Dana-Farber Cancer Institute, Boston, MA, USA; 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3

Ibrutinib in Combination With Low-Dose Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma: Results From a Multicenter Phase 2 Trial Paul G. Richardson, MD 1 *, William I. Bensinger, MD 2, Carol Ann Huff, MD 3, Caitlin L. Costello, MD 4, Nikoletta Lendvai, MD, PhD 5,6, Jesus G. Berdeja, MD 7, Larry D. Anderson, Jr. MD, PhD 8, David S. Siegel, MD, PhD 9, Sundar Jagannath, MD 10, Jacob P. Laubach, MD 1, Keith E. Stockerl-Goldstein, MD 11, Lisa Knapp 12, Long Kwei, PhD 12, Fong Clow, ScD 12, Thorsten Graef, MD, PhD 12, Elizabeth Bilotti, MSN 12, Ravi Vij, MD 11 1 Dana-Farber Cancer Institute, Boston, MA, USA; 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3 Johns Hopkins University, Baltimore, MD, USA; 4 University of California, San Diego, La Jolla, CA, USA; 5 Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 6 Weill Medical College of Cornell University, New York, NY, USA; 7 Sarah Cannon Research Institute, Nashville, TN, USA; 8 UT Southwestern Medical Center, Dallas, TX, USA; 9 Hackensack University Medical Center, Hackensack, NJ, USA; 10 Mount Sinai Medical Center, New York, NY, USA; 11 Washington University School of Medicine, St. Louis, MO, USA; 12 Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA, USA

Disclosures All presenters were independently selected by the organizing committee. Those presenters who disclosed affiliations or financial interests with the commercial organizations involved with products, to which they may refer, are listed below. Received an Advisory Committee honorarium from the following: Celgene Takeda Johnson&Johnson Novartis Bristol Myers Squibb

Mechanism of Action with BTK Inhibition in Multiple Myeloma (MM) Adapted from 1, 2 1. Yang Y, et al. Cancer Res. 2015;75:594-604. 2. Tai YT, et al. Oncotarget. 2012;3:913-914. 3. Bam R, et al. Am J Hematol. 2013;88:463-471. BMSC, bone marrow stromal cells; BTK, Bruton s tyrosine kinase; MM, múltiple myeloma. Ibrutinib targets both the MM cells and the bone marrow niche. In MM, BTK may help regulate myeloma stemness in the bone marrow. 1 Recent studies showed robust BTK expression in the majority of MM plasma cells in patients (pts) with MM. 2,3 Phase 1 results demonstrated activity at the highest dose tested in combination with lose-dose dexamethasone with acceptable tolerability. 3

Functional Sequelae of Btk Inhibition by Ibrutinib (PCI32765) in MM BM milieu Tai et al, Blood 2012 PCI32765 IL-6 SDF-1 MIP-1 MIP-1 M-CSF MCP-1 Colony formation Tumor microenvironment MM Stem Cell Adhesion Migration Homing PCI-32765 M-CSF, IL-6, MCP-1 MM Btk activation by IL-6, SDF-1 PCI32765 MIP-1, MIP-1, IL-8, TGF 1 RANTES, BAFF, TRAF2, CXCR4, LAT, PLC 2, MYD88, NFATc1 PCI-32765 TRAP5b SDF-1 IL-8 Activin A APRIL MIP-1 MIP-1 TGF 1 RANTES BAFF Stromal cells M-CSF RANK fms Osteoclast precursors Bone resorption Osteoclast

PCYC-1111: Phase 2 Study Design in RR MM Cohort 1* Ibrutinib 420 mg PO daily Cohort 3* Ibrutinib 840 mg PO daily Ibrutinib 560 mg PO daily 40 mg weekly Ibrutinib 840 mg PO daily 40 mg weekly *For cohorts 1 and 3, addition of dex 40 mg weekly permitted at disease progression per investigator discretion. Phase 2, open-label, nonrandomized, multi-cohort, multicenter study Primary objective: CBR defined as MR by IMWG criteria 1 Secondary objectives: duration of clinical benefit, ORR ( PR), duration of objective response, safety, and pharmacokinetics 1. Rajkumar SV, et al. Blood. 2011;117:4691-4695. dex, dexamethasone; CBR, clinical benefit rate; IMWG, International Myeloma Working Group; MR, minor response; ORR, overall response rate; PR, partial response. 3

Patient Characteristics Characteristic Cohort 1 Cohort 3 Median age, y (range) 62 (49-74) 66 (46-77) 66 (54-81) 65 (43-81) Male, n (%) 8 (62) 9 (50) 13 (72) 26 (61) ECOG PS 0/1, % 54/46 33/67 44/56 47/53 Median time since diagnosis, years 3.9 5.0 6.3 6.5 Median # prior therapies, n (range) 3 (2-10) 4.5 (2-11) 3.5 (2-15) 4.0 (2-10) Chromosomal abnormalities by FISH, n (%) t(11;14) del13q14 t(4;14) del17p 1 (8) 5 (38) 2 (15) 3 (23) 1 (6) 3 (17) 5 (28) 5 (28) 5 (28) 2 (11) 5 (28) 0 (0) 8 (19) 4 (9) 1 (2) 3 (7) ISS stage, n I/II/III 6/6 /1 6/8/4 8/8/2 23/16/4 ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; ISS, International Staging System. 6

Prior Treatment Exposure Prior Treatment Cohort 1 All patients (pts) received prior corticosteroid treatment. Cohort 3 Alkylator, % Refractory 100 39 94 50 78 39 95 35 Thalidomide, % Refractory 23 0 50 22 61 28 58 12 Lenalidomide, % Refractory 100 62 100 72 89 56 91 61 Pomalidomide, % Refractory 8 8 6 0 17 17 30 28 Bortezomib, % Refractory 100 39 100 67 83 56 91 49 Carfilzomib, % Refractory 8 0 28 28 33 33 33 26 Autologous stem cell transplant, % 85 78 72 77 7

Most Recent Treatment Cohort 1 Cohort 3 Disease status to last treatment, n (%)* Relapsed 5 (38) 2 (11) 4 (22) 11 (26) Relapsed and refractory 8 (62) 16 (89) 13 (72) 31 (72) PI and IMiD in the last line of therapy, n (%) PI and IMiD 4 (31) 3 (17) 3 (17) 9 (21) PI or IMiD No PI or IMiD 7 (54) 2 (15) 11 (61) 4 (22) 10 (56) 5 (28) 31 (72) 3 (7) Agent included in last line of therapy, n (%) IMiD Thalidomide 0 (0) 0 (0) 0 (0) 3 (7) Lenalidomide 6 (46) 7 (39) 8 (44) 9 (21) Pomalidomide 0 (0) 0 (0) 0 (0) 10 (23) PI Bortezomib 9 (69) 7 (39) 5 (28) 18 (42) Carfilzomib 0 (0) 4 (22) 4 (22) 8 (19) *Relapsed or relapsed and refractory disease status was unknown for 1 patient each in cohorts 3 and 4. Refractory defined as either no response or progression on or within 60 days of completion of therapy. PI, proteasome inhibitor; IMiD, immunomodulatory drug. 8

Best Overall Response by IMWG Criteria *Analysis was based on assigned treatment of single-agent ibrutinib and does not reflect any change in response following dexamethasone administration. CBR ( MR) was 23% for pts treated in cohort 4. Rate of disease stabilization or better increased with dose. (IMWG, International Myeloma Working Group); SD, stable disease; MR, minimal response; PR, partial response; CBR, clinical benefit rate; ibr, ibrutinib; dex, dexamethasone. 9

Progression-Free Survival Cohort 1 Cohort 3 Median time (mos) 0.9 4.2 2.8 5.4 (Range) (0.5, 32.3+) (0.8, 8.3) (0.4, 14.0) (0.0+, 16.4) 10

Hematologic Treatment-Emergent Adverse Events (>20%) Adverse Event Cohort 1 ibr 420 mg ibr 560 mg Cohort 3 Overall (N=92) Anemia 31 15 33 28 33 17 23 9 28 15 Thrombocytopenia 38 0 28 22 22 11 21 9 25 11 Neutropenia 8 0 0 0 17 6 2 2 5 2 ibr, ibrutinib; dex, dexamethasone. 11

Non-Hematologic Treatment-Emergent Adverse Events (>20%) Adverse Event Cohort 1 ibr 420 mg ibr 560 mg Cohort 3 Overall (N=92) Diarrhea 38 0 44 0 61 6 63 2 55 2 Fatigue 31 0 39 0 50 11 49 0 45 2 Nausea 46 0 28 0 44 0 23 0 32 0 Muscle spasms 31 0 33 0 17 0 21 0 24 0 Cough 31 0 17 0 11 0 26 0 22 0 Arthralgia 23 0 22 0 28 0 16 0 21 0 Upper respiratory infection ibr, ibrutinib; dex, dexamethasone. 23 0 11 0 39 0 16 0 21 0 14

Non-Hematologic Treatment-Emergent Adverse Events (>20%) Adverse Event Cohort 1 ibr 420 mg ibr 560 mg Cohort 3 Overall (N=92) Diarrhea 38 0 44 0 61 6 63 2 55 2 Fatigue 31 0 39 0 50 11 49 0 45 2 Nausea 46 0 28 0 44 0 23 0 32 0 Muscle spasms 31 0 33 0 17 0 21 0 24 0 Cough 31 0 17 0 11 0 26 0 22 0 Arthralgia 23 0 22 0 28 0 16 0 21 0 Upper respiratory infection 23 0 11 0 39 0 16 0 21 0 ibr, ibrutinib; dex, dexamethasone. 16

Safety Summary No significant differences in safety observed across all cohorts. Dose range of 420-840 mg of daily Ibrutinib 55% of all pts experienced a grade 3 treatment-emergent AE, while 29% experienced at least 1 serious AE. 13% of pts required a dose reduction due to an AE, and 10% of pts discontinued due to AE. Other AEs Peripheral neuropathy (PN) reported in 10% of pts (grades 1-2), of which 8 of 9 pts had a prior history of PN Acute kidney injury grade 3 occurred in 1 pt following administration of IV contrast. Rate of grade 3 hematologic AEs low: 23% overall, 19% in cohort 4. AE, adverse event. 17

Patient Disposition Disposition Cohort 1 Cohort 3 On treatment 8% 0% 0% 14% Discontinued treatment 92% 100% 100% 86% Progressive disease 46% 61% 67% 60% Investigator discretion 15% 33% 11% 2% Adverse event 8% 0% 17% 12% Other* 23% 6% 6% 12% *Includes patient withdrawal, noncompliance, and patient required prohibited concomitant medication. 18

Conclusions Safety profile manageable, with similar AE rates across dosing cohorts and consistent with those seen in other diseases (CLL, WM). No increase in toxicity was observed with 840 mg of daily ibrutinib. Ibrutinib ± weekly dexamethasone demonstrated activity in this heavily pre-treated RR MM population. Median of 4 prior therapies and 74% refractory to their most recent therapy Highest activity was observed in cohort 4, with 23% CBR 5% ORR 30% sustained SD and a median PFS of 5.4 months AE, adverse event; CBR, clinical benefit rate; ORR, overall response rate; PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma; SD, stable disease. 19

Future Directions Continued exploration of Ibrutinib is warranted and is ongoing in 2 combination studies: PCYC-1138 (NCT02548962) and PCYC-1119 (NCT01962792). PCYC-1119: a phase 1/2b study of Ibrutinib + Carfilzomib ± dexamethasone in relapsed MM and RR MM. 1 PCYC-1138 (NCT02548962): Ibrutinib+ Pomalidomide/dex underway Ibrutinib + Lenalidomide /dex planned (Alliance) 1. Chari A, et al. IMW 2015. Abstract 0204. MM, multiple myeloma; RRMM, relapsed/refractory MM. 20

Acknowledgments We especially thank the patients who participated in the study and their supportive families as well as the investigators and clinical research staff from the study centers. This study was sponsored by Pharmacyclics LLC, an AbbVie Company. Editorial support: Brian R. Haas, PhD, funded by Pharmacyclics LLC, an AbbVie Company. 21