Gonsalves, Wilson I.

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.

Abstract Background: Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma with a heterogeneous disease course. For nearly a decade, the International Prognostic Scoring system (IPSS), requiring 5 variables (platelet count, hemoglobin, age, Beta 2 microglobulin and immunoglobulin M size) has been used to prognosticate patients with active WM. In this study, we attempt to propose a simplified prognostic model for patients with active/symptomatic WM. Methods: All patients with active WM diagnosed between 01/01/1996 and 12/31/2017 and evaluated consecutively at Mayo Clinic, Rochester were included in the study after Institutional Review Board approval. Active WM was defined as ≥10% marrow infiltration with lymphoplasmacytic cells plus monoclonal IgM of any size requiring systemic therapy. The follow up and overall survival (OS) were calculated from the time of active WM until date of last follow up or death. Baseline parameters at active disease were used to assess prognostic factors for OS using a univariate followed by a multivariate (MV) Cox regression analysis. Independent variables on the MV analysis were given a score proportional to their risk ratios (RR). All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using log-rank test. Discriminatory ability of the IPSS and the currently proposed prognostic system was assessed using Harrell's concordance index wherein a higher c-statistic is associated with a better discriminatory ability. Results: We identified 889 patients with active WM. The median follow up was 8.2 years (95% CI: 7.5-9 years). The baseline characteristics of the patients are shown in Table 1. At the time of diagnosis of WM, 16% of patients had previously documented MGUS and 16% patients had smoldering (asymptomatic) WM. The course of WM was complicated by systemic amyloidosis in 8% (n=69), transformation to high-grade lymphoma in 4% (n=38), symptomatic hyperviscosity in 13% (n=118), myelodysplastic syndrome in 2% (n=17) and Bing-Neel syndrome in 1.4% (n=12) of patients. Of the patients tested, cryoglobulinemia was present in 17% (n=48), cold agglutinin disease in 34% (n=43) and Coombs positive hemolytic anemia in 9% (n=34) patients. The median OS was 10.6 years (95% CI: 9.7-11.4 years). The factors affecting OS are shown in Table 2. While the patients' MYD88L265P mutation status was not found to be prognostic for OS, age >65 years [RR 1.8 (95% CI: 1.2-2.8); p=0.01], LDH > upper limit of normal [RR 2.5 (95% CI: 1.3-4.6); p=0.003] and serum albumin <3.5 g/dL [RR 1.6 (95% CI: 1.1-2.5); p=0.02] were independently prognostic. Owing to comparable RRs, each of these were assigned a score of 1 point and a prognostic model with a minimum score of 0 and maximum score of 3 was constructed. A score of 0 was considered as low risk WM and 1 as intermediate risk WM. The patients with scores of 2 and 3 were analyzed together to form the high risk cohort due to comparable OS for these two groups. The patient outcomes based on this prognostic model are depicted in Figure 1. Using the new prognostic model (n-=341), the median OS for the low risk group (n=71, 21%) was 14.6 years (95% CI: 9 years- not reached) compared to 11 years (95% CI: 8.1-14.7 years) for intermediate risk (n=140, 41% ) and 7.2 years (95 % CI: 5.4-10 years) for the high risk group (n=130, 38%), p<0.0001. The data for the IPSS-WM were available in 319 patients in the entire cohort. The OS for low risk IPSS (n=56) was 14.6 years (95% CI: 12.1 years-NR), 15.6 years (95% CI: 8.3-18.5 years) for intermediate risk IPSS (n=131) and 9.1 years (95% CI: 6.8-11.2 yeas) for the high risk IPSS group (n=132; p=0.009). Among the 220 patients having data for IPSS-WM as well as our proposed model, the current three variable model held its prognostic significance (p=0.0004). The Harrell's c-index was 0.647 (95% CI 0.592-0.702) for our prognostic model and 0.58 (95%CI: 0.521-0.638) for IPSS-WM. Common frontline treatment comprised of rituximab monotherapy (n=277, 33%), rituximab with alkylator or purine analog combination (n=255, 30.5%) and other therapies, including alkylators/purine analog monotherapy, ibrutinib, proteasome inhibitors, etc., in 37% patients. Conclusion: A simpler, clinically useful, risk stratification model based on age, serum albumin and serum LDH with a potentially higher discriminatory value than IPSS-WM may be used to prognosticate patients with WM. This model requires external validation. Disclosures Ansell: Pfizer: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Abbvie: Consultancy; Prothena: Honoraria; Medscape: Consultancy; annexon: Consultancy; Amgen: Consultancy; Alnylam: Honoraria; Teva: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; celgene: Consultancy; Research to Practice: Consultancy; Apellis: Consultancy. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; 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. Kumar:Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: 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; Janssen: 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; AbbVie: 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; Novartis: 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; Roche: Research Funding; KITE: 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. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction Del(17p) detected by fluorescence in situ hybridisation (FISH) of bone marrow plasma cells (BMPCs) is an adverse prognostic factor in patients with multiple myeloma (MM). While the natural history and prognostic factors in patients with del (17p) detected at diagnosis have been studied, the outcomes of patients who acquire del (17p) later in their course are not known. We aimed to define the outcomes of MM patients who acquire del(17p). Methods We reviewed the Dysproteinemia database at Mayo Clinic, MN to identify 80 patients with MM who had their first FISH test negative for del (17p), but acquired del(17p) later in the course of the disease. Sixty (75%) patients had their first FISH within 6 months (mo) of diagnosis; 20 (25%) patients had their first FISH more than 6 mo after diagnosis of MM. Del(17p) included del(17p13.1) and/or monosomy 17. We identified 2 control patients for each case, who were diagnosed during the same time period, but did not demonstrate del (17p) at any time during follow-up. Results Characteristics of patients at acquisition of del(17p) are shown in Table 1. Of these, 76 patients had relapsed and/or refractory MM; in 4 patients, del (17p) was detected after having attained a response to prior therapy. Seventy (87.5%) patients had del (17p13.1); 5 (6.3%) patients had monosomy 17; 1 (1.2%) patient had both del (17p13.1) and monosomy 17. Four (5.0%) patients had relative loss of 17p. High-risk translocations (HRT) [t(4;14), t(14;16) and t(14;20)] were present in 14 (17.5%) patients. The percentage of PCs with del(17p) were available in 75 patients. The median percentage of PCs with del(17p) was 76 (range, 9-100). Sixty two (77.5%) patients received exclusively chemotherapy as subsequent treatment; stem cell transplant (SCT) was part of the next treatment in 16 (20%) patients (allogeneic SCT in 1). Among 71 evaluable patients, ≥very good partial response and ≥partial response were attained in 24 (33.8%) and 35 (49.2%) patients respectively. The median progression free survival (PFS) from detection of del (17p) was 5.7 mo (95% CI, 3.5-7.8); overall survival (OS) was 18.2 mo (CI, 13.1-27.5). From a comparable time point, the OS for 160 controls was 56.2 mo (CI, 37.1-75.3) (P<0.001). The results were similar when patients were stratified based on variables at diagnosis such as age, presence of HRT, international staging system (ISS) stage, serum lactate dehydrogenase (LDH) and PC proliferative rate, and proteasome inhibitor (PI)-containing induction and SCT within a year of diagnosis and before acquisition of del(17p). Evaluating outcomes from initial diagnosis, PFS in the acquired del (17p) and control groups were 23.0 (CI, 20.2-25.8) and 30.2 (CI, 26.7-33.9) mo (P=0.028) and OS were 68.2 (CI, 50.8-74.8) and 111.6 (CI, 103.4-127.8) mo respectively (P<0.001). High LDH at baseline [OR- 4.31 (CI, 1.34-13.86)] predicted acquisition of del(17p) while presence of HRT showed borderline significance [OR- 2.02 (0.90-4.54)]. Age ≥65 yrs, ISS III vs. I/II stage, t(11;14), any trisomy, monosomy 13, BMPC%, initial therapy and SCT in first year and before acquiring del (17p) were not predictive. We performed univariable analysis with variables at detection of del(17p) such as age ≥65 vs. <65 years, serum creatinine >2 vs. ≤2 mg/dL, BMPC% ≥50 vs. <50%, ISS III vs. I/II stage, elevated vs. normal LDH, presence vs. absence of a HRT, presence vs. absence of monosomy 13, presence vs. absence of any trisomy, high vs. low PC proliferation rate, PI and immunomodulatory drug (IMiD)-refractoriness and percentage of PCs with del(17p) as independent variables to determine their association with PFS and OS. ISS stage III, high PC proliferative rate and PI and IMiD-refractoriness were selected after univariable analysis and included in the multivariable Cox proportional hazards model. A higher PC proliferative rate alone predicted shorter OS. None of the above factors were associated with shorter PFS. The median OS in those with high PC-proliferative rate from detection of del(17p) was 10.9 mo (CI, 6.0-17.1) vs. 37.2 mo (CI, 18.2-47.5) in those with low PC proliferative rate (P=0.005). Conclusion The prognosis of patients who acquire del (17p) is poor with OS of 6.5 years against 9 years from diagnosis in patients who do not acquire del (17p). This was valid across prognostic sub-groups. High PC proliferative rate was the only factor which impacted OS once patients acquired del(17p). Disclosures Kapoor: Celgene: Research Funding; Takeda: Research Funding. Gertz:Research to Practice: Consultancy; Teva: Consultancy; Ionis: Honoraria; annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Apellis: Consultancy; Medscape: Consultancy; Amgen: Consultancy; janssen: Consultancy; celgene: Consultancy. Lacy:Celgene: 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Janssen: 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; KITE: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; 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; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract The plasma cell proliferative index (PCPI) provides an insight into plasma cell biology in plasma cell disorders. It recognizes cells that are actively synthesizing DNA and gives an indication of the proliferative rate of the malignant plasma cells.The PCPI has been shown to be a prognostic tool in patients with multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic impact of PCPI in 306 patients with smoldering multiple myeloma (SMM). The median age was 66 (56-73) years and 61% (n=186) were males. The median follow-up for the entire cohort was 10.2 years (95% confidence interval: 9.0-10.9). One-hundred sixty-nine (55%) patients were alive at the time of study analysis while 118 (39%) had progressive disease. The median time to progression was 5.9 years (95% confidence interval: 4.8-8.2). Symptomatic events at the time of progression included anemia in 41% (n=48), bone complications in 37% (n=44), renal complications in 9% (n=11), hypercalcemia in 2% (n=2) and development of amyloidosis in 2% (n=2). Seventeen patients (14%) were categorized as having progression due to rapid progressive elevation in the serum free light chains (sFLC) and/or progressive increase in the size of their M-spike. The median time between the diagnosis and PCPI date was 0 months (interquartile range 0-1). An elevated PCPI was defined as a level >0.5%. Seventy-nine (26%) patients had an elevated PCPI. Patients with an elevated PCPI were significantly older (median age: 69 years for elevated PCPI vs 64 years for low PCPI (p= 0.008) and predictably had more proliferative disease with a higher rate of patients with bone marrow plasma cells >20% (48% for elevated PCPI vs 34% for low PCPI, p=0.03). An elevated PCPI predicted a shorter time to progression (TTP); median 3.0 years versus 7.1 years for those with a low PCPI (p= 0.0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI; 49% versus 20% (p<0.0001). We constructed two multivariable models using the conventional and recently proposed Mayo risk stratification tools. In both models, an elevated PCPI was an independent predictor of to multiple myeloma. PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow up and consideration of early intervention trials. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Medscape: Consultancy; Apellis: Consultancy; Ionis: Honoraria. Lacy:Celgene: 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; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: 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; Roche: Research Funding; KITE: 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.

Abstract Introduction: IgM light chain amyloidosis (AL) is a rare complication of IgM associated disorders, with very limited data on biology and outcomes. Our study compares the clinical characteristics, laboratory findings and outcomes in a large cohort of patients with IgM vs. non-IgM AL to delineate the underlying disease biology of this entity. Methods: Patients with newly diagnosed AL (2006-15) were identified from a prospectively maintained institutional database and grouped by IgM heavy chain. Bone marrow (BM) morphology was reviewed by an expert hematopathologist (RLK). FISH testing included probes for t(11;14) and trisomies of odd numbered chromosomes. MYD88L265P testing was carried out by allele specific PCR and CXCR4WHIM mutation testing was performed by bridged nucleic acid (BNA)-enhanced Sanger sequencing. Results: Patients with IgM AL comprised 6.6% (75/1128) of the study cohort. Baseline characteristics are listed in Table 1. IgM AL patients were older and had a higher proportion of males. They had less frequent cardiac involvement (60 vs. 75%) and less frequent involvement of > 1 organ. Light chain burden was lower in this group (dFLC 12.5 vs. 22.7 mg/dL), while there was no difference in BM clonal cell percentage (10% each). Morphology: BM morphology in 71 patients with IgM AL revealed a pure plasma cell disorder (PPCD type) in 25% (n=18); low-grade B-cell lymphoma (LGBCL) with plasmacytic features (LPL type) in 62% (n=44) [well defined LPL: 38% (n=27), LGBCL with plasmacytic features: 24% (n=17)]; LGBCL, other: 6% (n=4). In the remaining 7%, three patients had other diagnoses and no BM disease in two patients. Median clonal cell % in LPL vs. PPCD type IgM AL was 20% vs. 5%, p<0.001. Genetics: In patients with IgM AL vs. non-IgM AL, t(11;14) was present in 27% vs. 49%, p=0.009 and trisomies in 9% vs. 24% of patients, p=0.06, respectively. In the IgM AL cohort, MYD88 mutation was seen in 56% (23/41) & CXCR4 mutation in 15% (5/34; S388 type: 3, other: 2) of patients. Importantly, MYD88 and CXCR4 mutations were found only in patients with LPL morphology, while t(11;14) was found only in the PPCD morphology group. There were no patients with both t(11;14) and MYD88 abnormalities (N=26 for both tested). Mutations seen in the LPL vs. PPCD type IgM AL were: MYD88, 88% (22/25) vs. 0% (0/14), p<0.001 and CXCR4, 26% (5/19) vs. 0% (0/13), p=0.02. Conversely, t(11;14) was seen in 0% (0/18) in LPL type vs. 60% (9/15) in PPCD type IgM AL, p <0.001. Treatment details were known in 63 patients with IgM AL; rituximab-based: 21 (33%), bortezomib/alkylator: 16 (25%), transplant 17 (27%), steroids: one and no treatment: 8 (13%). Treatment in IgM AL LPL type (n=36) was: rituximab based: 16 (44%),bortezomib/alkylator: 5 (14%), transplant: 10 (28%) and none: 5 (14%). In PPCD type [n=17), treatment was rituximab based: 2 (12%), bortezomib/alkylator: 8 (47%), transplant: 7 (41%). At 6 months, very good partial response or better was observed in 26% (10/39) vs. 41% (270/660) of patients with IgM vs. non-IgM AL, p=0.05. There was no difference in overall survival (OS) when all patients with IgM AL were compared to non-IgM AL (Fig 1a). However, when stratified by early (Stage 1/2) or advanced (stage 3/4) 2012 Mayo stage, patients with IgM AL fared worse (Fig 1b-c). On multivariate analysis, IgM AL was an independent predictor for inferior OS [HR with 95% CI: 1.6 (1.1-2.4), p=0.02] after adjusting for age, Mayo 2012 stage and type of therapy (transplant vs. not). However, when OS was adjusted for 6 month VGPR, there was no difference in OS for IgM AL vs. non IgM AL, p=0.2. In the IgM AL cohort, patients with LPL type IgM AL had inferior OS compared with PPCD type IgM AL, 21 vs. 82 months, p=0.01 (Fig 1d). Conclusions: Patients with IgM AL have distinct clinical and genetic features, with lower rates of cardiac involvement and a lower frequency of t(11;14) or trisomies compared with non-IgM AL. Even though IgM AL is a rare entity, we were able to delineate two distinct sub-types of IgM AL: LPL type and PPCD type, with implications for therapy and outcomes. Along with unique morphologic findings, presence of MYD88 and CXCR mutations was only seen in LPL type IgM AL and t(11;14) in PPCD type IgM AL. Despite lower cardiac involvement, IgM AL was associated with inferior OS outcomes, likely due to lower response rates, particularly in LPL IgM AL group, which had the lowest OS. Therapeutic approaches targeted towards disease biology to achieve deep responses are needed in this disorder. Disclosures Sidana: Janssen: Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Lacy:Celgene: Research Funding. Kumar: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; 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; Janssen: 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; Roche: Research Funding; Novartis: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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. Gertz:Abbvie: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; Apellis: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Teva: Consultancy; Alnylam: Honoraria; celgene: Consultancy; Medscape: Consultancy; janssen: Consultancy; Research to Practice: Consultancy; Physicians Education Resource: Consultancy; annexon: Consultancy.

Abstract Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been attained. Prior literature has used 10 years as a cutoff for "long-term survivorship". In this study, we have assessed the biological disease characteristics and outcomes of long-term survivors with MM (≥10 years from active disease). Methods All patients with active MM evaluated at the Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study after approval of the Institutional Review Board. Patients with smoldering multiple myeloma were excluded. The overall survival (OS) was calculated from the time of symptomatic disease requiring treatment. Patients were then divided into two cohorts: (1) long-term survivors, which included patients who had an overall survival of at least 10 years; and (2) short-term survivors, which included patients who had an overall survival of less than 5 years from the diagnosis of active MM. The baseline characteristics between these two groups were compared using Wilcoxon, chi-square, and Fisher's exact test as applicable. All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using Log-Rank test. Results During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. The median follow-up for the entire cohort was 12.6 years (95% CI: 12.5-13.4).The median OS for the entire cohort was 4.4 years (95% CI: 4.2-4.7 years). Three-hundred and ninety nine (18.7%) patients survived at least 10 years whereas 872 patients (41%) survived less than 5 years from the date of initial diagnosis. The median OS was 14.1 years for the long-term survivors (95% CI: 13.9-14.6 years) and 2.1 years for the short-term survivors (95% CI: 1.8-2.2 years). The clinical features at diagnosis comparing long-term survivors and short-term survivors are shown in Table 1. Among long-term survivors (n=399), based on the available data regarding remission and ongoing treatment status, 331 patients were categorized into 6 cohorts (Table 2). The MM specific survival data of these 6 cohorts is depicted in Table 2.Figure 1 shows survival outcomes from the 10-year landmark. Of the 6 cohorts, 38 patients in Cohort 1 and 19 patients in Cohort 2 (total 57; 17% of long term survivors, ~3% of the entire cohort ) have been off therapy for at least 5 years and remain in remission, representing a distinct group of patients with 100% 15-year survival. Conclusion In our large database with prolonged follow-up, long-term survivors appear to have distinct baseline characteristics, but also constitute a heterogenous group of patients with disparate outcomes. A small subset (17% of long-term survivors) was identified that may represent patients closest to being considered as 'operationally cured'. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; annexon: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kumar:KITE: 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; Merck: 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; AbbVie: 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; Roche: Research Funding; KITE: 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; 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.