Abstract Background: Invasive lobular carcinoma (ILC), the second most common histologic subtype of breast cancer, is increasingly recognized as a distinct tumor type compared to the more common invasive ductal carcinoma (IDC). While ILC is known to have lower rates of pathologic complete response to neoadjuvant chemotherapy, ILC tumors are biologically heterogenous. As such, genomic signatures might identify patients with ILC who might benefit from tailored treatment options. The gene expression signature MammaPrint (MP) classifies tumors as having a Low Risk or High Risk of distant recurrence. MP combined with BluePrint (BP), a molecular subtyping signature, categorizes tumors as Luminal A (MP Low Risk), Luminal B (MP High Risk), Basal or HER-2 type. ImPrint is a 53-gene signature that identifies HR+HER2- patients predicted to benefit from immune checkpoint inhibitors. RePrint is a 60-gene DNA repair deficiency (DRD) signature that identifies HR+HER2- patients who may benefit from PARP inhibitors with platinum agents. Response Predictive Subtypes (RPS), used in the I-SPY2 trial, combine clinical subtype and these genomic signatures to personalize treatment planning and improve outcomes. In this study, we determined the distribution of 3 RPS in HR+HER2-: (1) ImPrint-/RePrint-, (2) ImPrint-/RePrint+ (3) ImPrint+, in patients ILC compared to IDC enrolled in the FLEX trial. Methods: This study includes 1078 HR+HER2-women with ILC and 6078 with IDC enrolled in FLEX registry. FLEX (NCT03053193) is a prospective, observational trial that includes stage I-III breast cancer patients who undergo MammaPrint testing (with or without BluePrint) as standard of care, and consent to full transcriptome and clinical data collection. MP High Risk tumors were further stratified into High 1 and High 2. ImPrint and Reprint results were used to determine RPS. A two-tailed proportional z-test was used to assess differences between ILC and IDC as well as between RPS. Results: ILC patients had a significantly lower percentage of MP High Risk tumors in comparison to IDC. Among MP High Risk tumors, those with ILC had significantly more MP High 1 than patients with IDC. BP subtyping in ILC tumors showed significantly lower percentage of Basal, and Luminal B, and higher percentage of Luminal A compared to IDC tumors. For RPS, a higher percentage of ILC tumors were ImPrint-/RePrint- compared to IDC, whereas lower frequencies of ImPrint-/RePrint+ and ImPrint+ were found. Within the ILC ImPrint+ subgroup (n=14), 1 (7.1%) was classified as High 2 and 10 (71.4%) as High 1 and 3 (21.4%) as Low Risk. All 14 (100%) ImPrint+ patients were BP Luminal. In contrast, within the IDC MP High Risk ImPrint+ subgroup (n=328), 233 (71.0%) were High 2, 88 (26.8%) High 1 and 7 Low Risk (2.1%). Furthermore 193 (60.7%) were classified as BP Basal, 2 HER2 (0.6%) and 123 (38.7%) Luminal within this IDC RPS. Conclusions: This is the first study to investigate the distribution of Response Predictive Subtypes in ILC, which will be beneficial to optimize the treatment selection for patients with early-stage HR+/HER2- ILC. Though the percentage of ImPrint+ is lower in ILC, this study revealed a small subset of patients in ILC with potential response to Immunotherapy. Furthermore, these results underscore the heterogeneity of ILC tumors and generate further hypotheses to investigate the immune cell abundance in ILC compared to IDC and correlate immune cell abundance to ImPrint status. Table: Genomic and Tumor Characteristics of HR+HER2- ILC and IDC tumors Citation Format: Rita Mukhtar, Christina Yau, Denise Wolf, Adam Brufsky, Hannah Linden, Natasha Hunter, Reshma Mahtani, Abirami Sivapiragasam, Trevor Feinstein, Fengting Yan, Ian Grady, Priscilla McAuliffe, Michaela Tsai, Joyce O'Shaughnessy, Blanche Mavromatis, Sasha Davis, Josien Haan, William Audeh, Lavanya Samraj, FLEX Investigators' Group. Distribution of MammaPrint, BluePrint, and Response Predictive Subtypes based on ImPrint and Reprint in ER+/HER2- Invasive Lobular Carcinoma – A FLEX sub study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-03.

BACKGROUND: Immune checkpoint inhibitors in combination with chemotherapy have demonstrated an improvement of pathologic complete response (pCR) in patients with HR-HER2- and MammaPrint (MP) High Risk, HR+HER2- tumors in the I-SPY2 TRIAL. However, not all patients benefit from immune checkpoint blockade and these new agents come with additional financial burden and significant long-lasting side effects such as adrenal insufficiency. Thus, it is imperative to better understand who benefits. Response Predictive Subtypes (RPS) were developed in the I-SPY2 TRIAL using pre-treatment expression data from 987 MP High Risk patients; 39% of HR+HER2- tumors and 63% of HR-HER2- tumors were identified as immune sensitive. In I-SPY2.2, RPS tumor classification uses ImPrint, a 53-gene signature that has been independently validated to predict the likelihood of a pCR with PD1-PDL1 immune checkpoint inhibitors with high sensitivity and specificity. Using a real-world dataset of 10,000 patients enrolled in the FLEX trial, we identified immune sensitive (ImPrint+) patients within immunohistochemistry (IHC) subtypes and within MP and BluePrint (BP) subgroups. METHODS: FLEX (NCT03053193) is an ongoing registry trial with 97 sites open in the United States and 2 international sites. Patients enrolled in FLEX have early-stage breast cancer and receive standard of care MP testing with or without BP molecular subtyping and consent to clinically annotated full genome data collection. MP is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. MP High Risk can be further stratified into High 1 and High 2, which have demonstrated differences in chemosensitivity and pCR rates in the I-SPY2 TRIAL (NCT01042379). BP, an 80-gene molecular subtyping signature, categorizes patients’ tumors as Luminal-, HER2- or Basal-Type. RESULTS: Of the 10,021 patients, 9.1% of the FLEX patient population are ImPrint+ and are predicted to have a meaningful pCR rate with immune checkpoint inhibitors. Younger (≤ 50 years) or pre/peri-menopausal patients, patients with larger or node-positive tumors, and patients of Black or Latin race/ethnicity independently had a higher likelihood of having ImPrint+ tumors (Table 1). ImPrint+ tumors were identified in all clinical subtypes by IHC. There is a higher likelihood of ImPrint+ tumors being MP High 2 or BP Basal-Type tumors. Within BP Basal tumors, 74.7% of HR+ and 66.0% of HR- tumors were ImPrint+. CONCLUSIONS: The focus of immune therapy trials has been on patients with HR-HER2-, MP High Risk patients. Indeed, most patients who are predicted to benefit have MP High 2 or BP Basal-Type tumors, including some HR+ patients, which is consistent with I-SPY2 results. Importantly, this large real-world dataset enables the identification of populations who may benefit from immune therapy outside of traditional clinical trial populations and supports the testing of checkpoint inhibitors in the immune-positive subtype. Younger women and patients of Black or Latin race/ethnicity who typically have more aggressive tumors also have higher proportions of ImPrint+ tumors. Thus, it is critical that these populations be included in clinical trials. This first look at immune sensitivity in over 10,000 FLEX patients with ImPrint generates preliminary data and hypotheses that will be explored in future FLEX substudies, including an analysis of lobular cancers and long-term outcomes in ImPrint+ patients across all races and ages. Table 1. Clinical characteristics of ImPrint+ and ImPrint- tumors. Citation Format: Adam M. Brufsky, Midas Kuilman, Rita Mukhtar, Denise M. Wolf, Christina Yau, Joyce O’Shaughnessy, Cathy Graham, Vijayakrishna K. Gadi, Pat Whitworth, Alexander Hindenburg, Ian Grady, Gordon Srkalovic, Kent Hoskins, Ajay Dhakal, Cynthia Ma, Natasha Hunter, Jennifer Crozier, Blanche Mavromatis, Lorenza Mittempergher, Christine Finn, Shraddha Modh, Erin B. Yoder, Patricia Dauer, Andrea Menicucci, Bas van der Baan, William Audeh, Laura J. Esserman. ImPrint immune signature in 10,000 early-stage breast cancer patients from the real-world FLEX database [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-08.

Background: The PROMIS trial (NCT01617954) previously evaluated how a definitive result from the MammaPrint 70-gene signature (70-GS) can impact treatment recommendations for patients with an intermediate range recurrence score (RS 18-30) from the 21-gene assay (21-GA, Oncotype DX). Since publication of this study, TAILORx results published in 2018 (and further explored in June 2019) suggested an interaction between the 21-GA, patient age (≤50 yrs), and clinical risk. Initially, chemotherapy (CT) was recommended for all women ≤50 with a RS\u003e16. Based on the recent clinical-risk analysis, Ovarian Function Suppression (OFS) + endocrine therapy (ET) has been suggested as an alternative treatment for low clinical risk (clin-low) women ≤50yrs with an RS 16-25. This current analysis examines the updated treatment recommendations based on the interaction between patient age and clinical risk, and explores the impact that the 70-GS can have on adjuvant chemotherapy decisions for women ≤50 years of age. Methods: 70-GS risk of recurrence was determined for 21-GA intermediate patients by standard diagnostic testing (Agendia, Irvine, CA). Clinical risk was assessed using the MINDACT, modified Adjuvant Online! algorithm (Cardoso, NEJM 2016). The 70-GS High and Low Risk classification were subdivided by RS groups 18-20, 21-25, and 26-30 and by clinical risk stratification. Results: 181 patients in PROMIS were ≤50 yrs. Of those, 64% (116/181) were clin-low, and 35% (63/181) were high clinical risk (clin-high) (2 unknown). Among patients ≤50 yrs with RS 18-20, 60% (27/45) of clin-low and 56% (15/27) of clin-high were found to be 70-GS Low Risk. Among patients with RS 21-25, 55% (30/55) of clin-low and 30% clin-high (8/26) were Low Risk by the 70-GS. For patients ≤50 yrs with RS 26-30, 15% (4/27) were found to be 70-GS Low Risk. Of all patients with RS 26-30, 21% (32/156) were Low Risk by 70-GS. Conclusions: With the follow-up publication for TAILORx, incorporation of clinical risk in addition to age, RS group, and the assumed benefit of chemotherapy-induced menopause, has presented additional layers of complexity for physicians treating breast cancer. The current analysis demonstrates that 46% of women ≤ 50yrs with a RS 21-25 are 70-GS Low Risk, and based upon the prospective, randomized MINDACT* trial data, can safely avoid CT. Overall, the 70-GS can precisely identify 20-60% of women ≤ 50yrs with intermediate RS (18-30) as genomic Low Risk with excellent survival with ET alone (\u003e95% 5-yr DMFI [MINDACT]), who may otherwise be candidates for treatment with CT or OFS. *(Microarray in Node Negative and 1-3 Lymph Node Positive Disease May Avoid Chemotherapy) Citation Format: Michaela Tsai, Hatem Soliman, Shelly Lo, Rubina Qamar, Raye Budway, Ellis Levine, Pat Whitworth, Blanche Mavromatis, Robin Zon, Sarah Untch, Lisa Blumencranz, Joseph McKelley, William Audeh, PROMIS Investigators Group. Treatment recommendations in ER+ patients ≤ 50 years: Comparison of the 21-gene assay and 70-gene signature in the PROMIS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-11.

Background Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. Methods IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. Results The 70-GS classified 62.5% ( n = 224/358) of patients as LR and 37.5% ( n = 134/358) as HR. Treatment decisions were changed for 24.0% ( n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% ( n = 112/134) of 70-GS HR patient treatment plans, and 91.5% ( n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. Conclusions The IMPACt trial showed that treatment plans were 88.5% ( n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% ( n = 258/358) of cases after receiving 70-GS results. Trial registration “Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry” ( NCT02670577 ) retrospectively registered on Jan 27, 2016.

Abstract Background: The PROMIS trial (NCT01617954) previously evaluated how a definitive result from the MammaPrint 70-gene signature (70-GS) can impact treatment recommendations for patients with an intermediate range recurrence score (RS 18-30) from the 21-gene assay (21-GA, Oncotype DX). Since publication of this study, TAILORx results published in 2018 (and further explored in June 2019) suggested an interaction between the 21-GA, patient age (≤50 yrs), and clinical risk. Initially, chemotherapy (CT) was recommended for all women ≤50 with a RS>16. Based on the recent clinical-risk analysis, Ovarian Function Suppression (OFS) + endocrine therapy (ET) has been suggested as an alternative treatment for low clinical risk (clin-low) women ≤50yrs with an RS 16-25. This current analysis examines the updated treatment recommendations based on the interaction between patient age and clinical risk, and explores the impact that the 70-GS can have on adjuvant chemotherapy decisions for women ≤50 years of age. Methods: 70-GS risk of recurrence was determined for 21-GA intermediate patients by standard diagnostic testing (Agendia, Irvine, CA). Clinical risk was assessed using the MINDACT, modified Adjuvant Online! algorithm (Cardoso, NEJM 2016). The 70-GS High and Low Risk classification were subdivided by RS groups 18-20, 21-25, and 26-30 and by clinical risk stratification. Results: 181 patients in PROMIS were ≤50 yrs. Of those, 64% (116/181) were clin-low, and 35% (63/181) were high clinical risk (clin-high) (2 unknown). Among patients ≤50 yrs with RS 18-20, 60% (27/45) of clin-low and 56% (15/27) of clin-high were found to be 70-GS Low Risk. Among patients with RS 21-25, 55% (30/55) of clin-low and 30% clin-high (8/26) were Low Risk by the 70-GS. For patients ≤50 yrs with RS 26-30, 15% (4/27) were found to be 70-GS Low Risk. Of all patients with RS 26-30, 21% (32/156) were Low Risk by 70-GS. Conclusions: With the follow-up publication for TAILORx, incorporation of clinical risk in addition to age, RS group, and the assumed benefit of chemotherapy-induced menopause, has presented additional layers of complexity for physicians treating breast cancer. The current analysis demonstrates that 46% of women ≤ 50yrs with a RS 21-25 are 70-GS Low Risk, and based upon the prospective, randomized MINDACT* trial data, can safely avoid CT. Overall, the 70-GS can precisely identify 20-60% of women ≤ 50yrs with intermediate RS (18-30) as genomic Low Risk with excellent survival with ET alone (>95% 5-yr DMFI [MINDACT]), who may otherwise be candidates for treatment with CT or OFS. *(Microarray in Node Negative and 1-3 Lymph Node Positive Disease May Avoid Chemotherapy) AgeRS GroupClinical RiskNMP Low Risk% recommended ET alone based on 70 -GStreatment recommendation based on 21-GA≤ 50RS 18-20Clin-low452760%OFS+ET or ET aloneClin-high / (unknown)26 (1)1556%CT+ET or OFS+ETTotal724258% ≤ 50RS 21-25Clin-low553055%OFS+ETClin-high / (unknown)26 (1)830%CT+ET or OFS+ETTotal823846% ≤ 50RS 26-30Clin-low1616%All receive CT+ET regardless of clinical riskClin-high11327%Total27415% Citation Format: Michaela Tsai, Hatem Soliman, Shelly Lo, Rubina Qamar, Raye Budway, Ellis Levine, Pat Whitworth, Blanche Mavromatis, Robin Zon, Sarah Untch, Lisa Blumencranz, Joseph McKelley, William Audeh, PROMIS Investigators Group. Treatment recommendations in ER+ patients ≤ 50 years: Comparison of the 21-gene assay and 70-gene signature in the PROMIS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-11.

e24229 Background: Compared with breast invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) has been shown to be more strongly associated with risk factors that modulate hormone levels, including lifestyle factors such as obesity. We evaluated the effect of metabolic syndrome (MS) in patients with ILC vs. IDC histopathological tumor types using transcriptome gene expression analysis (GEA) and pathway analyses. Methods: This subanalysis included 492 patients from the PROMIS and IMPACt studies for whom metabolic characteristics were captured with informed consent. To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors (obesity, HTN, hypercholesterolemia, hypertriglyceridemia, DM). Risk of recurrence was established using the 70-gene signature (70-GS). Results: A similar proportion of ILC (34%, 26/76) and IDC (38%, 160/416) patients had MS. Significantly more ILC patients with MS than without MS were 70-GS high risk (42% vs. 12%, respectively, [P = 0.007]). There was no significant difference in the incidence of 70-GS high risk results for IDC patients. GEA identified 509 significant differentially expressed transcripts between MS and non-MS ILC patients; 120 transcripts were identified in IDC patients; only 6 transcripts overlapped between the two groups. Pathway analysis indicated immune pathways were affected in ILC, whereas growth-regulating pathways were affected in IDC tumors. Within MS patients, 262 transcripts were differentially expressed between ILC and IDC. Conclusions: Although ILC is generally considered to have a lower risk of recurrence than IDC, we show that ILC patients with MS have a significantly higher 70-GS risk of recurrence than their non-metabolic counterparts. GEA analysis indicated the biology of disease engages disparately for ILC and IDC. Larger studies are needed to characterize differences in tumor biology stratified by histology as it relates to optimizing duration or adding novel targeted therapeutics. Clinical trial information: NCT02670577.Tumor Type MS 70-GS High Risk 70-GS Low Risk P-value Total ILC (n = 76) No 6 (12%) 44 (88%) 0.007 50 Yes 11 (42%) 15 (58%) 26 IDC (n = 416) No 120 (47%) 136 (53%) 0.165 256 Yes 87 (53%) 73 (46%) 160

Importance Among patients who undergo the 21-gene assay (21-GA), 39% to 67% receive an intermediate risk result and may receive ambiguous treatment guidance. The 70-gene signature assay (70-GS) may be associated with physicians’ treatment decisions in this population with early breast cancer. Objective To determine whether 70-GS findings are associated with physicians’ decisions about adjuvant treatment and confidence in their recommendations and to evaluate the dichotomous (high- vs low-risk) and continuous distribution of 70-GS indices among this group of patients with intermediate risk. Design, Setting, and Participants The Prospective Study of MammaPrint in Breast Cancer Patients With an Intermediate Recurrence Score (PROMIS trial) was an impact study conducted from May 20, 2012, through December 31, 2015, that enrolled 840 patients with early-stage breast cancer and a 21-gene assay recurrence score of 18 to 30. Patients were treated in 58 US institutions. Interventions The 70-GS result was given to physicians before adjuvant treatment. Main Outcomes and Measures Change in physician treatment decision before vs after receiving the 70-GS result. With a treatment change of greater than 20%, the odds ratio (OR) was applied. Results Among the 840 patients who underwent 70-GS classification (mean age, 59 years; range, 27-93 years), 374 (44.5%) had a low-risk and 466 (55.5%) had a high-risk result. The distribution of 70-GS indices did not correlate with recurrence score within the 21-GA intermediate range, with 70-GS low- and high-risk patients observed at every recurrence score. A significant change in adjuvant treatment was associated with receiving the 70-GS classifications with an OR of 0.64 (95% CI, 0.50-0.82; McNemar test, P < .001) for all patients. Among the low-risk patients, 108 of 374 (28.9%) had chemotherapy removed from their treatment recommendation; among the high-risk patients, 171 of 466 (36.7%) had chemotherapy added. Results of the 70-GS were associated with the physician’s adjuvant treatment recommendation; 409 high-risk patients (87.8%) were recommended to receive adjuvant chemotherapy, and 339 low-risk patients (90.6%) were recommended no chemotherapy. Physicians reported having greater confidence in their treatment recommendation in 660 cases (78.6%) based on 70-GS results. Conclusions and Relevance The 70-GS provides clinically actionable information regarding patients classified as intermediate risk by the 21-GA and was associated with a change in treatment decision in 282 of these patients (33.6%). Chemotherapy was added or withheld by the treating physician based on the results of the 70-GS test. Physicians reported more confidence with their treatment recommendation after receiving 70-GS results.

Until only a few years ago, there was only one truly effective therapy for patients with metastatic melanoma. While long-term remission could be achieved in some patients, toxicities associated with high-dose IL-2 were significant. New insight related to molecular pathways of tumor cells indicated that an activating mutation of BRAF can be found in approximately 50-60% of all patients with melanoma. Proof-of-concept demonstrated in clinical trials of a drug targeting mutant BRAF led to the approval of vemurafenib by the US FDA in August 2011. Supplied in an oral dosage form, we provide an alternative method of administering vemurafenib in a patient unable to take anything by mouth.

Abstract Abstract 5046 Background: Bortezomib (B) is a reversible proteasome inhibitor approved by FDA for relapsed/refractory multiple myeloma (MM) patients (pts) in second and higher lines of therapy. The standard regimen includes i.v. injections of B 1.3 mg/m2 on days 1, 4, 8 and 11 in a 21-day cycle. The addition of dexamethasone (D) 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 increases responses as well as the toxicity of the treatment. Generally accepted protocol is to give up to 8 cycles of the treatment. In this abstract we describe preliminary results of open-label, Phase II clinical trial employing only 4 cycles of standard B+D regimen in order to improve safety and evaluate efficacy. Methods: Patients with relapsed/refractory MM who had at least one previous therapy qualified for the trial. In the study they were treated with 4 cycles of standard B+D regimen followed by B maintenance. Patients who achieved complete response (CR) by Blade/EBMT criteria within 4 cycles received up to 2 additional cycles of standard B+D and then were followed closely off study. Those who had partial response (PR) or stable disease (SD) were placed on maintenance therapy with B 1.6 mg/m2 i.v. injections on days 1,8,15,22 on 36-days cycle until progression of the disease (PD), development of unacceptable toxicity or decision to stop treatment. Patients with PD were taken of the study. A bone marrow biopsy and aspirate with cytogenetics evaluation were done at the start of the treatment and at the time of CR, PD or decision to stop treatment. MM disease assessment was done with each 21- or 36-day cycle. Thirty eligible and evaluable pts are planned to participate in the study. Primary objective of the study is to evaluate overall response rate (PR + CR). A two-stage accrual design is used in order to allow study to be terminated early, should preliminary results indicate poor activity of the regimen. Results: Fifteen relapsed/refractory MM pts were evaluable in this first analysis. Mean age was 67.2 years (range 51–84). Eleven pts were males and four females. Sixty percent (9/15) of them were IgG kappa MM, 13.3% (2/15) had IgG lambda and lambda light chain disease, respectively and other 2 had IgA kappa and IgA lambda MM, one each. Mean beta-2-macroglobulin level was 9.3 mg/L (range 2.4–79). Most of the patients (13/15) were stage II (7 pts) and III (6 pts) by International Staging System (ISS, 2005). Cytogenetic studies were available in 13 out of 15 pts. Twelve pts had normal findings and one pt was hyperdiploid. Number of previous lines of treatments was 1.7 (range 1–6). Almost all pts (13/15) had received one of the immunomodulators (thalidomide or lenalidomide), one pt was treated with B and one had autologus peripheral stem cell transplant. After 4 cycles of standard B+D, 9/15 (60%) pts responded to the treatment (20% CR and 40% PR). Three pts (20%) had SD and another 3 (20%) had PD. Eight pts continued maintenance treatment with once-a-week B and received 1–35 cycles. There were no additional responses during the maintenance phase. The most common grade (Gr) 3/4 hematological side effects were thrombocytopenia (40% of pts) and anemia (6.6%). Non-hematological Gr 3/4 toxicities were neuropathy (13.3%), infections (6.6%) and fatigue (6.6 %). Median time to progression and overall survival are presently evaluated. Conclusion: Although results of this Phase II study are very preliminary, treatment with reduced number of standard twice-a-week B+D cycles seem to result in significant overall response rates and very good tolerability in the group of pts with advanced relapsed/refractory MM. It is worth mentioning that 86% of pts were previously treated with immunomodulators. In addition, maintenance with weekly B seems to be very well tolerated and one of the pts is treated for more than 4 years without major complications. Disclosures: Al-Janadi: EPIC: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees. Srkalovic:EPIC: Speakers Bureau; Physicians Connect: Speakers Bureau.

Lower extremity ulcers are a late complication of connective tissue diseases and occur more commonly in patients with these diseases than in the general population. Although these lesions have historically been attributed to vasculitis, it is now recognized that inflammatory vessel injury accounts for fewer than 20% of ulcers in connective tissue disease. The pathogenesis of these lesions is complex, and often several processes act synergistically to initiate and perpetuate tissue injury. We review the evidence for antiphospholipid antibodies and prothrombotic states contributing to a vasculopathy in patients with connective tissue disease, precipitating ulceration and impairing healing.