Rajkumar, S. Vincent

Background: Within the heterogeneous genomic landscape of multiple myeloma (MM), clonal evolution including the acquisition of risk-defining mutations and chromosomal abnormalities is a recurrent event and can be detected by fluorescence in situ hybridization (FISH). The effects of acquired abnormalities on clinical outcomes have not been well defined. We previously reported that patients who acquired 17p deletion [del(17p)] during the course of their disease had a significantly reduced overall survival (OS) by 38 months compared to patients who did not acquire del17p (Lakshman et al 2019). Similarly, while de novo gain of the long arm of chromosome 1 (1q22 gain) is a known high-risk aberration associated with significantly shorter OS and progression-free survival (PFS) in MM, the prognostic significance of acquired 1q22 gain has not been described. The primary objective of this study was to analyze factors predictive for acquired 1q22 gain and determine its impact on survival. Methods: We identified MM patients from the Mayo Clinic Dysproteinemia Database who had at least one follow up FISH performed ≥6 months from diagnosis. The clinical characteristics, concomitant cytogenetic abnormalities, first line treatments administered, and OS were compared between patients with acquired 1q22 gain and patients who did not acquire this abnormality. The Mayo Clinic IRB approved this study. Results: A total of 1041 MM patients met the inclusion criteria. Of these, 63 patients (6.1%) had acquired 1q22 gain, defined as being negative for 1q22 gain on initial FISH at diagnosis and having this abnormality detected on subsequent FISH. Median age at diagnosis was 59 years and 56% were male. Median time to acquisition of 1q22 gain was 60 months (range 8-140 months). We identified one control patient for each case who was diagnosed within one year of the case and had a subsequent FISH performed at a similar duration from diagnosis. Patients with acquired 1q22 gain had similar baseline characteristics except for a higher proportion of high-risk (HR) FISH at diagnosis [t(4;14), t(14;16), t(14;20), and del(17p13)] when compared to controls (27% HR FISH versus 6% HR FISH; P<0.01). 1q22 gain was concomitantly present with trisomies in 33 patients (54%), monosomy 13 in 24 patients (39%), t(4;14) in 8 patients (13%), and del(17p13) in 7 patients (12%). All patients received treatment prior to acquisition of 1q22 gain. Of the 63 patients, first line induction therapy consisted of proteasome inhibitor (PI) with steroid in 43%, immunomodulatory drugs (IMiD) with steroid in 40%, and PI + IMiD with steroid in 17% of patients. 54 patients (85%) received upfront stem cell transplant (SCT) (median 5.9 months to SCT), compared to 50 patients (79%) in the control group who received SCT. The median follow up of all 126 patients was 6.8 years. There was a statistically significant reduction in median OS from diagnosis in patients with acquired 1q22 gain compared to the control group (10.8 years versus 13.0 years; P = 0.02; Figure 1). Predictors of acquisition of 1q22 gain were identified using a case-control method. Age ≥70 at diagnosis and presence of HR FISH at baseline appeared to increase the risk of acquiring 1q22 gain. Conclusion: Acquisition of 1q22 gain is a relatively uncommon occurrence, but notably reduced OS by 2.2 years compared to patients who did not acquire 1q22 during the course of their disease (P = 0.02). Older age and the presence of HR FISH at diagnosis increased the risk of acquisition of 1q22 gain. The presence of high-risk translocations at baseline suggests that acquisition of 1q22 gain occurs in the context of more aggressive disease biology. Disclosures Kapoor: Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Alnylam: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Intellia: Research Funding; Janssen: Research Funding. Gertz:Prothena: Consultancy; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Dingli:Apellis: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Janssen: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Cellectar: Other; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Carsgen: Other, Research Funding; Tenebio: Other, Research Funding.

Introduction: First degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), and African Americans, have an increased risk of having MGUS and MM compared to the general population. However, current guidelines do not advocate for screening family members of MM for plasma cell disorders (PCD). Understanding the epidemiology of familial plasma cell disorders (PCDs) is essential in order to identify people at highest risk of developing PCDs who may benefit from targeted screening strategies. The aims of this study were to assess the prevalence of MM patients with a family history of PCD, and the implications of a family history of PCD on the overall survival (OS) of MM patients. Methods: We retrospectively reviewed the electronic medical records of patients with symptomatic MM followed at Mayo Clinic and diagnosed between January 1989 and June 2019. Clinical notes were reviewed for documentation pertaining to family history of PCDs. Kaplan Meier survival analysis was used to assess the OS, where OS was calculated from the date of diagnosis of symptomatic MM until death; patients were censored if they were alive at the date of last follow up. A Cox proportional hazards model was used to provide risk estimates for OS. Results: A total of 8403 patients with symptomatic MM were included in this study. Family history was documented in 1521 patients, and 291 patients (3.5% of all patients, 19% of those with any documented family history) had a documented family member with a PCD. The median age at diagnosis of symptomatic MM was significantly lower in patients with (n=291) versus without (n= 8112) a family history of PCD (60.9 versus 63.6 years, p<0.0001). The median OS of MM patients with a family history of PCD was significantly longer than MM patients without a family history of PCD (8.1 versus 4.9 years, respectively, with p<0.0001, see figure 1). Using a multivariable Cox proportional hazards model, MM patients with a family history of PCD had a significantly lower risk of death compared to those without a family history of PCD (HR 0.66, 95% CI 0.55-0.78, p<0.0001) even after adjusting for sex, age at diagnosis (above versus below age 65), self-reported race (African American versus not African American), or date of diagnosis (before versus after 2010). When restricting the analyses to the 1521 patients with clearly documented family history, the survival benefit amongst patients with versus without a family history of PCD was similar. In probands with a PCD family history, 182 (63%) had a first degree relative with PCD, whereas 109 (37%) had a second degree relative with PCD. The most common reported PCD amongst family members was MM (figure 2). Nineteen (6.5%) probands with a family history of PCD had 2 or more relatives with a PCD (6 MM patients had 2 or more first degree relatives, 5 MM patients had at least 1 first and 1 second degree relative, and 8 MM patients had 2 or more second degree relatives with a PCD history). There was no significant difference in the median OS between MM patients with a first degree versus second degree relative with PCD (HR 1.03, 95% CI 0.74-1.46, p=0.837), or MM patients with 1 versus 2 or more relatives with PCD (HR 1.01, 95% CI 0.53-1.96, p=0.962). Conclusion: We reviewed patients with symptomatic MM seen at Mayo Clinic over the last 30 years and found that the prevalence of patients with a documented family history of PCD was 3.5%. MM patients with a family history of PCD were diagnosed with MM at a younger age and survived longer than patients without a family history of PCD. Further work is needed to understand factors underlying the survival benefit in patients with a family history of PCD, and whether they present with less aggressive or less advanced disease at diagnosis. Disclosures Dispenzieri: Intellia: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Abbvie: Other; Amgen: Other: personal fee; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Prothena: Other: personal fee; Teva: Speakers Bureau; Celgene: Other; Research to Practice: Other; Sanofi: Other; DAVA oncology: Speakers Bureau; Annexon: Other: personal fee; Appellis: Other: personal fee; Ionis/Akcea: Other: personal fee; Alnylam: Other: personal fee; Aurora Bio: Other; Proclara: Other; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties. Kumar:Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments.

Introduction: Since 2018, immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, has replaced immunofixation for the detection and isotyping of serum monoclonal proteins at Mayo Clinic. MASS-FIX has advantages including increased sensitivity, specificity, and the ability to distinguish therapeutic monoclonal antibodies. Herein, we report the laboratory characteristics and distribution of diagnoses of patients tested clinically at Mayo Clinic. Methods: MASS-FIX was performed on patient samples as previously described (Kohlhagen et. al. Clin Chem Lab 2020). Demographics and laboratory data, including quantitative M-spike, serum free light chains (FLC), and quantitative immunoglobulins at the time of MASS-FIX were recorded. For patients with multiple samples during the study period, only the initial MASS-FIX was evaluated. We identified 9195 unique patients with MASS-FIX performed between 7/24/2018 and 3/6/2020. Seven-thousand nine hundred and forty-six patients provided consent for study enrollment, and 7689 had data available on index diagnosis. Given considerable variability in the interpretation of diagnostic criteria for light chain (LC) MGUS, patients with this diagnosis (1360, 18%) were excluded. Patients were considered to have negative results (2211 in total) on MASS-FIX if: 1) no monoclonal protein was identified (1081, 49%); 2) the interpretation was "cannot rule out monoclonal protein" (945, 43%); 3) multiple, nonspecific spectral peaks were identified consistent with immune reconstitution (29, 1%); or 4) the only monoclonal protein identified was consistent with a therapeutic monoclonal antibody (156, 7%). Results: The final cohort consisted of 4118 patients with a positive MASS-FIX and 2211 patients with a negative MASS-FIX, all in the setting of underlying PCDs. Figure 1 illustrates the numbers and percentages of patients who are MASS-FIX positive versus MASS-FIX negative by diagnosis. MGUS and multiple myeloma (MM) were the most common diagnoses overall, and both were more common in the MASS-FIX positive cohort. More than 90% of patients with Waldenstrom's macroglobulinemia (WM), smoldering WM, smoldering MM, and cold agglutinin disease were positive by MASS-FIX. For MASS-FIX positive patients, IgG isotype was identified in 2575 patients (63%), IgA in 703 (17%) and IgM in 710 (17%). Bence Jones proteinemia was identified in 283 patients (7%) with lambda restriction being the most common (57%). 3625 patients (88%) had a monoclonal pattern, 228 patients (6%) had a bi-clonal pattern, and 7 (<1%) had a tri-clonal pattern. The majority of patients (58%) were kappa LC restricted by MASS-FIX, 222 (5%) had N-glycosylated LC, and 2 patients (<1%) had a heavy chain with no light chain. Conclusions: This single institution experience illustrates the practicality of MASS-FIX in detecting and following monoclonal proteins for a wide range of PCDs in a tertiary center. In this cohort, the percentage of patients who were MASS-FIX positive varied by diagnosis, reflecting cross sectional sampling of patients throughout their disease course. Disclosures Gertz: Research to Practice: Other; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Johnson and Johnson: Speakers Bureau; Sanofi: Other; Amgen: Other: personal fee; Appellis: Other: personal fee; Annexon: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee; Proclara: Other; DAVA oncology: Speakers Bureau; Celgene: Other; Teva: Speakers Bureau; Abbvie: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau. Kumar:AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Adaptive Biotechnologies: Consultancy; Novartis: Research Funding; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding; Cellectar: Other; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Kapoor:Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Celgene: Honoraria. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Alexion: Consultancy; Sanofi-Genzyme: Consultancy; Janssen: Consultancy; Apellis: Consultancy; Millenium: Consultancy. Lin:Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Takeda: Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Murray:The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Dispenzieri:Alnylam, Intellia, Janssen, Takeda, Pfizer, Prothena, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Lytic bone lesions are one of the most common clinical characteristics of patients with multiple myeloma (MM) and identification of bone lesions help distinguish between patients with smoldering multiple MM and active MM. Given this, the most recent update of the diagnostic criteria for MM incorporates advanced imaging approaches for distinguishing between the two entities. Several small retrospective studies have compared conventional skeletal survey (SS) with whole-body low dose computed tomography (WBLDCT) scan or the CT portion of a positron emission tomography (PET) scan. Conducting prospective studies comparing these two modalities side by side is limited by the radiation exposure. We undertook this study to provide a comparison between these two imaging modalities in terms of their ability to recognize lytic bone lesions in patients with MM. Patients and methods: This was a retrospective study of consecutive patients with the diagnosis of MM treated at Mayo Cinic Hospital during 2004- 2018. Patients were included if they had a conventional skeletal survey no more than 3 months before MM diagnosis or any time after diagnosis and also had a WBLDCT or PET-CT within a 12-month period following the skeletal survey. We chose this approach since it is unlikely that a patient would have had both modalities done at the same time as part of standard of care (SOC). This approach was also facilitated by a gradual change in our SOC for skeletal imaging from conventional skeletal survey to WBLDCT. To measure the robustness of our findings, we performed a sensitivity analysis in patients who had the exam ≤6 months apart. Proportions were compared using a chi-square test and survival estimates were calculated using the Kaplan- Meier methodology and compared using log rank test. Results: The overall study cohort had 1040 patients, median age was 62 years at diagnosis (range, 24-94), 61% were male and 39% were female. The median time to the skeletal survey was 8 months from diagnosis (range, 0-160) and the median time to WBLDCT or PET-CT from SS was 2 months (0-12). A PET-CT was available in 789 (76%) of patients and WBLDCT in 251 (24%) of patients. Among the 300 patients with no lesions identified by SS, 188 (63%) had lytic lesions identified by CT, while in 60/740 (8%) patients with a positive SS did not have lytic lesions observed on the CT (p<0.0001). Overall, CT identified lytic lesions in 868 (84%) patients compared with 740 (71%) patients with lytic lesions seen on SS. Although the proportion of lytic lesions was slightly higher with PET compared to WBLDCT, the analysis did not reach statistical significance (65% vs. 56%; p = 0.17; Table 1a). After restricting the analysis to those with ≤6 months gap between low dose CT and SS (n=737), the result did not change (Table 1b). Further examination demonstrated that presence of lytic lesions by SS had no impact on OS from diagnosis, detection of lesions on the CT exam was associated with an inferior survival (112 vs. 81 months, p<0.0001). (Figure 1) Conclusion: Skeletal survey has been the screening technique of choice for evaluation of bone involvement in MM for decades. However, CT based approaches have higher sensitivity with lytic lesions identified in a higher proportion of patients. The prognostic value of lytic disease is evident with CT based detection, again suggesting that this provides a more accurate estimate of the skeletal disease burden. Low dose CT rather than conventional radiographs should be the modality of choice for monitoring disease-progression and diagnosing active multiple myeloma. Disclosures Kapoor: Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Gertz:Abbvie: Other; Celgene: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau; Annexon: Other: personal fee; Research to Practice: Other; Sanofi: Other; Proclara: Other; DAVA oncology: Speakers Bureau; Springer Publishing: Patents & Royalties; Appellis: Other: personal fee; Amgen: Other: personal fee; Prothena: Other: personal fee; Aurora Bio: Other; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee. Dispenzieri:Takeda: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Dingli:Alexion: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding. Lin:Merck: Research Funding; Takeda: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy. Kumar:Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding.

Background: Patients with newly diagnosed MM can be quite symptomatic as a result of end organ damage related to MM as well as presence of other comorbidities in this relatively older patient population. Prior studies have shown that the performance score as well as other quality of life (QOL), frailty and comorbidities scores can have prognostic value in these patients. However, many of these questionnaires are lengthy and complex, and not practical in a busy outpatient practice. We implemented a three question symptom assessment score in 2010 in our outpatient practice. Here we present the results of the analysis looking at the impact of this measurement in patients with newly diagnosed MM. Patients and Methods: Patients seen in the outpatient Hematology practice at Mayo Clinic, Rochester MN, were asked to grade the symptoms of fatigue, pain, and QOL on a 0 to 10 scale during the past 7 days, with 10 being the worst and the QOL on a similar scale but with 10 being the best. For the purpose of the current analysis the QOL score was reversed.These three scores were added for a total score. We looked at the impact of the baseline score as well as the score after four cycles of therapy, at the time of best response, and at the time of the first progression, wherever they were available. Survival curves were generated by the Kaplan-Meier method and compared using the log rank test. The Cox proportional hazards model was used for assessment of the impact of different prognostic variables. Results: Data from 735 patients with newly diagnosed MM seen at Mayo Clinic between 2011 and 2018 were available from baseline. The median total score was 10 (0-30), and for fatigue, pain and QOL were 4, 3 and 7 respectively, all with range of 0-10. Based on the baseline scores, patients were grouped into tertiles (Group 1 with score < 8, group 2 with score 8 to 14 and group 3 with a score ≥ 15). There were 256 (34%), 272 (37%) and 207 (28%) patients in groups 1, 2 and 3 respectively. The median overall survival (OS) (95% CI) from diagnosis was NR (7.9, NR), 7.7 (6.2, NR) and 5.4 (4.2, 6.9), respectively for groups 1, 2 and 3 (P < 0.0001) (Figure 1a). The prognostic value of the score was independent of age, FISH based risk status and the ISS stage. When evaluated after 4 cycles (n=325), the OS was significantly different for the 3 groups (P<0.01) (figure 1b). We then examined the impact of the score at best response to initial therapy (n=446) on OS from that timepoint and saw similar trend, but the results were not statistically significant (P=0.09) (Figure 1c). When evaluated at the time of first disease progression, the score again identified three groups with different OS from progression (P<0.001) (Figure 1d). Conclusions:Patient-reported outcomes are associated with survival in patients with MM. This simple, easy to complete patient-reported outcome 3-item scale can be easily completed in a busy practice and is a clinically useful tool to assess potential outcomes of patients at various disease stages, including at diagnosis and at relapse. Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Genecentrix: Consultancy; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Gertz:Proclara: Other; Springer Publishing: Patents & Royalties; Abbvie: Other; Celgene: Other; Aurora Bio: Other; Medscape: Other: personal fee, Speakers Bureau; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Other: personal fee; Appellis: Other: personal fee; Annexon: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Prothena: Other: personal fee; Physicians Education Resource: Other: personal fee; Research to Practice: Other; Ionis/Akcea: Other: personal fee; Alnylam: Other: personal fee. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Dingli:Rigel: Consultancy; Millenium: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy; Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding.

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder, which progresses at a rate of 1% per year to multiple myeloma (MM), or other plasma-cell or lymphoid disorders. MGUS is common and occurs in approximately 3% and 5% of persons 50 and 70 years of age or older, respectively. Clinical factors reported to be associated with MGUS progression include MGUS isotype, abnormal serum free light-chain ratio (FLCr), and high serum monoclonal protein (M protein) level (>=1.5 g per deciliter). Body mass index (BMI) has also been seen associated with MGUS progression, but has not been evaluated in context of established clinical prognostic factors. Here, we evaluate the contribution of BMI to MGUS progression beyond clinical prognostic factors in a population-based study and examine differential associations by sex. Methods We studied 594 patients residing in Olmsted County Minnesota, who were identified with MGUS in a screening study conducted between1995 through 2003. Patients with light-chain MGUS were not included. Patients were screened for M-protein [normal (<1.5 g/dl) or high (≥1.5 g/dl)], FLCr [normal (0.26-1.65) or abnormal (<0.26 and/or >1.65)], and isotype (IgG, IgM, IgA, bi-clonal). Follow-up time was calculated from date of MGUS screening to date of last follow-up, death, or progression to MM or another plasma-cell or lymphoid disorder. BMI (kg/m2) was calculated using height and weight values reported close to sample date (80% of patients within 2 years), and then categorized into BMI<25 and BMI≥25. We used Cox regression to estimate the association of BMI with risk of MGUS progression to MM or another plasma-cell or lymphoid disorder, univariately, and accounting for clinical factors. Analyses were also stratified by sex. We report hazard ratios (HR) and 95% confidence intervals (CI). Results Of the 594 patients, 51% were male, and the median age at screening date was 73 (range:50-98 years). The immunoglobulin type was IgG in 71% of patients, IgM in 17%, IgA in 10%, and bi-clonal in 2%. High M protein level was observed in 22% and abnormal FLCr in 28%. BMI≥25 was observed in 67% of patients. The median follow-up time was 10.5 years (range:0-25). Over a median of 6,846 person-years, 465 patients (78%) died and 57 patients progressed and developed MM (N=39), amyloidosis (N=8), lymphoma (N=5), or Waldenstrom macroglobulinemia (N=5). The overall rate of progression was 0.87 events (CI:0.67-1.12) per 100 person-years, and higher among males (1.01, CI:0.73-1.42) than in females (0.72, CI:0.48-1.08), however, the difference was not statistically significant (P=0.24). In univariate analyses, BMI≥25 (HR=2.14, CI:1.05-4.36, P=0.04), non-IgG isotype (HR=2.84, CI:1.68-4.80, P=0.0001), high M protein (HR=2.57, CI: 1.50-4.42, P=0.001), and abnormal FLCr (HR=3.39, CI:1.98-5.82, P<0.0001) were associated with increased risk of progression (Table 1.A). These four factors were independently associated with MGUS progression in a multivariable model, with a c-statistic=0.75 (CI:0.68-0.82). When stratifying by sex, associations of BMI with progression were stronger among females than males (Table 1.B) [c-statistic=0.81 (CI:0.72-0.90) vs 0.71 (CI:0.60-0.82) for females vs. males respectively], however, a test for interaction between BMI and sex was not statistically significant (P=0.15). Conclusions In this study we found evidence that high BMI is a prognostic factor independent of isotype, M protein, and FLC ratio in the full cohort, however, this was mainly driven by the effect in females rather than males. Future studies should further investigate sex differences in evaluating prognostic factors among MGUS patients. Disclosures Dispenzieri: Intellia: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kumar:Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Kite Pharma: Consultancy, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member.

Introduction High risk (HR) multiple myeloma (MM) constitutes approximately 25 % of newly diagnosed patients and is a subgroup of MM patients that is variably defined. Patients with 17p deletion are considered HR and their optimal treatment approach has not been determined. Various strategies have been suggested to improve outcomes in MM patients harboring del 17p, including tandem transplants. Recently, the long-term outcomes of the phase 3 EMN02 trial were published with the study group receiving bortezomib, cyclophosphamide and dexamethasone (VCd) induction prior to transplant. There are no data demonstrating that tandem transplant is applicable to the US population using induction containing immunomodulatory agents and bortezomib. Aim To report on outcomes of newly diagnosed MM patients with del 17p that underwent autologous stem cell transplantation (ASCT). Methods Retrospective study of all consecutive newly diagnosed MM patient with del 17p that underwent ASCT at Mayo Clinic, Rochester, Minnesota. Patients were defined by the Mayo Medical Lab as 17p deleted and included if they met the following criteria: If 50 cells in the bone marrow sample and 10 cells with the deletion were identified (20%) or if the bone marrow sample had between 20-50 total cells and 20% cells with the deletion were identified. We excluded patients that relapsed prior to ASCT (as those patients were excluded in the EMN02 trial), patients that underwent ASCT more than 12 months from the diagnosis and patients that underwent tandem ASCT (defined as two consecutive ASCT within 180 days of each other without relapse in between). Consolidation treatment was defined as treatment given after transplant for up to six 28-day cycles and maintenance was defined as all treatment given after ASCT for more than 6 months. Combined maintenance was defined as maintenance regimens that included two novel agents. Results 116 patients with MM and 17p deletion underwent ASCT at Mayo Clinic between January 2013 and April 2020. The median age at diagnosis was 62 (IQR 57-68, range 34-76) years. Forty-five (39%) patients were over 65 years. Nine patients (8%) had triple-hit MM and 34 (29%) had double-hit MM. Median follow-up of the survivors was 33 months (IQR 21-54). Consolidation therapy was given to 36 patients (31%) and maintenance was given to 91 patients (78%). Seven patients relapsed before day 100. There was no difference in the OS (P=0.72) or PFS (P=0.1) between patients that received VRd (bortezomib, lenalidomide and dexamethasone) versus VCd (bortezomib, cyclophosphamide and dexamethasone) induction (Figure 1). When comparing patients that received proteasome inhibitors (PIs)+ immunomodulatory agents (IMiDs) as induction to patients that received VCd induction, PFS was longer for patients that received the PIs + IMiDs (HR 0.53 P=0.04, 95% CI=0.3-0.98) (Figure 2), however there was no OS difference (P=0.61). Maintenance therapy was given to 94 patients (81%). There was no OS (P=0.34) or PFS (P=0.36) difference between IMiD based and PI based maintenance, but there was a PFS advantage to patients that received two drug maintenance (HR= 0.41, P=0.037, 95% CI 0.14-0.95) (Figure 2). The median OS and PFS of the entire cohort were not reached and 29 months, respectively. Conclusions The outcomes of our patients were similar to that of the single arm ASCT in the EMN02 trial, and no difference in outcomes were found between patients that received VRd and VCd induction, suggesting that tandem transplants should be considered for 17p deleted MM patients. Dual novel agent maintenance therapy is important in improving outcome. Disclosures Kapoor: Celgene: Honoraria; GlaxoSmithKline: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding; Carsgen: Other, Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; MedImmune: Research Funding. Dispenzieri:Pfizer: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Celgene: Research Funding. Dingli:Alexion: Consultancy; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Millenium: Consultancy; Karyopharm Therapeutics: Research Funding; Rigel: Consultancy; Apellis: Consultancy. Gertz:DAVA oncology: Speakers Bureau; Proclara: Other; Abbvie: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Research to Practice: Other; Ionis/Akcea: Other: personal fee; Celgene: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Annexon: Other: personal fee; Alnylam: Other: personal fee; Prothena: Other: personal fee; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Aurora Bio: Other; Springer Publishing: Patents & Royalties; Sanofi: Other; Amgen: Other: personal fee.

Proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) and C3 glomerulopathy (C3G) with monoclonal gammopathy (MG) are kidney diseases related to monoclonal gammopathy of renal significance (MGRS). Rituximab or combination of cyclophosphamide, bortezomib and dexamethasone have been used with variable success but no clinical trial has been performed up to now. In this phase 2 trial, we evaluated the safety and efficacy of daratumumab (an anti-CD38 plasma therapy) in patients with PGNMID and C3G with MG. The primary objective was safety and tolerability of daratumumab. The secondary objective was the response rate to daratumumab. Response was defined by complete remission (CR) (proteinuria <500 mg/d and no more than 10% drop in eGFR) or partial remission (PR) (50% reduction in proteinuria with no more than 30% drop in eGFR) at 6 and 12 months. Daratumumab was administered intravenously at a dose of 16mg/kg once weekly for 8 weeks followed by once every other week for an additional 8 doses. Twelve patients were recruited. There was only one patient with C3G with MG recruited and one patient with PGNMID did not finish the first infusion of daratumumab. Both were excluded from evaluation of the secondary objective. The patient with C3G was excluded as later it was noted that the disease was not triggered by the MG but rather due to activation of her alternative complement pathway due to high-risk allele for complement Factor H (CFH) and C3. Mean age was 51.2 ± 22.6 (18-87) years. All patients were White and 5 were male. For the primary objective, there were five serious adverse events (SAE). Two were serious infections that occurred in the patient with C3G with MG. At the time of these infections, patient was receiving additional immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. One was a febrile episode attributed to a virus that resolved with stopping additional immunosuppression, and another was an episode of C. difficile colitis that resolved following treatment. There were 3 episodes of uncomplicated UTI that resolved following antibiotic therapy and one episode of URI that required no treatment. The other two SAE were eye chemosis and headache in the same patient that resolved. Last SAE was an episode of acute closed angle glaucoma that occurred 45 min into the 1st infusion. This patient was withdrawn from the study. The most common side effect was infusion related reaction (with first infusion) that included cough, congestion, and throat irritation that resolved by the end of the infusion. There were no grade 3 or 4 anemia, thrombocytopenia or leukopenia. At 6 months, 2 patients achieved CR, 6 achieved PR and 2 had no response (NR). At 12 months, the 2 patients who had NR had entered PR and 2 additional patients that had achieved PR entered CR, but 3 patients relapsed (1 from CR and 2 from PR group). Overall, at 12 months, 3 patients achieved CR, 5 achieved PR and 2 had NR (due to relapse). The median 24hr baseline urinary protein declined from 4346 mg (3245 - 7943) to 702 mg (435 - 3057), at 6 months (p=0.001) and 1264 mg (463 - 3645) at 12 months (p = 0.004). There was also significant improvement in serum albumin, hemoglobin, total and LDL cholesterol, and complement 3 levels from baseline to 12 months follow-up (Table 1). Estimated GFR remained unchanged from 61.1 ± 31.9 to 65.0 ± 31.7 at 12 months (p=0.4). In this trial, daratumumab has shown to be safe and well tolerated. Daratumumab was also shown to be effective in reducing the proteinuria dramatically in patients with PGNMID secondary to MGRS along with stabilization of renal function. In conclusion, this is the first clinical trial of daratumumab in patients with MGRS and the promising results deserves further study. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Daratumumab - off label use for treatment of PGNMID

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (<75 vs 75-80 vs >80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; >4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (>5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged <65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged <65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged <65 years, 0.615 (95% CI 0.467-0.810, p<0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were <20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (<10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy and genetic abnormalities contribute to disease heterogeneity and outcome. Primary abnormalities, namely recurrent immunoglobulin (Ig) heavy chain translocations and hyperdiploidy, occur early in disease course. Secondary events, such as MYC abnormalities occur upon progression. Earlier studies showed MYC abnormalities detected by FISH or by capture sequencing were independently associated with poor outcome (Walker, et al., BCJ, 2014), while recent studies using WGS did not support this finding (excluding MYC/IGL) (Mikulasova, et al. Haematologica, 2020; Misund, et al. Leukemia, 2020). We hypothesize these discrepancies are due to differences in methods and sensitivities of detection of MYC abnormalities by FISH vs. WGS. Given that MYC abnormalities often display remarkable genomic heterogeneity with numerous gene partners, reduced detection of MYC abnormalities by FISH is not unexpected. This hypothesis is supported by lower frequencies of MYC abnormalities found by FISH (15%) vs. NGS (30-35%) consistent with ~50% false-negative rate of the MYC FISH probe (Smadbeck, et al. BCJ, 2019). To better understand the role of MYC in myeloma disease outcome, we compared the MYC abnormality subtype identified by FISH or NGS vs. MYC gene expression levels and overall survival. Methods: We performed a retrospective study of newly diagnosed MM patients seen at Mayo Clinic or enrolled in the MMRF CoMMpass trial. For Mayo cases, MYC FISH results (breakapart probe, Abbott) were obtained from the Mayo Clinic Genomics database (N=1342) and mate pair sequencing (MPseq) was performed on 140 cases. For CoMMpass cases, we obtained tumor long-insert whole genome sequencing (WGS), RNA sequencing (RNAseq) for gene expression and clinical outcome data. Overall survival (OS) was defined as time from diagnosis to death from any cause or to last follow up. Survival curves were estimated using Kaplan Meier and compared using the Log-Rank test. Statistical analyses performed using SPSS and JMP with significance determined when P <0.05. Results: We first evaluated the impact of MYC abnormalities on OS when detected by FISH or NGS. In Mayo cases, OS was significantly shorter in patients with MYC abnormalities compared to patients without MYC abnormalities using FISH (5.3 vs. 8.0 years, P<0.001, N=1342). In contrast, there was no significant difference in OS between patients with or without MYC or abnormalities using MPseq or WGS in both the Mayo and CoMMpass cohorts (Mayo: 6.4 vs. and 6.9 years P=0.78, N=140; CoMMpass: 4.9 vs. and 5.1 years P=0.74, N=546). Since FISH-detected MYC abnormalities were associated with poor outcome, we evaluated differences in the types of MYC abnormalities identified FISH and genome sequencing; 270 of 658 CoMMpass cases had a MYC abnormality and 12 abnormality subgroups were identified. In the Mayo cases, FISH preferentially detected translocations and complex abnormalities and missed insertions with flanking duplicating sequences or terminal tandem duplications (TTD) that occur telomeric to MYC. Since the level of MYC expression should be a consequence of the various genomic abnormalities altering the MYC gene region, we compared MYC expression levels in relation to MYC abnormality subgroups. Highest expression was seen with MYC amplification, followed by Ig abnormalities, non-Ig abnormalities, complex deletion/duplications, proximal deletions, non-Ig insertions, terminal deletions, TTD, trisomy 8, no MYC structural variation, monosomy 8 and cases with MAX mutations had the lowest expression. Abnormalities identified by FISH had higher MYC expression (83.5 TPM) compared to cases predicted to be missed by FISH (63.2 TPM). We tested if high MYC expression, irrespective of MYC structural abnormality, was associated with differences in OS. Boxplot analysis was used to categorize MYC expression in 631 CoMMpass patients as top quartile/high MYC expression (Q4≥ 75 TPM, n=159) and bottom quartile/low MYC expression (Q1≤ 16.5 TPM, n= 158) (see Figure). OS was significantly shorter in patients with high MYC expression compared to patients with low MYC expression (4.6 vs. 5.3 years, P <0.038). Conclusion: We show that FISH detects only a subset of the MYC abnormalities detected by genome sequencing, and that FISH-detected MYC abnormalities are associated with higher MYC gene expression and decreased survival. Figure 1 Disclosures Kumar: Kite Pharma: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Dr. Reddy's Laboratories: Honoraria; Cellectar: Other; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Tenebio: Other, Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; MedImmune: Research Funding; Adaptive Biotechnologies: Consultancy.