Rajkumar, S. Vincent

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 Waldenstrom macroglobulinemia (WM) is a rare disease accounting for only 1-2% of all hematologic malignancies and with an overall annual, age-adjusted incidence of approximately 3.5 to 5.5 cases per million-person years. With approximately 13,000 active hematologist/oncologists in the US, most of who are in the community oncology setting, it's estimated that a hematologist/oncologist will only diagnose a WM case approximately every 8 years. Therefore, the clinical experience of a general hematologist/oncologist in the management of WM is likely very limited compared to more prevalent malignances. Previous studies in the setting of rare cancers suggest a correlation between higher volume of care and improved outcomes. Therefore, we explored the volume-outcome relationship in WM using the National Cancer Data Base (NCDB). Methods Patient-level data from the NCDB, a nationwide, facility-based, database covering approximately 70% of all newly diagnosed cancer cases in the US, was queried for all new WM cases diagnosed between 2004 and 2014. Only patients requiring treatment were included. Treatment facilities were divided into quartiles based on the average annual volume of newly diagnosed cases of WM seen. Cox regression was used to analyze the association between facility WM volume and survival, adjusted by demographics (sex, age, race), socioeconomic status (income, education, insurance type), geography (area of residence, treatment facility type, travel distance), comorbidity factors (Charlson-Deyo score), and year of diagnosis. Time-to-event analysis was calculated from frontline therapy initiation date using the Kaplan-Meier method and the log-rank test. Results A total of 3,732 patients with WM treated in 831 facilities were included. The median age at diagnosis was 70 years and 75% of the patients were treated within 20 miles from their residency zip code. Patient characteristics per treatment facility volume quartile are shown in table 1. The median annual facility volume was 1 new WM patient/year (range 0.1 to 21). The median follow-up from frontline treatment was 5 years. The unadjusted median OS by facility volume was: Q1: 6.5 years (95% CI: 5.7-7.4), Q2: 7 years (95% CI: 6.3-8.2), Q3: 8.2 years (95% CI: 7.1-8.9), and Q4: NR (95% CI: 8.5-NR), p<0.0001 (figure 1). The estimated 5-year OS by facility volume was: Q1: 56%, Q2: 61%, Q3: 64%, Q4: 71%, p<0.0001. Multivariate analysis including all variables showed in Table 1 demonstrated that facility volume was independently associated with all-cause mortality. Compared to patients treated at Q4 facilities, patients treated at lower-quartiles facilities had a higher incremental risk of death (Q3 hazard ratio [HR], 1.07 [95% CI: 0.88 to 1.29] p=0.46; Q2 HR, 1.34 [95% CI: 1.11 to 1.63] p=0.002; Q1 HR, 1.52 [95% CI: 1.23 to 1.88] p=<0.0001). Conclusion Our results suggest that a volume-outcome relationship exits in WM as patients treated initially at higher-volume facilities had a lower risk of mortality. Although differences in the underlying disease biology, referral patterns after initial therapy, or cumulative treating-physician experience could not be assessed, these potential biases would only underestimate the magnitude of the volume-outcome relationship reported. Disclosures Ansell: Celldex: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding. Gertz:Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Ionis: Honoraria; Physicians Education Resource: Consultancy; Prothena: Honoraria; Teva: Consultancy; Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Takeda: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar: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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 448 Background: POEMS syndrome is a rare form of plasma cell dyscrasia that presents with polyneuropathy and various other systemic findings. Patients with 1–3 lesions and bone marrows without clonal plasma cells have been given targeted radiation as the initial and potentially definitive therapy. Outcomes of patients treated thus have not been systematically studied. Patients and Methods: One hundred and forty-six patients with POEMS syndrome were seen at the Mayo Clinic in Rochester, MN between January 1999 and September 2011. Charts of patients with research authorization were reviewed with IRB approval. Patients who had been given targeted radiation as their initial primary therapy were eligible for this study. Thirty-eight patients satisfied criteria and comprise the study population. Three patients had either short or poorly documented follow-up and were excluded from the response and time to next treatment analyses. Patients were categorized by systems that were involved at diagnosis, time of radiation, response after radiation, and the need for further therapy. Statistical analyses were performed using JMP statistical software (SAS, Carey, NC). Results: The median age was 50, with 76% of the population being male. Median time from diagnosis to radiation was 0.7 months, ranging from 0 to 9.4 months. 20, 14, 11 and 2 patients had immunosuppressive therapy with corticosteroids, IVIG, plasmapheresis, or rituximab, respectively, directed at a prior presumptive, but incorrect, diagnosis of CIDP. Five patients had one cycle or less of alkylator, lenalidomide, or bortezomib, prior to receiving what was hoped to be definitive radiation therapy. The median number of bone lesions was 1, range 1–6. In total 55 lesions of the possible 64 were irradiated being mostly found in the pelvic bones including the sacrum, ileum, ischium, and pubis. The median dose of radiation given was 45 Gy range 35 Gy to 54 Gy. Forty-nine percent had clinical improvement, 26% had a mixed clinical picture, 3% merely stabilized, and 23% had a clinical worsening. 29% had a complete hematologic response, 9% had a very good partial hematologic response, 9% had a partial hematologic response, 26% had no hematologic response, and the remaining were either non- or oligo-secretory or undocumented. 11% had a complete FDG-PET response, 11% had a partial FDG-PET response, 11% had no FDG-PET response, and the remaining had no documented FDG-PETs to analyze. 11% had a complete VEGF response, 3% had partial VEGF response, 14% had no VEGF response, and the rest were either not documented or unevaluable. The median follow up of living patients is 30 months, and the 4-year OS is 95%. Forty-eight percent of patients went on to receive additional therapy after their radiation (Figure). The median time to next therapy (TTNT) for these patients was 7.6 months (range 2.2 –73 months). Subsequent therapies included high dose chemotherapy with autologous hematopoietic stem cell transplant (n=10), low dose alkylator (n=2), thalidomide/lenalidomide (n=3), and more radiation (n=3). None of the baseline characteristics predicted for whether a patient would receive (or require) subsequent therapy, including the number of bone lesions at baseline. Conclusion: The results show that radiation is sufficient to produce clinical improvements and hematologic and radiographic responses approximately 50% of patients, even those with as many as 3 lesions. Disclosures: No relevant conflicts of interest to declare.

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 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.

Abstract Background Limited data exist with respect to outcome and optimal therapeutic strategies in patients with central nervous system (CNS) involvement in multiple myeloma (MM). We present a single center experience of patients with myelomatous CNS involvement in newly diagnosed and relapsed / refractory MM. Methods Of 4060 patients with MM seen at Mayo Clinic, Rochester, MN between January, 1st 1998 and December, 31st 2012, 26 patients had identifiable CNS involvement confirmed by biopsy / presence of plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement by imaging (MRI/CT). Patients were risk stratified by mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria. Overall survival (OS) from diagnosis and the time of CNS involvement was calculated using the Kaplan-Meier method. Results Myelomatous CNS involvement occurred in 26 (0.6%) patients with MM of whom 3 were newly diagnosed. The median time to detection of CNS involvement was 24 months (range: 0-125) from diagnosis of MM. Median age at CNS myeloma diagnosis was 58 years (range 37-80) and 73% were male. Abnormally high LDH was observed in 11 out of 22 patients at the time of CNS involvement. Lumbar puncture was performed on 16 patients, 13 (81%) of whom had plasma cells in the CSF detected by cytology/flow-cytometry. Two patients, without evidence of plasma cells, had abnormally high CSF protein and 1 had normal CSF analysis. Of the 25 patients who underwent MRI, 16 (64%) had at least one of the following significant abnormalities; intraparenchymal disease (37%), leptomeningeal enhancement (68%) or direct extension of MM (31%). The neurological symptoms at or after diagnosis of CNS myeloma included headache (38%), cranial nerve palsy (38%), visual disturbance (38%), gait disturbance (35%), paresthesias (35%), limb weakness (31%), confusion (30%), nausea/vomiting (15%), dysarthria (12%), seizures (8%) and urinary incontinence (4%). Fluorescent in-situ hybridization (FISH n=7), cytogenetics (n=8) and/or plasma cell labeling index (PCLI n=12) were available in 18 patients prior to the diagnosis of CNS disease. Ten (56%) out of those 18 patients had high-risk features at least by one criterion. At the time of CNS involvement, six additional patients demonstrated high risk features [5 by PCLI (≥ 3%) and 1 by FISH]. Overall, 16 out of 26 (62%) patients were classified as high risk by mSMART criteria prior to or at the time of CNS involvement. Four (27%) out of 15 had a deletion p53 or monosomy 17 chromosomal abnormality. Median OS was 42 (95% CI, 19-55) months from the diagnosis of MM and 3 months (95% CI: 1-7.9) from the time of CNS involvement (Figure). OS of patients with high risk features was significantly worse (27 months) compared to standard risk disease (67 months, p=0.02) from diagnosis of MM. Eighteen patients received radiation therapy for CNS myeloma. Five of those patients also received intrathecal (MTX and ARA-C) therapy. One patient received intrathecal and systemic chemotherapy. Four patients did not receive any treatment. Novel agents, including bortezomib (23%), thalidomide (15%), and pomalidomide (4%) were administered to the patients post diagnosis of CNS disease. Six (23%) patients underwent autologous stem cell transplant post diagnosis of CNS disease with a median OS of 19 months (95% CI: 10-122 months) from the time of CNS involvement. Conclusion CNS involvement is a rare complication of MM that portends a poor survival outcome. It is likely that the rates in this study are an underestimate of the true incidence due the perceived futility of CNS directed therapy in this disease. Among those recognized, high-risk genetic and markers of increased proliferative activity, including deletion p53 / monosomy 17 and elevated PCLI (≥ 3%) appear to cluster in this cohort. Current therapeutic approaches are largely ineffective in managing this aggressive subset of myeloma patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Maintenance therapy has been extensively explored as a strategy for prolonging the duration of disease control and potentially survival following ASCT. To date, only lenalidomide has been approved for this indication. However, lenalidomide maintenance is associated with the development of second primary malignancies and tolerability issues. PIs are a backbone of MM treatment, and bortezomib-based maintenance has shown promising activity post-ASCT, yet the benefit of PI-based maintenance has not been demonstrated in a phase 3 trial vs placebo. Moreover, the feasibility of bortezomib maintenance in routine clinical practice is limited due to tolerability and the need for regular parenteral administration. There is a need for an oral PI maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients. Methods The phase 3, double-blind, placebo-controlled, multicenter TOURMALINE-MM3 study (NCT02181413) compared weekly ixazomib vs placebo maintenance in NDMM patients who had at least a partial response (≥PR) to induction therapy with a PI and/or immunomodulatory drug (IMiD) followed by single ASCT. Patients were randomized (3:2) to receive ixazomib or matched placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease (PD) or unacceptable toxicity. Randomization was stratified by induction regimen (PI without IMiD vs IMiD without PI vs PI+IMiD), pre-induction ISS stage (I vs II or III), and post-ASCT response (complete response [CR] or very good partial response [VGPR] vs PR). Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The ixazomib dose was 3.0 mg during cycles 1-4, increasing to 4 mg from cycle 5 if tolerated during cycles 1-4. The primary endpoint was PFS per independent review committee (IRC), who were blinded to treatment assignment. The key secondary endpoint was OS. Here, we report data from the final analysis for PFS (data cut-off: April 16, 2018). Results 656 patients were randomized (395 ixazomib; 261 placebo). Patient demographics were balanced between groups; overall median age was 57 years (range, 24-73), 37% vs 63% had ISS I vs II or III, 59%/11%/30% had received PI without IMiD / IMiD without PI / PI+IMiD induction therapy, 34%/45%/21% had achieved CR / VGPR / PR following induction/ASCT, and 18% had high-risk cytogenetics [del(17p), t(4;14), or t(14;16)]. After a median follow-up of 31 months with 54% of PFS events, there was a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio [HR] 0.72; 95% CI: 0.582, 0.890; p=0.002; Figure). In a landmark analysis from ASCT, PFS was 30.7 vs 24.9 months (HR 0.684; 95% CI: 0.551, 0.848; p<0.001). Median PFS2 and OS have not yet been reached in either arm. Ixazomib maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95% CI: 1.10, 1.80; p=0.004). Conversion from documented MRD positivity at study entry to MRD negativity occurred at a higher rate with ixazomib compared with placebo (12% vs 7%). PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625). Discontinuation due to AEs was low (7% ixazomib vs 5% placebo). With ixazomib vs placebo, 42% vs 26% of patients had grade ≥3 AEs; 27% vs 20% had serious AEs; and 1 patient vs 0 died on treatment. Common grade ≥3 AEs were infections (15% vs 8%) including pneumonia (6% vs 4%), gastrointestinal disorders (6% vs 1%), neutropenia (5% vs 3%), and thrombocytopenia (5% vs <1%). Peripheral neuropathy rates were 19% vs 15% (<1% vs 0 grade 3). Rate of second primary malignancies was 3% in both arms. Global Quality of Life scores (EORTC QLQ-C30) on ixazomib were similar to placebo. Conclusions This study demonstrated a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib maintenance, with deepening of responses and increased conversions to MRD negativity over control, as well as a favorable safety profile, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy, supporting ixazomib as a valuable option for maintenance therapy in responding patients post-ASCT. Figure. Figure. Disclosures Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Takeda Celgene, Amgen, BMS, and Roche: Other: Advisor; Janssen, Amgen, Takeda, Celgene, BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Abbvie: Consultancy; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Schjesvold:Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Beksac:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Goldschmidt:Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Mundipharma: Research Funding. Maisnar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chng:Merck: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Aslan: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding. Kaiser:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Iida:Janssen: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Astellas: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Toyama Chemical: Research Funding; MSD: Research Funding; Gilead: Research Funding; Teijin Pharma: Research Funding; Sanofi: Consultancy. Morgan:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Dash:Takeda Pharmaceuticals International Co.: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.