Interactive Cases: test your ability to manage patients clinicaloptions.com/oncology