Citations

Introduction: Isocitrate dehydrogenase 1 and 2 (IDH1/2) are metabolic enzymes in the citric acid cycle, producing alpha-ketoglutarate (αKG). Mutations in specific regions of these genes have been characterized in gliomas, AML and chronic myeloid neoplasms such as MDS and MPN. These mutations produce an oncometabolite 2-hydroxyglutarate (2HG) that disrupts the epigenetic phenotype of myeloid cells promoting oncogenesis. While this process has been characterized for arginine hot spot (R132/R140) mutations, there exist variants of unclear significance (IDHVUS), with potential pathogenic predictions using in silico assessment models. With the availability of mutant IDH inhibitors in practice, it has become important to characterize these VUS. We carried out this study to functionally interrogate potentially pathogenic IDHVUS in MDS and MPN. Methods: After institutional approval, bone marrow (BM) DNA of patients with MDS and MPN, including overlap syndromes were subjected to next generation sequencing (29-gene, including the entire coding region of IDH1/2) by previously described methods (Patnaik et al., BCJ 2016). A sub-set of patients with available plasma [IDH wild type (IDHWT), bona fide IDH mutations (IDHMT) and IDHVUS with predicted pathogenicity (≤0.01% minor allele frequency, and predicted damaging in silico scores)] were submitted for mass spectrometry (LC-MS) based detection of IDH-related metabolites; D and L isomers of 2HG, αKG, and total 2HG. The impact of variations on protein secondary structure was assessed by the GorIV prediction algorithm. Potential alterations within the tertiary structure of the proteins was evaluated by in silico mutagenesis. Results: One hundred and seventeen patients were included in the study; median age 68 years (range, 39-94), 68% male. Of these, 40 (34%) had MDS, 42 (36%) MPN, and 35 (30%) MDS/MPN overlap syndromes. Eighty six (74%) had IDHMT, including n=28 (24%) with IDH1MT (R132C/G/H/S) (11 MDS, 8 MPN, 9 MDS/MPN) and n=59 (50%) with IDH2MT (R140G/Q/W) (22 MDS, 20 MPN, 17 MDS/MPN). IDHVUS were detected in 32 (27%) patients, including 1 IDH1MT patient, and involved IDH1 in 14 (12%) cases and IDH2 in 18 (15%) cases. All IDHVUS were missense, except for a 2 amino acid insertion in IDH2, with the most frequent VUS being IDH1Y183C (7%) and IDH2T352P (7%). While there were no phenotypic differences between IDH1/2MUT and IDH1/2VUS, in comparison to patients with IDH1/2MT, those with IDH1VUS were more likely to have higher WBC counts (median 8.1 vs 3.6 x109/L, p=0.0322), higher neutrophil counts (median 3.3 vs 1.3 x109/L, p=0.0203), and lower BM blast % (median 1 vs 3%, p=0.02061). Compared to IDH1/2MT patients, those with sole IDH1/2VUS more frequently had mutations in SF3B1 (p=0.0167), while they were associated with a lower frequency of SRSF2 mutations (p=0.0002). Interestingly, TET2 mutations were detected in only 5% of patients with IDHMT and 16% of IDHVUS patients, although without reaching statistical significance. LC-MS analysis on 75 plasma samples (n=43 IDHMT, n=9 IDHVUS, n=20 IDHWT, 3 normal) revealed a significant increase in total 2HG levels in IDHMT vs IDHVUS (p=0.0089), and IDHWT (p=0.0020) cases (Figure 2A-D). While there were no significant differences in αKG levels between the groups, the D-2HG enantiomer levels were higher in IDHMT samples vs IDHVUS (p=0.0199) and IDHWT (p=0.0055). On examination of the crystal structures of the IDH genes using PDB, while we observed a direct interaction between R132/R140/R172 and the catalytic core, the IDHVUS were located away from this active center and were hence thought to be allosteric in nature (Figure 2F). These VUS however, did demonstrate predictive steric clashes in the tertiary structure context of IDH1 using the PyMol artificial mutagenesis tool. The absence of wild-type crystal structure for IDH2precluded a similar analysis for IDH2. Median overall survival (OS) of the entire cohort (Figure 1) was 36 (range, 0-190) months, with OS being inferior in IDH1/2MT patients (34 months) vs those with IDH1/2VUS (50 months, p=0.0255). Conclusion: Our study demonstrates that in spite of predictive pathogenicity of IDH1/2VUS using in silico predictive tools and crystal studies, the lack of involvement of the arginine hot spot precludes IDH neomorphic activity, as shown by normal 2HG levels. In addition, in comparison to IDHMT patients, those with IDHVUS had fewer BM blasts and a better survival. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Background: Combinations of alkylating agents with proteasome inhibitors have demonstrated efficacy in newly diagnosed and relapsed multiple myeloma (MM), with melphalan or cyclophosphamide combinations being some of the commonly used regimens for initial treatment of MM. Ixazomib (Ixa) is an oral proteasome inhibitor that is approved for use in combination with lenalidomide for patients with relapsed MM. We examined if Ixa can be effectively combined with cyclophosphamide (Ctx) in order to develop a less expensive, all oral regimen for patients with relapsed MM. Patients and Methods: Patients with relapsed MM, who were proteasome inhibitor naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation, were enrolled. The primary objective was to determine overall response rate (ORR). Treatment consisted of Ixa 4mg PO days 1, 8, 15; Ctx 300 mg/m2 PO days 1, 8, 15, 22 and dexamethasone (Dex) 40 mg PO weekly in a 28-day cycle. Overall, 37 patients were accrued; data on 33 eligible patients were available for analysis as of July 18, 2019. Results: The median age was 71 (48-89), 61% were male and the median duration from diagnosis was 46 months (mos). Median number of prior lines of therapy was 4 (range 1-5), 76%, 42% and 67% respectively had a prior IMiD, proteasome inhibitor or stem cell transplant, respectively. At data cutoff, 22 (67%) had progressed, 4 (12%) had died and the median follow up of those alive was 21.3 mos. Fourteen patients are still receiving treatment, with median of 8.5 cycles. Most common reason for treatment discontinuation was disease progression (10 pts; 53%). The ORR was 60% including 6% CR and 24% VGPR. The median event free survival was 11.3 mos (95%CI: 9.0 - 26.8). Overall, 401 cycles have been administered across the study, with dose modifications/ hold required for Ixa, Ctx, and Dex in 9 (27%), 14 (42%), and 22 (67%) patients respectively, the most common reason being hematologic toxicity. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 77% of patients, hematologic in 67% and non-hematologic in 30%. (Table 1) The most commonly observed hematologic toxicities included thrombocytopenia, neutropenia, lymphopenia and anemia; for non-hematologic was nausea, diarrhea, peripheral neuropathy toxicity and fatigue. Conclusions: The combination of Ixa, Ctx and Dex (ICd) offers a convenient, all oral regimen for treatment of relapsed disease not refractory to proteasome inhibitors. The regimen has good efficacy in this group f heavily pretreated patients, with an acceptable toxicity profile. Disclosures Lacy: Celgene: Research Funding. Gertz:Ionis: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria. Ailawadhi:Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy. Bergsagel:Janssen Pharmaceuticals: Consultancy; Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy. Fonseca:AbbVie, Amgen, Bayer, Celgene, Kite, Janssen, Juno, Merck, Pharmacylics, Sanofi, Takeda: Other: Consultant/Advisor; Prognosticatin of MM based on Genetic Categorization by FISH: Patents & Royalties; Adaptive Biotechnologies: Other: Scientific Advisory Board. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding. Chanan-Khan:AbbVie: Research Funding; Pharmacyclics: Research Funding; Xencor: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Stewart:Roche: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; Ionis: Consultancy; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Ono: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with <10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p<0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with <10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

INTRODUCTION: Primary plasma cell leukemia (pPCL) is the most aggressive form of multiple myeloma (MM). Recently, pPCL has been defined by as few as >5% circulating plasma cells (cPCs) detected morphologically on a peripheral blood smear. However, this technique may not be sufficiently sensitive and is dependent on inter-observer bias to properly identify and quantify cPCs. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs. However, an optimal quantitative cutoff for cPCs by MFC to define the presence of pPCL has not been established to date. Thus, this is the first study to date that determines an optimal cutoff of cPCs/ microliter that could identity patients with pPCL at diagnosis. METHODS: We retrospectively evaluated all newly diagnosed MM patients seen at the Mayo Clinic, Rochester from January 2007 to December 2017 who had their peripheral blood samples evaluated morphologically by peripheral blood smear and immunophenotypically by MFC prior to beginning therapy. Patients with a peripheral blood smear detecting >5% cPCs were classified as having pPCL. Six-color MFC was performed on peripheral blood mononuclear cells by isolated by Ficoll gradient, and stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda immunoglobulin light chains. The data was collected using Becton Dickinson FacsCanto II instruments collecting 150,000 events and analyzed using the BDFacs DIVA Software. The gating strategy employed first used the expression of CD38, CD138, and cytoplasmic immunoglobulin light chains to identify all plasma cells in the specimen. The cPCs were then discriminated from polyclonal/normal plasma cells based on differential CD19 and CD45 expression. The cPCs detected were reported as the number of clonal events/150,000 collected total events and converted to the absolute number of cPCs/microliter using their absolute lymphocyte count and monocyte count determined at the time of the blood draw for cPC MFC assessment. A receiver operator curve (ROC) was performed to determine the absolute cPCs/microliter by MFC that best identified those patients with >5% cPC on their peripheral blood smear. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. RESULTS: A total of 591 patients were included in this analysis of which 59% were male and the median age was 66 years (range: 27 - 95) with 22% being 75 years of age or older. From this cohort, 133 (24%) patients had high risk FISH cytogenetics, 172 (30%) were classified as ISS 3 at diagnosis, 83 (15%) had an elevated LDH level and 61 (17%) had a plasma cell labeling index (PCLI) of 2% or greater. There were 65 (11%) patients with any amount of cPCs detectable by peripheral blood smear of which only 22 (4% of the total population) met criteria for pPCL with >5% cPCs. With MFC, 403 (68%) patients had detectable cPCs. The median number of cPCs per microliter was 0.81 (0 - 10,455) with 273 (46%) having >1 cPC/microliter. A ROC analysis determined that the presence of >50 cPCs/microliter by MFC was the optimal cutoff to identify patients with >5% cPCs by blood smear with approximately a specificity of 94% and a sensitivity of 86%. The presence of >50 cPCs/microliter by MFC was associated with higher presence of high risk FISH cytogenetics, ISS 3 classification, elevated LDH and PCLI > 2%. The median time to next treatment (TTNT) for patients with and without >5% cPCs by peripheral blood smear was 18 months vs. 30 months (P < 0.001). The median TTNT for patients with and without >50 cPCs/microliter by MFC was 19 months vs. 30 months (P < 0.01). The median overall survival (OS) for patients with and without >5% cPCs by peripheral blood smear was 25 months vs. 71 months (P < 0.001; Fig 1A). The median OS for patients with and without >50 cPCs/microliter by MFC was 38 months vs. 71 months (P < 0.01; Fig 1B). CONCLUSION: This is the largest study that attempts to identify an optimal cutoff of cPCs/microliter by MFC for diagnosing pPCL patients. The presence of >50 cPCs/microliter is an optimal cutoff by MFC that best predicts for the presence of >5% cPCs by peripheral blood smear. However, there remains discordance in the OS outcomes between the two cutoffs by different methodologies for pPCL. This could signify the presence of biological processes associated with the presence of >5% cPCs when detected by peripheral blood smear that are not captured by MFC. Disclosures Dispenzieri: Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lacy:Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Celgene: Honoraria. Leung:Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Russell:Imanis: Equity Ownership. Gertz:DAVA oncology: Speakers Bureau; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Introduction: Several patient and disease biology characteristics that impact overall survival (OS) outcomes of patients with newly diagnosed multiple myeloma (NDMM) have been well described. However, several prior population-based registry studies in the US such as SEER and NCDB databases have demonstrated the negative prognostic impact of socio-economic (SE) factors such as low median household income based on US national census bureau data for zip code of residence as well as absence of marital support on the OS of NDMM patients. Whether such SE factors are independent of established host and disease biology related factors remains unknown due to the absence of detailed patient-level data in population-based cancer registries. Thus, we evaluated whether such SE factors independently affected the OS of NDMM patients in our institution when accounting for patient and disease biology related factors. Methods: We analyzed a retrospective cohort of consecutive NDMM patients seen at the Mayo Clinic from January 2005 to December 2015. Median household income for each patient's area of residence was estimated by matching their home zip code at diagnosis with data available through the US National Census Bureau. Median household income < $63,000 for a zip code were used to classify patients as having low income based on the National Cancer Database classification of the bottom three quartiles. Absence of marital support was considered in patients divorced, single or widowed at the time of diagnosis. Survival estimates were calculated using the Kaplan-Meier method. Patient and disease biology related factors taken into consideration included age, FISH cytogenetics, ISS stage and LDH levels. Survival estimates were compared between groups using the log-rank test. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Results: A total of 2,621 MM patients were analyzed from the Mayo Clinic cohort of which 60% were male and the median age was 64 (22 - 96) years with 14% being 75 years of age or older. In this cohort, 541 (33%) patients had ISS 3 disease and 370 (22%) had high risk cytogenetics by FISH. The median OS based on estimated average household income was 65 months for the group of patients with low household income (N = 32%) and 80 months for the remainder (P = 0.001) (Fig 1A). The median OS based on marital support was 59 months for those without marital support at diagnosis (N = 21%) versus 76 months for remainder (P = 0.003) (Fig 1B). However, in a multivariable analysis that included the aforementioned SE factors and patient and disease biology characteristics , only age of 75 years or older (p < 0.001), the presence of high-risk FISH cytogenetics (p < 0.001), presence of ISS 3 disease (p < 0.001) and elevated LDH (p = 0.005) retained independent statistical significance in predicting for worse OS. Lower household income (p = 0.264) and absence of marital support (p = 0.054) were not independent predictors of worse OS. Conclusions: With the caveat of patient selection bias in a tertiary academic center, SE factors such as estimated average household income and marital support at diagnosis do not appear to impact OS of NDMM patients when considered in the context of traditional host and disease biology risk factors. These findings are in contrast to those suggested by population based registry studies; nevertheless, similar patient-level assessments should be considered in patient cohorts from non-tertiary medical centers as these results may likely be different. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Lacy:Celgene: Research Funding. Kapoor:Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding. Russell:Imanis: Equity Ownership. Gertz:Medscape: Consultancy, Speakers Bureau; Research to Practice: Consultancy; Springer Publishing: Patents & Royalties; Ionis/Akcea: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

AbstractRisk stratification of multiple myeloma (MM) at diagnosis is critical. We examined the ability of hematopoietic indices including mean corpuscular volume (MCV), hemoglobin (Hgb), and platelet (Plt) to predict outcomes. This was a retrospective study of patients treated at Mayo Clinic between January 2004 and April 2018. We incorporated three variables (Hgb < 10 g/dL, Plt < 150 × 109/L, and MCV > 96 fL), assigning a score of 1 to each. We identified 1540 newly diagnosed MM patients, of whom 707 (46%) had a score of 0, 513 (33%) had a score of 1, 260 (17%) had a score of 2, and 60 (4%) had a score of 3. The score risk stratified patients into four groups with differing survivals. The median PFS was 32.3 months for score 0, 24.8 months for score 1, 21.7 months for score 2, and 18.3 months for score 3, for P < .001. The median OS was 80.7 months for score 0, 59.9 months for score 1, 51.7 months for score 2, and 31.3 months for score 3, P < .0001. Predictors of OS on the multivariable analysis were age ≥ 65 (HR, 1.93; P < .0001), R‐ISS stage (1‐2 vs 3) (HR, 0.48; P < .0001), and hematopoietic score (0‐2 vs 3) (HR, 0.51; P = .006). A hematopoietic score can predict survival in newly diagnosed myeloma patients.

Abstract INTRODUCTION: Our group has demonstrated that MASS-FIX is a quick, inexpensive, and accurate means to diagnose and monitor the serum and urine of patients with plasma cell disorders. Screening can be done with a MALDI-TOF MS and samples reflexed to microflow liquid chromatography coupled with electrospray ionization (ESI) and Q-TOF MS (microLC-ESI-Q-TOF MS). Because this technique provides a mass/charge (m/z) for a given patient's monoclonal protein, this method can provide greater sensitivity and specificity to monitor for complete response (CR), especially in patients receiving therapeutic monoclonal antibodies. Our goal was to assess the performance of miRAMM in patients with AL who have been classified as complete response using conventional means. METHODS: We identified 77 patients with AL who had both documented CR by immunofixation (Seibia) of the serum (SIFE), urine IFE (UIFE), and serum free light chain (FLC; The Binding Site) and paired serum samples to test by MALDI-TOF and ESI-TOF. No urine samples were available to test. Paired serum samples from baseline and approximately one year post-therapy were immunoaffinity purified using nanobodies targeting kappa, lambda, alpha, gamma and mu as previously described. For the MALDI-TOF (Bruker Microflex, LT), a range of 9,000 to 32,000 m/z was acquired. The m/z distribution was then visually inspected for the presence of a peak that was distinct from the polyclonal background in both the M+1 and M+2 light chain mass ranges. For the ESI-TOF, spectra were also collected on an TripleTOF 5600 quadrupole time-of-flight mass spectrometer (ABSciex, Vaughan ON, CA) in ESI positive mode with a Turbo V dual ion source with an automated calibrant delivery system. TOF MS scans were acquired from m/z 600−2500 with an acquisition time of 100 ms. RESULTS: Median age of the cohort was 58 (range 42, 81). Fifty-eight percent were male. No test was 100% sensitive at baseline with positive results as follows: abnormal FLC ratio, 82%; positive SIFE, 70%; 73% positive UIFE; positive serum MASS-FIX, 71%; and ESI-TOF, 79% . There was light chain isotype agreement in all cases, except for 2 patients for whom the SIFE and the FLCr disagreed. Of the 56 patients with baseline positive MASS-FIX, there was evidence of the original monoclonal protein in 5 patients (see figure for example of spectra illustrating same m/z before and after therapy). Of the 63 patients who had baseline positive ESI-TOF, there was evidence of the original monoclonal protein in 8 patients. Small unrelated monoclonal proteins were seen both by SIFE and by mass spectrometry techniques. With the spectrometry techniques, however, these transient oligoclonal bands could be distinguished from the original monoclonal protein when they shared the same isotype based on the difference in m/z. DISCUSSION: At baseline, the MALDI was able to identify the baseline monoclonal protein in a comparable number of patients as SIFE, UIFE, and FLC. Approximately 10% of patients thought to be in CR using routine screening tests were found to have persistence of their original clone by MALDI and by ESI-TOF. Small post-therapy unrelated monoclonal proteins were also seen both by IFE and by MALDI, but either the presence of a different isotype or in the case of MALDI, a different m/z, made it clear that the monoclonal protein was not related to the original clone. The sensitivity of the assay will improve significantly when we formalize the introduction of free light chain magnetic beads to capture the serum FLCs. Routine use of MASS-FIX of the urine will also increase performance characteristics. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Prothena: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Physicians Education Resource: Consultancy; annexon: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Amgen: Consultancy; janssen: Consultancy; Research to Practice: Consultancy; Abbvie: Consultancy; Ionis: Honoraria. Kumar:Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership.

Abstract Background: Modern clinical practice places time restrictions on the amount of information and processing that can be done in a typical office visit. Meeting patient needs within the healthcare system is challenging, contributing to patient (pt) and clinician dissatisfaction and potential suboptimal outcomes. We developed an electronic point-of-care case management system for cancer patients. The system's goal is to obtain patient-reported quality of life (PROQOL) outcomes and provide clinicians with information regarding QOL issues to address. We tested this system in a prospective randomized study against usual care (UC). The primary objective was to determine if PROQOL system would improve mean QOL over time. Methods: Eligible pts were adults with multiple myeloma (MM) or light amyloidosis (AL), seen at Mayo Clinic. Pts were randomized 2:1 to PROQOL system or usual care. PROQOL system was offered prior to every visit. Pts select from various categories about their single biggest concern, and receive a printed list of actionable resources based on selected concern. Clinicians also receive the PROQOL results to review with pts. Providers and pts randomized to PROQOL completed a "was it worth it survey" (WIWI). An 8 item Linear Analogue Self-Assessment was used to assess QOL, the primary endpoint. Secondary endpoints included distribution of choices of most important concern and their relationship to demographic and clinical variables. The study was powered to detect a 0.5 standard deviation difference in QOL between groups. Results: There were 233 patients enrolled (171 MM, 62 AL) in this study between July 1, 2016 and April 17, 2018. Median age was 65 years (range 31-87), and 59% were male. Median time from diagnosis to study consent was 37 months (PROQOL 36.3 versus UC 39.6). Median follow up for all patients was 15 months (range: 0.7-22 months), and median follow up for PROQOL pts was 16 months and 14 months for UC pts (p=0.027). There were 25 pts that have died since enrollment and 208 alive. No statistical significant difference in QOL between PROQOL and UC (median QOL 7 vs 7, p=0.75). The most prevalent main concerns selected were Physical Health (37%) and Cancer and Diagnosis (27%), the pattern remained even when pts were given the option to pick a second major concern 26% and 20% respectively. No other concern was listed more than 8% at baseline. All category selections and percentages are shown in the Figure. The average time to complete the instrument was 6 minutes. Pts found the PROQOL system was worth their time (75%), they would choose it again (87%) and recommend it to others (82%). Eighty-two percent of clinicians did not think the PROQOL tool negatively impacted their practice and 75% believed they may see improvement in pt wellbeing. Discussion: The PROQOL system was well received by pts and clinicians but did not improve QOL relative to UC in this study. The PROQOL demonstrates that majority of patients strongly desire more information regarding ongoing therapy, clinical trials, prognosis and toxicity. Further investigation is needed to understand whether communication is limited by time or mechanism of information delivery, such as verbal or written, or whether it should be undertaken in a separate allied health care visit. Figure. Figure. Disclosures Gertz: spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Research to Practice: Consultancy; annexon: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Teva: Consultancy; Apellis: Consultancy; Ionis: Honoraria; celgene: Consultancy; Prothena: Honoraria. Kumar:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: 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, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.