Kourelis, Taxiarchis

8031 Background: Our prior studies identified the prognostic significance of ≥400 cPCs/150,000 analyzed events quantified by MFC in NDMM. We evaluated if a similar quantification of cPCs using MFC can add prognostic value to the current R-ISS classification of NDMM pts. Methods: We evaluated all NDMM pts seen at the Mayo Clinic, Rochester from 2009-2017 who had their peripheral blood samples evaluated by 6-color MFC prior to therapy. The cPCs detected were reported as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 566 consecutive pts with NDMM with a median age of 66 years (27-95). The distribution of the R-ISS classification of this cohort is as follows: Stage 1- 128 (23%) pts, Stage 2- 369 (65%) pts and Stage 3- 69 (12%) pts. The median number of cPCs was 59 (0-46,412) / 150,000 events. The median time-to-next-treatment (TTNT) and overall survival (OS) for pts with ≥400 cPCs (n = 140, 25%) was 19 months and 46 months compared with 34 months and 77 months for those with < 400 cPCs respectively (n = 426, 75%) (p < 0.001 for both). The median TTNT and OS for pts based on their R-ISS classification as well as with and without the presence of ≥400 cPCs by MFC was as follows in the following Table. Conclusions: Quantifying ≥400 cPCs/150,000 analyzed events by MFC can potentially upstage the R-ISS classification of a subset of NDMM pts with stage I and II disease and identify those pts with a worse than expected survival outcome.[Table: see text]

8019 Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF > 200 pg/ml, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.

7509 Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 & 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, & 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]

8516 Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.

AbstractThe diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.

SummaryWe sought to dissect the tumour microenvironment in a small cohort (N = 10) of patients with POEMS at diagnosis and after therapy using mass cytometry. We included 10 MGUS patients as controls. We identified 29 immune cell subsets in the CD45+ and CD3+ compartments. Double positive T cells and PD‐1 positive CD4 T cells were expanded and naïve CD4 T cells were decreased in the bone marrow of patients with newly diagnosed/progressing POEMS. These findings provide evidence for possible antigenic‐driven selection as a driver of disease pathogenesis in POEMS.

Background: The current commonly used regimens in newly diagnosed multiple myeloma (NDMM) utilize steroids (dexamethasone or prednisone) in various combinations: bortezomib, lenalidomide and dexamethasone (VRd), bortezomib, thalidomide and dexamethasone (VTd), daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib, melphalan and prednisone (DVMP). However, steroid therapy may be associated with various adverse effects, including, but not limited to mood changes, insomnia, hypertension, hyperglycemia, osteoporosis, adrenal suppression, muscle weakness, and increased risk of opportunistic infections. A recent trial demonstrated improved tolerability of a regimen (Rd-R) involving an abbreviated course of dexamethasone, without compromising the efficacy in patients with intermediate-fit NDMM (Lorocca A., et al., ASH 2018). We designed a phase 2 clinical trial to examine the safety and efficacy of daratumumab, an anti-CD38 monoclonal antibody in combination with an all-oral regimen of ixazomib, a proteasome inhibitor, lenalidomide, an immunomodulatory drug, and modified dose dexamethasone (IRd). Patients and Methods: NDMM patients with measurable disease and adequate organ function were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response (CR) to daratumumab-IRd. Treatment consisted of daratumumab, 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks, ixazomib, 4 mg days 1, 8, 15, lenalidomide, 25 mg days 1-21, and dexamethasone upto 40 mg intravenously weekly for no more than two cycles, followed by use only as a prophylactic premedication for daratumumab-associated infusion reactions. Myeloma risk stratification was assessed by cytoplasmic immunoglobulin fluorescence in-situ hybridization (cIg FISH) analysis. Results: Overall, 40 patients were accrued, with data available on all patients for analysis at the cutoff date of July 19, 2019. The median age at enrollment was 64.5 (33-81) years; 37.5% were female. Eight (20%) patients were high risk by FISH. The median number of cycles was 6 (2-11) and the median follow up was 6.1 (2-11.7) months. Among 40 patients who had received at least 2 cycles of therapy, responses were attained rapidly; at the end of cycle 2, 88% patients achieved at least a partial response and 33% at least a very good partial response (VGPR) that improved to 52% at the end of 4 cycles among 29 patients who had completed at least 4 cycles. The overall best confirmed response rate among all 40 patients (Figure 1) was 95%, including 10% stringent CR, 5% CR and 23% near CR (13% VGPR excluding nCR). Stem cell collection was completed in 17 patients so far, all of whom required filgrastim and plerixafor. The median CD34+ cell count was 7.7 (range 2.9-11.6) million/kg . All patients were alive and 39 (97.5%) patients were progression-free at last follow up. Four (10%) patients proceeded to autologous stem cell transplantation off study, per patient and/or investigator discretion (1 in CR, 2 in PR, 1 with progressive disease). Overall, 224 cycles have been administered across the study, with dose reduction/ hold required in a subset of patients; ixazomib (10%), lenalidomide (20%), daratumumab (0%) and dexamethasone (13%); the most frequent reasons for dose adjustment were skin rash and hematologic toxicities. A grade 3 or higher adverse event, at least possibly attributed to the study drugs, was observed in 40% of patients; hematologic in 30% (lymphopenia 25%, neutropenia 15%, thrombocytopenia 5% and anemia 2.5%) and non-hematologic in 18% of patients (hyperglycemia 8%, diarrhea 5%, infections 5%, ileus 2.5%, maculopapular rash 2.5%, and fatigue 2.5%). Updated results with additional 6 months of follow up and minimal residual disease assessment related data will be presented at the meeting. Conclusion: Our early results suggest that the combination of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone is well-tolerated, with excellent activity, and does not adversely impact stem-cell mobilization in patients with NDMM. Disclosures Kapoor: Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Daratumumab in combination with Ixazomib, lenalidomide and dexamethasone for the management of newly diagnosed multiple myeloma

Introduction: Advances in the understanding of disease biology, the introduction of new drugs, and better supportive care have improved outcomes in multiple myeloma (MM). Most improvements have been observed in clinical trial and tertiary referral center populations but questions remain about the generalizability of these findings to patients treated in the community. Methods: We studied all patients diagnosed with MM between 01/01/2001 and 12/31/2015 who had complete demographic and overall survival (OS) data available and were seen at Mayo Clinic (MAYO) or followed in the Surveillance, Epidemiology, and End Results Program (SEER, 18 registry data 2000 - 2016, 11/2018 submission). We retrieved age at diagnosis, sex, date of diagnosis, date of last follow-up, and OS for all patients. OS was defined as the time from diagnosis to death from any cause. Patients who were alive at the end of follow-up (12/31/ 2016) were censored. OS estimates were calculated using the Kaplan-Meier method. Age- and sex-adjusted Cox models were used to assess the association between the 5-year interval of diagnosis and OS. Expected OS estimates were calculated based on United States general population rate tables (Human Mortality Database) using a conditional approach. Standardized mortality ratios (SMR) were calculated by dividing the number of observed deaths by the number of expected deaths in age- and sex-matched general United States population controls. Linear regression models were fit to test for linear trends in early mortality and SMR over time (per 5-year interval). P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 3 years lower in patients at MAYO (64 years, 15% ≥ 75 years, 60% male, n = 3293) compared to SEER (67 years, 29% ≥ 75 years, 55% male, n = 61779). After a median follow-up of 2.8 years the median OS was longer in MAYO compared to SEER (5.4 versus 4.0 years, HR 0.82, 95% CI 0.78 - 0.86, p &lt; 0.001) and remained statistically significant after adjusting for age and sex (HR 0.91, 95% CI 0.86 - 0.95, p &lt; 0.001). Early mortality (1-year mortality) decreased between 2001-2005 and 2011-2015: From 20% to 11% at MAYO and from 26% to 19% in SEER. When grouping OS by year of diagnosis (in 5-year-intervals) improvements were seen in both populations (A) and remained statistically significant after adjusting for age and sex. The relative improvements were similar comparing the 5-year period after the introduction of the novel therapies (2006 - 2010) to 2001 - 2005 and more pronounced in MAYO for the most recent 5-year interval (2011 - 2015, A). This trend was reflected in a steady temporal improvement in 5-year OS estimates in MAYO including the most recent 5-year interval (2011 - 2015, B bottom left). In SEER there was a comparable increase between the first two 5-year intervals but a lesser improvement in more recently (2011 - 2015, B bottom left). A diagnosis of MM remained associated with significant excess mortality in all age groups over time in both populations (B top). There was a decrease in excess mortality over time at MAYO (SMR decline per 5-year interval 1.3, 95% CI 0.9 - 1.8, p &lt; 0.001) while there was little change in SEER (SMR decline 0.0, 95% CI -0.3 - 0.3, p = 0.917, B bottom right). Further stratifying by age at diagnosis, the decrease in excess mortality was observed mostly in patients &lt; 75 years at MAYO (SMR decline per 5-year interval 1.7, 95% CI 1.5 - 2.0, p &lt; 0.001, C bottom left) and to a lesser extent in older patients (SMR decline 0.4, 95% CI 0.2 - 0.6, p &lt; 0.001, C bottom right). No such trends towards improvement were observed in either age group in SEER (C bottom). In older patients, early mortality remained approximately 30% in both populations despite continued improvements, while the 5-year OS estimates for the most recent 5-year interval (2011 - 2015) were 37% at MAYO and 26% in SEER (C top). Conclusions: Both early mortality and long-term survival have improved over time. Reductions in excess mortality were largely confined to younger patients with access to specialized care. Patients ≥ 75 years represent more than a quarter of all patients in the community, a third of them died within one year of the diagnosis, and only one in four was alive five years later. Older patients with MM remain a vulnerable population and have derived only limited benefit from recent advances in the field. Safe and effective therapies for older patients with MM remain an unmet need. Figure Disclosures Gertz: Ionis/Akcea: Consultancy; International Waldenstrom Foundation: Research Funding; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding. Dispenzieri:Alnylam: Research Funding; Akcea: Consultancy; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Celgene: Research Funding. Lacy:Celgene: Research Funding. Maurer:Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Takeda: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

AbstractWe evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10−5; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD‐negative rate after one‐line of therapy was 71% (20/28). And, MRD negative rates were higher with stem‐cell transplant as first‐line therapy (86%, 18/21) vs chemotherapy alone as first‐line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD‐negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow‐up of 14 months, the estimated 1‐year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk‐adapted trials may help optimize treatment in AL amyloidosis.