Vesole, David H.

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Abstract Abstract 38 INTRODUCTION: Lenalidomide and bortezomib have moved into the management of newly diagnosed multiple myeloma leading to dramatically improved outcomes. As a consequence, the role of upfront autologous peripheral blood stem cell transplant (ASCT) has become more controversial. The ECOG E4A03 clinical trial randomized newly diagnosed MM patients to lenalidomide with high-dose dexamethasone (LD) vs lenalidomide with low-dose dexamethasone (Ld) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). Upon completing four cycles of therapy, pts had the option of ASCT or continuing on the assigned therapy. The purpose of this abstract is to determine the outcome of patients on this trial pursuing early ASCT according to various age-groups. MATERIALS and METHODS: This is a post hoc, retrospective analysis of overall survival within age subgroups stratified by early ASCT status. This is a landmark analysis including only pts surviving the first 4 cycles of therapy. RESULTS: In all three age-groups studied, 1, 2, and 3-year survival probability estimates with ASCT were excellent (Tables 1, 2, and 3). For patients under the age of 65 who survived the first 4 cycles of therapy, overall survival at 3-years was 94% with early ASCT, 78% in pts continuing protocol therapy. Although direct comparison with patients not going to early transplant is not possible because the assignment to early ASCT versus no early ASCT was not randomized, survival with ASCT at 3-years appeared higher. While we attempt to correct for age, the differences may be influenced by other factors such as performance status, comorbidities, response to therapy, etc. The presumption that treatment related mortality (TRM) should be more problematic for older pts undergoing ASCT is addressed by looking at the >65 and >70yo cohorts. In the >65 age group, one-year mortality is similar between the early ASCT population and the no early ASCT population. In the >70 age group, no adverse impact of early ASCT was seen in the first year on overall survival but the sample size is extremely small. In all age groups early ASCT seemed to mitigate some of the survival disadvantage associated with randomization to the LD arm. CONCLUSIONS: This analysis shows that the strategy of lenalidomide plus dexamethasone induction followed by early ASCT has a remarkably good outcome in terms of overall survival in all age groups studied and supports the continued role of early consolidative ASCT in newly diagnosed patients. The risk of early mortality was notably low in the first year in all age groups. The risk of early mortality seems to increase at 2 years for the LD pts not choosing early ASCT and at 3 years for the Ld pts not choosing early ASCT. Selection bias makes it difficult to compare results for pts that chose early ASCT directly to the patients who did not receive early ASCT in this trial. As such, these results emphasize the need for randomized trials investigating the timing of ASCT in myeloma in the era of novel therapy. Disclosures: Siegel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for front line therapy. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 3017 Introduction: Multiple myeloma (MM) is a malignancy of clonal plasma cells with resulting in an increase production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly to those organisms in which opsonization is one of the key defense mechanisms, e.g. strep and staph infections. Treatment of MM is virtually always associated with further immunosuppression, at least in the immediate term, until the malignant clone is eradicated and normal immunoglobulins are produced. Rationale: Due to further compromise of an already incompetent immune system by initial chemotherapy and the previous suggestion (Oken et al Am J Med 1996; 100:624-628) that prophylactic antibiotics may reduce infectious complications, this study was designed to evaluate the impact of prophylactic antibiotics on the incidence of serious bacterial infections during the first two months of treatment. Methods: Pts with untreated MM receiving chemotherapy were randomized on a 1:1:1 basis to receive either a daily ciprofloxacin (C; 500 mg), trimetheprim-sulfamethoxazole (T; DS bid) or observation (O) for the first 2 months of treatment. Pts were evaluated for serious bacterial infection (grade 3 or 4) during the first two months of myelotoxic/suppressive therapy. Secondary endpoints (EP) included: incidence of non-bacterial infections, resistant organisms due to prophylaxis, the incidence of infection the third month OFF of antibiotic prophylaxis and whether protection against infection is associated with an improved response rate. Results: From July 1998 to January 2008, 212 untreated, symptomatic MM pts being treated with myelotoxic/suppressive chemotherapy were randomized to C (n=69), T (n=76) or O (n=67) for the first 2 months of treatment. The incidence of serious infection (> grade 3 ECOG toxicity criteria and/or hospitalization) was comparable among groups: C=10 (14.7%), T=5 (6.9%), O=9 (14.5%); p= 0.268 which was the primary EP. The incidence of any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, p=0.910). There were 25 grade 2 infections and 4 grade 3 infections involving respiratory (n =13), sepsis/bacteremia (n = 4), and urinary (n =3), joint/bone (n =2), unknown (n =2) or various GI tract (n = 5) and skin (n =1). Eight pts expired within the first 2 months: 2 from MM, 3 cardiac, 2 respiratory, 1 renal (unrelated to MM or Rx) occurring in the C (4), T (1), O (2). Secondary EPs failed to show a difference in the incidence of serious bacterial infection during the third month in the absence of prophylaxis (C=3%, T=4%, O=2%; p=0.874), development of resistant infections, initial response to therapy or overall survival. Conclusions: The use of prophylactic antibiotics did not decrease the incidence of serious infection (> grade 3 and/or hospitalization) nor of any infection within the first 2 months of treatment. Infection prophylaxis did not affect the incidence of infection upon completion of 2 months of therapy (nor, ultimately, at any time during the subsequent 2 years), the response to therapy or to overall survival. Incidentally, there were no documented cases of PCP despite the assumption that MM pts, with compromised immune systems, are more susceptible. The incidence of serious infections in this study, in which few patients received novel agents, is comparable to that observed in more modern regimens even in the presence of mandated/recommended prophylactic antibiotics. Utilizing either lenalidomide plus dexamethasone or clarithromycin, lenalidomide and dexamethasone resulted in > grade 3 infectious complications in 16.7% and 9.7%, respectively, as reported by the Mayo Clinic and Cornell groups, respectively (Gay et al Am J Hematol, in press). Furthermore, in the ECOG E4A03 randomized trial of lenalidomide plus either high dose dexamethasone (LD) or low dose dexamethasone (Ld) in which prophylactic antibiotics were recommended, the incidence of > grade 3 infectious complications were 9.4% and 6.4%, respectively (Rajkumar et al Lancet Oncol 2010; 11: 29–37). We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy. Prophylactic antibiotics should be considered on a case-by-case basis after analyzing the potential infection risk in individuals. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 308 Introduction: The Eastern Cooperative Oncology Group (ECOG) has previously reported the superior 1 and 2 year survival of Ld versus LD as initial therapy in newly diagnosed symptomatic multiple myeloma (MM) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). The 1 year and 2 year OS for Ld vs LD were 96% and 85% vs 88% and 78%, (p < 0.01), respectively. This despite higher ORR in LD vs Ld (79% vs 68%; p = 0.008). The difference in OS was predominantly due to early death in the LD group (5% vs 0.5%; p = 0.003). As a result of this analysis, Ld is now considered the standard of care. However, it should be noted that the majority of these deaths occurred in pts > 65. In this analysis, we evaluated the impact of age on dexamethasone dose intensity and OS. Methods: 445 pts were randomly assigned: 223 to LD and 222 to Ld. Pts were analyzed on an intent-to-treat basis for OS. The pts were analyzed by age in 2 groups: < 65 and > 65 (the age corresponding to transplant eligibility outside the US). The pts > 65 were then further subdivided into >70 and > 75 yrs. Results are expressed as OS probability at 1 and 2 years post randomization. In addition, to eliminate the early death ‘penalty’ in the LD group in the original analysis, a landmark analysis was performed at 4 months. Results: Overall Survival Probability: Intent-to Treat Analysis Overall Survival Probability: 4 month Landmark Analysis Conclusions: As previously reported, OS in the trial at 1 and 2 years was superior with Ld. OS was not superior with LD compared with Ld in any age group despite a higher response rate. This was true even when using a landmark analysis to eliminate the 5% early deaths seen in the first 4 months of treatment. We conclude the following: 1) LD is not definitively superior to Ld in any age group; 2) Given the higher toxicity in the absence of a clear survival benefit with LD, Ld remains the best choice for all ages. This analysis confirms the original opinion that low-dose dexamethasone is the standard of care for all newly diagnosed MM pts, regardless of age. Disclosures: Vesole: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centorcor-Ortho-Biotech: Speakers Bureau. Off Label Use: Lenalidomide for front-line therapy in multiple myeloma. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy; Intellikine: Consultancy. Siegel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: MM is an incurable disease with an anticipated overall survival ranging from months to decades. Novel therapies like bortezomib have activity in both the relapsed/refractory and up front settings. There are sparse data on whether novel therapies may overcome high risk features. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients received bortezomib 1.3 mg/m2 every other week indefinitely. Patients relapsing on maintenance schedule resumed full induction schedule. Responses were defined by the EBMT criteria. The primary end-point was the response rate (90% power to detect a response rate of >=50% ). Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled. Among the 43 eligible patients, median age was 63; 51% were male. All had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Response data are available for 37 of the 43 eligible patients. The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patients with CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable). The median progression free survival is 9.4 months. Thirty-three percent of patients completed the 8 cycles of planned induction therapy and moved to maintenance. Reasons for discontinuing therapy have included progression or death (n=18), adverse events (n=6), and other (n=14). Only 12% of patients remain on active therapy: 0% of deletion 13q patients; 25% of t(4:14) and 12% each of high B2M and high PCLI patients. Of the 14 patients who entered the maintenance phase of treatment, 3 have progressed. Of these 3, 2 took re-induction, and neither responded. Median time to progression for those entering maintenance was12.4 months from the time of starting maintenance. The most common adverse events of grade 3 or higher included neutropenia (33%), diarrhea (31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%), fatigue (14%). Grade 1–2 sensory peripheral neuropathy occurred in 53% of patients, with only 2% having grade 3 sensory neuropathy. One patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses of protocol treatment due to heart block and asystole. Updated results on the full study population will be presented at the meeting. Conclusions: In high risk patients, upfront bortezomib appears to result in comparable response rates to those reported for unselected cohorts of newly diagnosed myeloma patients. Continued follow-up of these patients will provide information about whether this will translate into better overall outcomes. Figure Figure

Abstract Purpose: Deep vein thrombosis (DVT) is increasingly recognized as a major complication of thalidomide (T; Thal) and lenalidomide (R; Rev) based therapy for multiple myeloma. Estimated incidence varies widely in the literature. There is no consensus on specific risk factors, indications for thromboprophylaxis or the agent of choice for DVT prophylaxis. The purpose of this study was to develop a consensus among members of the IMWG. Patients and Methods: A survey was electronically mailed to 67 IMWG members on July 21, 2006 and consisted of 24 multiple-choice questions. Results: Twenty-three IMWG members (34%) sent in their responses by the cut-off date. All (100%) felt that DVT was an important question, but most (95%) did not avoid Thal/Rev based therapy because of the DVT risk. Overall results are summarized in the Table below. A majority of physicians felt that concomitant therapy with high dose dexamethasone (90% of physicians), alkylators (55%), doxorubicin/liposomal doxorubicin (90%), and erythropoietin (75%) increase the risk of DVT associated with Thal or Rev based therapy. Aspirin (81 mg or 325 mg per day) was the preferred choice of prophylaxis when necessary. However, 65% of respondents preferred warfarin to a therapeutic INR or LMW heparin if either doxorubicin or liposomal doxorubicin was added to the regimens. Most (95–100%) felt that DVT prophylaxis was not indicated for: VAD, MP, bortezomib +/− dexamethasone regimens. Seventy-five percent felt it to be safe to resume therapy with Thal/Rev after therapeutic anticoagulation. Most (95%) believed randomized trials were needed. Conclusion: DVT is recognized as a major clinical problem associated with Thal/Rev containing regimens. Most respondents felt that the DVT risk did not warrant any prophylaxis when either Thal or Rev were used as single agents. Aspirin was the preferred form of DVT prophylaxis for most Thal/Rev containing regimens, except when doxorubicin/liposomal doxorubicin or melphalan were added. Additional responses will be analyzed both electronically and by conference call prior to the meeting. Therapy Estimated incidence of DVT (% respondents) Choice of thromboprophylaxis (% respondents) Single agent thal <5% (61%) None (65%) Single agent Rev <5% (80%) None (65%) Thal-Dex 10–20% (52%) Aspirin (60%) Rev-Dex 10–20% (48%) Aspirin (60%) MPT 10–20% (65%) Aspirin (40%) R-MP 5–10% (57%) Aspirin (70%)

Abstract Aim: A phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was response rate at 4 months, with the null hypothesis being that the response rates in the two 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. All analysis were performed on an intent to treat basis. An independent DMC recommended release of study results. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 17 months. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities, including DVT/PE and infections, were significantly higher in the high dose dex arm (see Table). Overall survival (OS) at the second pre-planned interim analysis was significantly superior with lenalidomide plus low dose dex, P<0.001; one year survival 96% (Rd) versus 87% (RD). The 18 month survival rate is 91% versus 80%, respectively. OS differences in favor of the low dose dex arm were seen in pts <65 (P=0.022; one year rate 97% vs 92%) as well as pts 65 and older (P=0.002; one year rate 94% vs 83%), respectively. Sixty-one patients have died; 42 in the RD arm and 16 in Rd arm. The cause of death has been verified by detailed chart review in 38 patients. Of 29 verified deaths in the RD arm, 13 were due to disease progression, 6 thrombosis/embolism, 3 infection, 3 cardiac ischemia, 1 stroke, and 1 respiratory failure. Of 9 verified deaths in the Rd arm, 5 were due to disease progression, 2 infection, 1 thrombosis/embolism, and 1 cardiac arrest. Response rate data are expected to be available at the time of the meeting. Conclusions: Lenalidomide plus low-dose dexamethasone (Rd) is associated with superior OS compared to lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM. The increased mortality in Arm A is due to disease progression (myeloma deaths) as well as increased toxicity. This study has major implications for the use of high-dose dexamethasone in the treatment of newly diagnosed MM. Major Grade 3 or Higher Adverse Events Toxicity Arm A % Arm B % P value Neutropenia 10 19 0.01 DVT/PE 25 9 <0.001 Infections 16 6 <0.001 Any grade 3 or higher non-hematologic 49 32 <0.001 Any grade 4 or higher non-hematologic 20 9 <0.001 Deaths in first 4 months 5 0.5 0.006

Abstract Background: Immunomodulatory agents and proteasome inhibitors have significantly improved outcomes in the management of patients with multiple myeloma (MM). As a consequence, the role of upfront autologous stem cell transplant (ASCT) has become more controversial. The ECOG-ACRIN Cancer Research Group trial E4A03 demonstrated the superiority of lenalidomide (LEN) and low-dose dexamethasone (DEX; Ld) over LEN and high dose DEX (LD) in newly diagnosed MM (Rajkumar SV, Lancet Oncol, 2010). This led to the universal acceptance of Ld as a standard induction regimen. More recently, the FIRST study demonstrated the superiority of Ld as continuous therapy vs Ld given x 18 cycles and melphalan-thalidomide-prednisone x 12 cycles proving continuous Ld should be considered standard of care (Benboubker L, NEJM, 2014). Upon completion of four cycles of therapy, patients enrolled in E4A03 had the option of proceeding to ASCT or continuing on their assigned Ld or LD. A prior post-hoc retrospective landmark analysis (Siegel DS, Abstract, Blood 2010) comparing outcomes of early ASCT vs. no early ASCT showed that in patients <65, 65-70, and >70, the survival with early ASCT at 3 years appeared higher, supporting the role of early consolidative ASCT in newly diagnosed patients. This analysis is the long-term follow-up of the aforementioned study. Methods: A post hoc, retrospective landmark analysis was performed evaluating overall survival (OS) by early ASCT vs. no early ASCT overall and within age subgroups. The Kaplan-Meier method was used to estimate survival distributions and Cox regression for hazard ratio (HR) estimates. The landmark analysis included only patients surviving the first four cycles of therapy. Results: 21% of patients opted for early ASCT (n=90). At baseline (four cycles prior), early ASCT patients were younger (median 57.5y vs 66y), more fit (ECOG PS 0 45% vs 56%) and with less aggressive disease (ISS Stage 3 12% vs 28%). Median treatment duration was 7.6m for no early ASCT patients. The 1, 2, 3, 4, and 5-year survival probability estimates were higher for early ASCT vs. no early ASCT at 99%, 93%, 91%, 85%, and 80% vs. 94%, 84%, 75%, 65%, and 57%. The median OS in the early ASCT vs. no early ASCT was not reached vs. 5.8 years, respectively (Table 1). The survival hazard ratio (HR) for early ASCT was 0.55 [95%CI (0.38-0.80)]. In a further subgroup analysis of patients </= 65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 79% [95%CI (67-87)] vs. 62% [95%CI (54-69)], respectively. In patients </= 65, median OS in the early ASCT vs. no early ASCT was not reached vs. 7.4 years and the survival HR was 0.74 [95%CI (0.48-1.15)]. For patients >65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 83% [95%CI (56-94)] vs. 52% [95%CI (45-59)], respectively. In patients >65, median OS in the early ASCT vs. no early ASCT was not reached versus 5.2 years and the survival HR was 0.38 [95%CI (0.17-0.87)]. In all age groups, overall response rate was similar prior to the decision of proceeding with ASCT vs. no early ASCT. In a multivariable model adjusting for baseline prognostic factors, early ASCT retained marginal significance. Conclusions: The landmark analysis demonstrated that patients opting for ASCT after induction Ld/LD had a higher 1, 2, 3, 4, and 5- year survival probability and improvement in median OS regardless of DEX dose density. Results were stronger within the older age cohort and upheld in adjusted models. Limitations include lack of randomization and data on salvage therapy. At a time when lenalidomide and dexamethasone as induction is gaining worldwide acceptance in all age groups, early ASCT is safe and efficacious and should remain a standard of care for newly diagnosed MM even in the era of novel therapies. Table 1. Survival Probabilities (Time from Registration) for all Patients Included in the Landmark Analysis Median 1 year 2-year 3-year 4-year 5-year N Events Median (Yrs)(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) No Early ASCT All 341 195 5.78(5.11 - 6.59) 22 0.94 (0.90 - 0.96) 53 0.84 (0.80-0.88) 84 0.75 (0.70-0.79) 119 0.65 (0.59-0.69) 144 0.57 (0.51 - 0.62) Early ASCT All 90 34 NR 1 0.99 (0.92 - 1.00) 6 0.93 (0.86 - 0.97) 8 0.91 (0.83 - 0.95) 13 0.85 (0.76 - 0.91) 18 0.80 (0.69 - 0.87) NR = not reached Disclosures Biran: Celgene: Speakers Bureau. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Fonseca:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Vesole:Idera Pharmaceuticals: Research Funding; Celgene Corporation: Speakers Bureau. Williams:Celgene: Consultancy, Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

PURPOSE To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

e19525 Background: Rearrangements of the immunoglobulin heavy chain (IGH) on chromosome 14 are identified by FISH in about 15-20% of patients (pts) with newly diagnosed multiple myeloma (MM). Historically there is variation on the significance on prognosis of these rearrangements: typically, t(4;14), t(14;16) and t(14;20) have high risk (HR), and t(11;14) have standard risk (SR). A recent study (Kaufman et al, Leukemia. 2016 30:633-9) suggests that t(11;14) may confer a worse prognosis We report the prognostic significance of t(11;14) in a single-institution MM cohort. Methods: 87 pts with t(11;14) by CD 138 selected FISH at diagnosis were identified, pts without symptomatic MM were excluded. Cox regression was used for statistical analysis. Progression free survival (PFS), and overall survivals (OS) from diagnosis and post autologous stem cell transplant (ASCT) were analyzed by Kaplan-Meier. Results: Median age at diagnosis was 62 years, 45 pts (52%) were male, and 24 pts (27%) had ISS 3. All pts received either a proteasome inhibitor or an immunomodulatory agent, and 42 (48%) received triplet treatment as induction. Sixty-nine (79%) pts had ASCT, and overall response rate (ORR, partial response or better) post ASCT was 73%. For pts with HR FISH (defined as t(14;16), p53 del, 1q21 gain or 1p del) compared to SR FISH, the ORR post ASCT was 70% vs 77% (p = 0.67). OS from diagnosis was 93% at 3 years, 74% at 4 years and 51% at 5 years. Seven patients (8%) developed plasma cell leukemia, and there was no association between HR and SR FISH (p = 0.66). In multivariate analysis, ISS stage was an independent risk factor for mortality; pts with stage 3 had 7.3 times (CI: 1.16-36.4) and 5.7 times (CI: 1.63-20.0) the risk of mortality than pts with stage 1 and 2. Having an ASCT reduced mortality by 87% (CI: 0.04-0.41). Conclusions: Despite the use of novel therapies the OS at 5 years of our pts with MM was not significantly improved compared to SEER data from 1992-2013 (51% vs 48.5%). Pts with t(11;14) who had ASCT had increased survival compared to those who did not. Our results suggest that t(11;14) may confer a worse prognosis. Further prospective studies evaluating the risk of t(11;14) are warranted.