1. Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM) MQ. Lacy, B. LaPlant., P. Richardson, A. Jakubowiak, K. Laumann, S. Kumar, M.A. Gertz, S.R. Hayman, F. Buadi, A. Dispenzieri, J.A. Lust, P. Kapoor, N. Leung, S.J. Russell, D. Dingli, R. Go, Y. Lin, W. Gonsalves, R. Fonseca, P.L. Bergsagel, V. Roy, T. Sher, A. Chanan Khan, A.K. Stewart, C. Reeder, S.V. Rajkumar, J.R. Mikhael Mayo Clinic; Dana Farber Cancer Center; University of Chicago

2. Background Pomalidomide and dexamethasone (Pom/dex) has been extensively studied and has response rates of 25-35% in patients with lenalidomide refractory myeloma The combination of IMiDs and proteasome inhibitors have potential for deeper and more durable responses The MM005 trial phase I study of twice weekly bortezomib with pomalidomide and dexamethasone and reported with promising results. ORR of 75% and 30% ≥ VGPR. (Richardson, ASH 2013) This trial was designed to evaluate the safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone – Pom-Bor-Dex or “PVD.” Results of the phase I portion were reported (Mikhael, ASH 2013)

3. Goals This study was activated on March 21, 2012. A total of 50 patients have been accrued (dose level (DL)1: 3, DL 2: 6, Phase II: 41). This summary will focus on patients treated at the MTD (DL2 and Phase II) Primary: Phase II: To evaluate the confirmed response rate (PR, VGPR, or CR) of pomalidomide, bortezomib and dexamethasone in patients with lenalidomide refractory relapsed myeloma Secondary: Overall survival, progression-free survival, and duration of response To assess the toxicity of pomalidomide, bortezomib and dexamethasone in this patient population

4. Eligibility Previously treated, relapsed MM 1-4 prior regimens. Resistant/refractory to lenalidomide. Refractory defined as progression on or within 60 days of stopping RX Prior bortezomib was allowed but patients could not have been refractory Measurable disease (one of the following) : Serum M-spike  1.0 g/dL 24-hour Urine M-spike >200 mg Serum immunoglobulin FLC > 10 mg/dL with abnormal ratio Measurable soft tissue plasmacytoma > 30% plasma cells in bone marrow ANC  1000/μL and PLT  75,000/μL Creatinine  3 mg/dL ECOG PS 0, 1, or 2.

5. Treatment Pomalidomide 4 mg daily days 1-21 Bortezomib 1.3 mg/m2 (IV or SC) Dexamethasone 40 mg Thromboprophylaxis was given to all patients as either aspirin or full dose anticoagulation Responses assessed by IMWG criteria; Toxicity assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 28 day cycle days 1, 8, 15, 22 After 8 cycles, dex and BTZ were stopped and pom continued until progression

6. N=47 Age, median (range)66 (45-83) Gender, male49% Months from Diagnosis to On Study, median (range)49 (15-142) ECOG Performance Score 0/1/262% / 36% / 2% Prior treatment disease status Relapsed off treatment 18 (38%) Relapsed on treatment 28 (60%) Refractory (never responded) 1 (2%) Refractory to immediate prior therapy, yes13 (28%) Patient Characteristics

7. N=47 Prior regimens IMIDs Thalidomide8 (18%) Lenalidomide47 (100%) Bortezomib27 (57%) Other proteosome inhibitors17 (36%) Alkylators25 (53%) Autologous SCT32 (68%) Number of prior regimens 128% 225% 328% 417% 52% Median2 Prior Regimens

8. Risk Factors Total (N=47) Cytogenetics Normal 60% Abnormal 36% Not Available 4% FISH Normal 9% Abnormal 81% Not done / Insufficient cells 10% Fish Results 17p- 10 t(4;14) 5 t(14;16) 2 Del 13 8 Other 31 mSMART Risk High 11 (23%) Intermediate 8 (17%) Standard 28 (60%) High risk defined as deletion17p, t(4;14), or t(14;16) by FISH or deletion 13 by conventional cytogenetics or PCLI >3%

9. Follow Up Total (N=47) Progression Status No Progression22 (47%) Progression25 (53%) Follow-up Status Alive45 (96%) Dead2 (4%) Months of Follow-up (Alive Patients) Median, range12 (1.4-26) Last Cycle Received Median, range8.0 (1-22) Currently Receiving Treatment20 (43%) Reason For Ending Treatment Disease Progression25 (93%) Other (MD discretion, stem cell transplant)2 (7%)

10. Adverse Events At Least Possibly Related N=47 Grade 3+ 39 (83%) Grade 4+ 10 (21%) Grade 5 0 (0%) Heme Grade 3+ 34 (72%) Heme Grade 4+ 9 (19%) Non-heme grade 3+ 12 (26%) Non-heme grade 4+ 1 (2%)

11. Hematologic Toxicity Attributions of possible, probably or definite

12. Non Hematologic Toxicity Attributions of possible, probably or definite 64%

13. Responses

14. Patient Outcomes N=47 Response Rate 85% No. of Responders 40 sCR 3 CR 6 VGPR 12 PR 19 Overall Survival, medianNA %Event Free at 6 mo100% %Event Free at 12 mo94% Progression Free Survival, median 10.7 mo (95%CI: 9.4-18.5) Duration of Response, median 13.7 mo (95%CI: 8.5-16.8) 45% VGPR+

15. Responses in High Risk Patients High/Intermediate Risk (N=19) Standard Risk (N=28) Response Rate16 (84%)24 (86%) Overall Survival, medianNA %Event Free at 6 mo100% %Event Free at 9 mo92%95% Progression Free Survival, median 9.5 mo 16.3 mo %Event Free at 6 mo78%85% %Event Free at 9 mo57%81% %Event Free at 12 mo35%60%

16. Overall and PFS

17. PFS by risk group

18. Conclusions PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in 85%. Weekly administration of bortezomib and dex enhanced the tolerability and convenience of this regimen Toxicities are manageable, mostly consisting of mild cytopenias PVD is a highly attractive option in patients with relapsed and refractory MM

19. Rochester V. Rajkumar, MD Francis Buadi, MD David Dingli, MD A Dispenzieri, MD Morie Gertz, MD Suzanne Hayman, MD Shaji Kumar, MD Robert Kyle, MD Nelson Leung, MD John Lust, MD Steve Russell, MD S Zeldenrust, MD Prashant Kapoor, MD Wilson Gonsalves, MD Yi Lin, MD, PhD BioStats Betsy LaPlant Kristina Laumann Arizona Joseph Mikhael, MD Leif Bergsagel, MD Rafael Fonseca, MD Craig Reeder, MD Keith Stewart, MD Florida Vivek Roy, MD Asher Chanan Khan, MD Taimur Sher, MD Sikander Ailawadhi, M.D. Dana Farber Cancer Center Paul Richardson, MD University of Chicago Andrzej Jakubowiak, MD