Abstract: Abstract 1869 Poster Board I-894 INTRODUCTION: Perifosine is an orally -bioavailable, novel signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and clinical activity in 73 evaluable Vel relapsed and Vel refractory patients (pts) (ASH 2008 # 870). Herein, we report on the updated safety, overall response rate (ORR), time to progression (TTP) and overall survival (OS) results of perifosine + Vel (+/− Dex), in multiple myeloma (MM) pts with advanced disease and who were previously relapsed from and/or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles. The phase II enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform criteria. RESULTS: A total of 84 pts have been enrolled comprised of 51 men and 33 women, median age 63 y (range 35 – 89): 83% of pts had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (75%), thalidomide (74%) and SCT (57%), with pts receiving a median of 2 prior Vel-based treatments. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common (≥ 10%) grade 1 / 2 events included nausea, diarrhea, vomiting, fatigue and anorexia, which were manageable with supportive care and dose reductions. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia, neutropenia, anemia, hyponatremia and diarrhea. No DVT has been seen, and only 1 worsening peripheral neuropathy from grade 1 to 3 was reported, which proved reversible after treatment discontinuation. Two pts had perifosine reduced to 50 mg (GI related) in the phase 1 and 5 pts reduced to qod dosing in the phase II: 15 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment related mortality was seen. Of the 11 pts who were inevaluable for efficacy, 6 were due to toxicity resulting in failure to complete two cycles or more of therapy; 3 for withdrawal of consent/ non-compliance, and 2 due to rapid disease progression within 1 cycle. ORR, TTP, and OS are as follows: As of August 2009, the median OS for all evaluable study pts and Vel relapsed pts has not been reached with 40/73 (55%) pts and 14/20 (70%) pts alive, respectively. 26/53 (49%) Vel refractory pts remain alive (range 9 mos to 3 years). The median OS for the 60/73 pts (82%) with stable disease or better is currently 33.4 mos. CONCLUSIONS: Perifosine in combination with Vel (+/− dex) has been generally well tolerated and continues to demonstrate impressive activity in both heavily pre-treated, Vel-refractory pts, with an ORR of 38% and OS of 16 mos, and in Vel-relapsed pts with an ORR of 55%, a median TTP of 8.8 months and a median OS of 25 mos, to date. Moreover, 80% of pts achieved stable disease or better, with a median OS of 33.4 mos. A phase III randomized, trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) and is expected to commence by the end of the year. Disclosures: Richardson: Keryx Biopharmaceuticals: Honoraria. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Keryx Biopharmaceuticals: Consultancy.

Abstract: Abstract 815FN2 INTRODUCTION: Perifosine, an orally-bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, NFkB and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and preliminary clinical activity in relapsed and refractory multiple myeloma (MM) patients (pts) (ASH 2009 # 1869). We report final results, including overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) for the treatment of MM pts previously relapsed from and/or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles, which enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform Criteria. RESULTS: A total of 84 pts were enrolled comprised of 51 men and 33 women, median age 63 y (range 35–89): 88% of pts had relapsed and refractory MM (73% Vel refractory), with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (76%), thalidomide (75%) and SCT (58%), with pts receiving a median of 2 prior Vel-based treatments. Median interval between diagnosis and inclusion was 4.5 years. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common grade 1/2 events included nausea, diarrhea, fatigue and musculoskeletal pain, which were manageable with supportive care and dose reductions. Grade 3/4 adverse events included thrombocytopenia, neutropenia, anemia, pneumonia and musculoskeletal pain. Two pts had grade 3 peripheral neuropathy (PN), which was reversible with Vel dose reduction and/or treatment discontinuation. No grade 4 PN was observed. Overall 26 (31%) pts had treatment-related PN of any grade. Two pts had perifosine reduced to 50 mg (for GI related toxicity) in the phase 1 portion of the study, and 8 pts reduced to qod dosing in the phase II: 23 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment-related mortality was seen. Eleven pts were inevaluable for response due to unrelated toxicity (n=5), rapid disease progression ( 〈 1 cycle received; n=3), or withdrawal of consent (n=3). For 73 response-evaluable pts, the ORR was 41%, including 4% CR, 18% PR and 19% MR. Prior best response (≥ PR) to last Vel-based regimen was 43% (36/84 pts), of which most were triple drug combinations (eg RVD). Of 53 pts who were refractory to prior Vel, ORR to perifosine, Vel +/− Dex was 32%, including 2% CR, 11% PR and 19% MR. ORR for 20 Vel-relapsed pts was 65%; 10% achieved a CR and 35% a PR. Median PFS was 6.4 mos with a range of 5 wks to over 3 yrs (95% CI: 5.3, 7.1), and 8.0 mos (95% CI: 6.4, 9.8) for the 30 evaluable pts who achieved ≥ MR. Median PFS for the 53 Vel-refractory pts was 5.7 mos (95% CI: 4.3, 6.4), with 40% of pts achieving PFS of 〉 6 mos. For the 20 Vel-relapsed pts, median PFS was 8.8 mos (95% CI: 6.3, 11.2), with 70% of pts achieving PFS of 〉 6 mos. Importantly, median PFS for all pts receiving prior Vel-based regimens prior to study entry was 5.3 mos. As of August 2011, median OS for all evaluable study pts was 25 mos (95% CI: 16.3, 31.1), 22.5 mos (95% CI: 14.2, 31.1) for the Vel-refractory pts and 30.4 mos (95% CI: 17.8, NR) for Vel-relapsed pts. Median OS for those pts who achieved PR + CR was 37 mos (95% CI: 13.8, NR) and for those pts who achieved SD + MR was 29 months (95% CI: 18, 32.4). CONCLUSIONS: Perifosine in combination with Vel (+/− dex) demonstrated impressive and durable activity in both heavily pre-treated, Vel-refractory pts (with an ORR of 32% and median OS of 22.5 mos), and in Vel-relapsed pts (with an ORR of 65%, median PFS of 8.8 mos and OS of 30.4 mos), with manageable toxicity. Survival data were encouraging, even in pts exposed to and refractory to Vel, as well as prior IMiDs, so providing another example of a rational combination strategy integrating novel therapies to further improve patient outcome. An international phase III randomized trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) status and is currently underway to confirm the efficacy of this approach. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Keryx Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wolf:Millennium: Honoraria, Speakers Bureau. Jakubowiak:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Medtronic: Consultancy; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Krishnan:Millennium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Acetylon: Research Funding. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Allerton:Keryx Biopharmaceuticals: Consultancy. Hideshima:Acetylon: Consultancy. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees.

Abstract: Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (DACi), which induces cytotoxicity at & lt;10nM in multiple myeloma (MM) cell lines resistant to conventional therapies. It modulates 2 targets implicated in MM by controlling cell proliferation and survival through HSP90 and inducing apoptosis through the aggresome pathway. Here we report the preliminary results of a Phase II, single arm, multicenter study of panobinostat in patients with measurable MM disease who had received at least 2 prior lines of therapy (including bortezomib and lenalidomide or thalidomide) and who were also refractory to their most recent line of therapy. The study was designed to assess: response rate (CR/PR) by the IBMTR/EBMTR criteria, safety, and tolerability of 20 mg/day of oral panobinostat given on a Monday/Wednesday/Friday (MWF) dosing schedule. 3 or more responders in 25 patients in stage 1 of the study were required for the initiation of Stage 2. A total of 38 pts (24 males, 14 females; median age 61 years [43–72] ) have been enrolled between February and October 2007. Median time since last prior therapy was 33 days, median number of prior therapies was 5 (2–12). Median treatment duration was 45 days (5–377 days). Overall, panobinostat was well tolerated, and no new safety signals were reported. Mild or moderate level of nausea, as well as fatigue/asthenia, occurred in half of the patients. The most common Grade 3/4 AEs were cytopenias, with neutropenia, thrombocytopenia, and anemia in 32%, 26%, and 16% of patients, respectively. Other Grade 3/4 AEs included infections: 8 occurrences (3 of pneumonia; 2 of septic shock; and back pain, hypercalcemia, and hypokalemia in 3 pts each). No cardiac (including significant QTc prolongation, pericarditis, or pericardial effusion) or thromboembolic events were reported. SAEs potentially related to study drug were observed in 3 pts and included nausea (2), diarrhea and vomiting (1), and reduced general condition (1). 5 patients discontinued therapy for AE: 2 due to acute renal failure which was progression coincident, 2 due to elevated creatinine suspected to be study drug related, and 1 for worsening on study of peripheral neuropathy (non-related). 1 patient died on study due to a cerebral vascular accident (assessed by the investigator as not study drug related). QT intervals (QTcF) were monitored per study protocol and out of & gt;1500 post dose ECGs, 1 pt showed a Grade 2 prolongation of QTcF value above 480 ms, 2 pts had a QTcF increase of ≥60 ms compared to baseline, and 10 pts had a minimal 30– & lt;60 ms increase of QTcF compared to baseline. A clinical durable response was observed in a 43-yr-old female patient, whose urine kappa light chain MM with bone lesions was progressing on lenalidomide/dexamethasone prior to enrollment. The patient had 5 prior lines of therapy, including auto-SCT twice (5 years apart), bortezomib, and thalidomide. Response was rapid, with a 60% reduction of urine M protein at Cycle 2 and 90% at Cycle 4. PR was confirmed in Cycle 7, including stabilized bone lesions, and is sustained at 11 months on therapy with urine light chain stable below the “measurable disease” level of 100mg/24hrs and urine IF still positive, thus a VGPR. A quick and dramatic reduction in angiogenesis markers (VEGF, sVEGFR1, and bFGF) was seen starting on Cycle 1, Day 8 of treatment, as well as a reduction (50%) of seric free light chain, which continued further throughout the later cycles. A second patient on study for & gt;12 months is continuing to show clinical benefit after failing 10 prior lines of therapy (including Auto-SCT, bortezomib, lenalidomide, and thalidomide) and is maintaining MR. Stable disease observations of & gt;3 months occurred in 3 pts. Single-agent, oral panobinostat at 20 mg/day thrice weekly was well tolerated and safe in this study. Evidence has since been obtained from clinical responses in patients with various hematological malignancies that higher doses of single-agent panobinostat can provide more optimal dosing schedules than the 20 mg dose. Thus, although the current study at the 20 mg schedule did not meet its objective, the observation of 1 durable VGPR and 1 durable and ongoing MR, in addition to transient disease stabilization in 3/38 patients, are encouraging results, especially at this low dose, warranting further clinical investigation of panobinostat. The analysis of final study results will be presented.

Abstract: Background: This phase II trial evaluated the response rate of sequential bortezomib (VELCADE®), cyclophosphamide (Cytoxan®), and dexamethasone ([VCD]; 3 cycles) followed by bortezomib, thalidomide (Thalomid®), and dexamethasone ([VTD] ; 3 cycles) as first-line therapy for patients with multiple myeloma. The primary endpoints were overall response, achievement of „d very good partial response (VGPR), as well as assessment of safety and tolerability. Methods: Patients with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of bortezomib 1.3mg/m2 days 1, 4, 8, and 11, cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg p.o. or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of bortezomib 1.0mg/m2 days 1, 4, 8, and 11; thalidomide 100 mg p.o. daily and dexamethasone same as cycles 1–3. Patients received thrombosis prophylaxis with ASA 325mg daily during cycles 4–6. Upon completion of the 6 cycles, patients proceeded to autologous stem cell harvest, transplant and/or maintenance therapy. Responses were defined as a decrease in serum and/or urine monoclonal (M) protein by 50% or greater. VGPR and other responses were as per the International Response Criteria. Results: This report provides results for all 44 eligible patients: median age 59 years; 68% male; 61% Stage III (D/S); documented ISS Stage II/III 59%; IgG 66%, IgA 17%; 17% light chain only. To date the first 30 patients are fully evaluable for response with 28-day post therapy follow up. The overall response rate (ORR; ≥PR) is 90% with 18/30 (60%) achieving CR + VGPR (CR 33%); 9/30 (30%) PR and 3/30 (10%) stable disease or not evaluable. Overall, both components of the sequential regimen were very well tolerated. One patient had a ruptured colonic diverticulum possibly related to dexamethasone, but recovered well and achieved VGPR on trial. There have been 49 therapy attributed toxicity events which have required drug/schedule adjustments. Of these, 9 events were Gd 3/4: 3 attributed to cyclophosphamide, 3 to dexamethasone, 2 attributed to bortezomib and 1 to thalidomide. DVT occurred in one patient who was at high risk because of prior bilateral hip surgery. Fourteen patients have proceeded to successful stem cell harvest and autologous transplant. Post transplant follow up as well as response information for all 44 patients will be presented. Conclusion: This bortezomib/cyclophosphamide/dexamethasone (VCD) based combination induction therapy followed by VTD is a promising addition to the treatment armamentarium for previously untreated patients. The response rates: ORR 90%; □ VGPR (60%) and CR (33%) are extremely encouraging and improve over our bortezomib/dexamethasone 2-drug experience which produced 90% □ PR and 38% □ VGPR. This very well tolerated new regimen is potentially an important step forward in induction therapy with presentation of more mature data. Supported by the Aptium Oncology Research Network and a research grant from Millennium Pharmaceuticals, Inc.

Abstract: Background: Combination regimens incorporating bortezomib (VELCADE®, Vc), lenalidomide (REVLIMID®, Rev), dexamethasone (Dex) and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC] ), have all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count 〈 25,000/mm3 lasting 〉 7 days or any platelet count 〈 10,000/mm3; grade 4 neutropenia lasting 〉 7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a 〉 2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in 〉 1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4

Abstract: Bortezomib (VELCADE®; Vc) has become the standard of care for patients with relapsed multiple myeloma (MM). Generally, therapies to treat MM are used sequentially, and are not typically repeated. Unlike most other therapies, which treat until progression, treatment with Vc follows a specified time-course (~8 cycles). Thus, bortezomib may be an ideal candidate for repeat therapy, although its utility in this setting has not yet been determined. This retrospective case series was designed to clarify the utility of Vc as a repeat therapy. We reviewed the records of patients from the phase 2 (SUMMIT and CREST) and 3 (APEX) registration studies who were subsequently retreated off protocol. Medical records review at 3 major cancer centers yielded 22 patients who completed Vc retreatment following at least a 60 day treatment free interval. This sample had the following demographics: median age of 60, isotypes IgG 68%, IgA 13.6%, IgD 4.5%, and light chain 9.0%; 55% were female. Patients had had a median of 3.5 therapies prior to their initial Vc treatment. Retreatment occurred as a median 6th line of therapy. Patients were determined to have responded to treatment if the greatest mean reduction in serum/urine M-protein or bone marrow plasma cells was 〉 50%. During initial Vc therapy, patients received a median of 4.9 months (7.5 cycles) of Vc treatment and the response rate was 68% (15/22) to Vc alone or Vc plus dexamethasone. The median treatment-free interval was 12.6 months between the end of the first Vc treatment and the next MM treatment (range 2 weeks to 45 months). For 55% of these patients (12/22), treatment following relapse after the first Vc treatment was with a different agent or combination of agents. Retreatment with Vc was typically part of combination therapy and lasted a median of 3.8 months (5.5 cycles); 59% (13/22) added one or more of the following: dexamethasone, doxil, thalidomide, melphalan, decadron, and/or radiation therapy. Of the 15 patients who responded to the first Vc treatment, 9 (60%) responded to retreatment. Of the 7 patients who did not respond to the first Vc treatment, 2 (29%) responded to re-treatment. This was likely due to either longer treatment or the addition of a second agent. Overall, the Vc retreatment response rate was 50% (11/22). During retreatment, no patients experienced a dose reduction due to peripheral neuropathy, compared to 4 patients (2 with grade 2 and 2 with grade 3) during initial treatment. Termination of therapy due to any unmanageable toxicity was similar during both initial and retreatment. Finally, no patients were hospitalized for Vc-related adverse events during retreatment, while 3 patients had been hospitalized during initial treatment. On the basis of these data, Vc retreatment appears to be safe and effective, yielding high clinical response rates and low rates of toxicity and/or hospitalization. Although the numbers of patients in this study are small, the observed patterns are instructive; the data reported here suggest that repeated treatment with Vc may result in prolonged disease control, even if the patient had failed to respond to the first treatment with Vc. Additional prospective trials are ongoing.

Abstract: Background: Multiple myeloma (MM) treatment has advanced considerably with proteasome inhibitors, immunomodulatory drugs (IMiDs), and, most recently, monoclonal antibodies. However, treatment response is quite heterogeneous, and many patients still progress even with novel combination therapies. Thus, understanding the factors that underlie response to treatment is a priority. Several somatic genomic aberrations and mutations predict poor response to therapy. However, germline variation has not previously been investigated as a predictor of treatment response in MM. We used genome-wide association and transcriptome-wide association approaches to identify germline genetic predictors of treatment response in MM. Methods: We included 510 MM patients from Mayo Clinic and 324 MM patients from UCSF diagnosed from 1999-2015. Basic demographics, laboratory values and pathology at diagnosis, type of initial therapy, duration of therapy, and follow-up were ascertained by chart review. Patients were grouped into categories of treatment based on their first line therapy: proteasome inhibitor-based regimen, IMiD based regimen, combination proteasome and IMiD based regimen, or other. Response was assessed using International Myeloma Working Group (IMWG) response criteria after 4-6 cycles of induction. As such, response was categorized into progressive disease (PD), minimal response (MR), partial response (PR), very good partial response (VGPR), or complete response (CR). Germline samples were genotyped using Illumina or Affymetrix arrays and were imputed based on the Haplotype Reference Consortium (HRC). For the genome-wide association study (GWAS), we included all SNPs with minor allele frequency 〉 0.01 and imputation r2 of 〉 0.5. We tested each SNP for association with treatment response using a linear regression model that adjusted for age, gender, and genetic ancestry (from principal components analysis (PCA)). To perform the transcriptome-wide association study (TWAS), we calculated predicted gene expression data using PREDIXCAN software on a reference cohort of 922 individuals with genotype and RNA expression data from peripheral blood. We then tested the association between predicted gene expression and response to therapy using linear regression models. Both the GWAS and TWAS were performed on subgroups of patients who received either proteasome inhibitors or IMiD therapies. The analyses of patients on proteasome inhibitors were adjusted for IMiD use as a covariate and analyses of patients on IMiDs were adjusted for proteasome inhibitor use. The threshold for genome-wide significance loci was set at P = 5 x 10-8 and the threshold for suggestive loci was set at P = 10-6. The threshold for significance for TWAS was set at P = 4 x 10-6 by using a Bonferroni correction for the number of genes for which genetic models of expression could be developed by PREDIXCAN. Results: Overall, 42.7% (59 of 138) of patients on proteasome inhibitors alone, 32.5% (66 of 203) of patients on IMiDs alone, and 58.1% (50 of 86) of patients on combination achieved at least a VGPR. There were no significant differences in response across centers in analyses that adjusted for age, sex and types of therapy. There were no genome wide significant loci to predict for response. We identified 8 suggestive SNPs associated with proteasome inhibitor response and 4 suggestive SNPs associated with IMiD response. TWAS identified ZNF622 as a candidate genetic modifier of proteasome inhibitor effect that was significant after correction for multiple hypothesis testing (P = 1.6 x 10-6). Higher genetically predicted expression was associated with improved response to proteasome inhibitor therapy. Among patients above the median of predicted expression of ZNF622 on proteasome inhibitors, 62.6% achieved at least VGPR; among patients at or below the median of expression, only 37.6% achieved at least VGPR. Conclusions: We identified an association between predicted expression of ZNF622 and clinical response to proteasome inhibitor therapy among MM patients. ZNF622 is a zinc finger binding protein which is known to be co-activator of B Myb activity and to affect apoptosis in response to oxidative stress. Our work highlights the potential importance of pharmacogenetic modifiers of treatment response in MM. Disclosures Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wong:Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

Abstract: Introduction: Novel therapeutic agents, such as bortezomib (VELCADE®; btz), thalidomide, and lenalidomide, are being used in combination with dexamethasone (dex) as frontline therapies in MM. Phase 2 and 3 trials with limited follow-up have reported a high response rate and feasibility of high-dose therapy and stem cell transplantation (HDT-SCT). Here we present longer follow-up on our phase 2 trial of btz±dex as frontline therapy. Methods: Patients (pts) with measurable disease and KPS ≥50% received btz 1.3mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle for up to 6 cycles. Oral dex 40mg was added on the day of and day after btz for pts achieving & lt; partial response (PR) after 2 cycles or & lt; complete response (CR) after 4 cycles. Responses were assessed using European Group for Blood and Marrow Transplantation criteria, with the addition of near CR (nCR; CR but positive immunofixation). Results: 48 pts were accrued and were evaluable for response; a further 2 registered on the trial declined to proceed. Median age was 60 years, 46% were male, 64% had IgG and 21% IgA, and 50% were Durie-Salmon stage III. At the end of btz±dex treatment, overall response rate (ORR; CR+nCR+PR) was 90% with 19% CR/nCR; an additional 8% achieved a minimal response (MR). Response to btz alone was rapid; response rate by end of cycle 2 was 50%, including 10% CR/nCR. Dex was added for 36 (75%) pts: 17 at cycle 3, 18 at cycle 5, and 1 at cycle 6. Addition of dex improved best responses to btz in 23 (64%) pts, with 12 improving from stable disease to MR or PR, 9 from MR to PR, 1 from PR to nCR, and 1 from nCR to CR. Median time to best response was 1.9 months. For all 48 pts, with a median follow-up of 24 months, median time to alternative therapy (TTAT) was 7 months (range: 2–25; this includes pts who went on to HDT-SCT), and median overall survival (OS) has not been reached; 1-year survival rate was 90%. For pts not proceeding to HDT-SCT, median TTAT was 22 months, median OS has not been reached; 1-year survival rate was 80%. 23/48 pts proceeded to HDT-SCT. Median CD34+ harvest was 12.6 x 106 cells/kg (range: 5.1–40.4 x 106) from a median of 2 collection days (range: 1–8). All pts had complete hematologic recovery; median time to neutrophil (ANC & gt;1000/mm3) and platelet ( & gt;100,000/mm3) engraftment was 11 days (range: 8–13) and 17 days (range: 10–98), respectively. In the 23 HDT-SCT pts, median TTAT and OS have not been reached; post-transplant 1-year survival rate was 90%. The most common grade ≥2 adverse events for btz±dex were sensory neuropathy/neuropathic pain (37%), fatigue (20%), constipation (16%), nausea (12%), and neutropenia (12%). Two pts developed grade 4 events (1 neutropenia, 1 thrombocytopenia). Conclusion: Btz±dex is an effective frontline therapy for MM, with an ORR of 90%, including 19% CR/nCR, and OS rate of 80% at 1 year. The treatment is well tolerated and toxicities were manageable and reversible. Addition of dex to btz provides improved responses. TTAT for patients not undergoing HDT-SCT was 22 months. The regimen does not prejudice subsequent HDT-SCT; stem cell harvest and engraftment were successful in all pts proceeding to transplant. Consolidation with HDT-SCT further increases the response rate and durability of response. Btz+dex is being compared to VAD as induction therapy prior to HDT-SCT in a phase 3 study.

Abstract: e20569 Background: Light chain amyloidosis (AL) is a plasma cell dyscrasia characterized by organ dysfunction, morbidity, and early mortality. Treatment focuses on suppressing monoclonal light chain production as measured by hematologic response criteria (Comenzo et al., 2012). Daratumumab (DARA), a monoclonal CD38 antibody, has demonstrated efficacy in heavily pretreated AL patients (Kaufman et al., 2017). We report the outcomes of newly diagnosed AL patients treated with a DARA-based regimen. Methods: A single-center retrospective chart review with an IRB-approved protocol was performed on newly diagnosed AL patients treated with first line DARA-based regimens between 1/2018 – 12/2019. Results: Fourteen patients were evaluated. The median age was 69 years (45 – 87), 50% were male, and 50% produced monoclonal lambda light chains. All patients had cardiac and renal involvement. Per the 2004 Mayo staging system, 1/14 (7%) patients had stage I cardiac disease, 2/14 (14%) had stage II, and 11/14 (79%) had stage III, of which two were stage IIIb. Regarding renal staging (Palladini et al., 2014), 10/14 (71%) patients were stage I, 3/14 (21%) stage II, and 1/4 (7%) stage III. Most patients (11/14) received DARA in combination with bortezomib and dexamethasone, while one patient received DARA and dexamethasone (DEX). Two patients received DARA in combination with bortezomib, cyclophosphamide, and DEX. Patients received a median of 5 cycles of DARA (1 – 14). After a median follow-up of 4.4 months (1 – 19), all patients were still receiving DARA. DARA was well tolerated, with 4 patients (29%) experiencing grade 1 infusion reactions and no additional toxicities observed. Responses were rapid, with a median time of 11 days (7 – 61) to first response and 46 days (9 8– 168) to best response. First response was classified as partial response (PR) in 8/14 patients (57%), very good PR (VGPR) in 3/14 (21%), and complete response (CR) in 1/14 (7%). Best response included a PR in 3/14 (21%), VGPR in 7/14 (50%), and CR in 2/14 (14%). In most patients, responses deepened over time. Cardiac response was seen in 5/7 (71%) evaluable patients with median time to response of 39 days (21 – 263). Renal response was seen in 2/4 (50%) evaluable patients with median time to response of 152 days (94 – 194). Conclusions: First line use of DARA in AL amyloidosis produced rapid and deep hematologic and organ response, resulting in a 93% objective hematologic response rate. DARA was well-tolerated and efficacious even among patients with extensive organ involvement and cardiac dysfunction. Prospective studies of first line DARA are warranted.