Lacy, Martha Q.

8116 Background: POEMS syndrome, or osteosclerotic myeloma, is an uncommon plasma cell disorder associated with Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes, as well as bone lesions, Castlemans disease, and edema. The pathogenesis of POEMS is poorly understood, and its clinical course is distinct from Multiple Myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). While various cytogenetic abnormalities have been well described in MM and MGUS, we provide the first report of testing for these abnormalities in POEMS syndrome. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of POEMS seen at our institution, identifying 36 with metaphase cytogenetic testing results, and 9 with fluorescence in situ hybridization (FISH) testing results. Combined cytoplasmic immunoglobulin/FISH testing (cIg- FISH) was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9, 11, 15 and 17; del13/del13q; 14q32 split/del14; and t(11;14). Results: Five patients had insufficient plasma cells for cIg-FISH, and 9 were adequate for testing. Monosomy 13 was seen in 5 of the 9 cIg-FISH samples of which 2 of these cases also had apparent monosomy 14. cIg-FISH in one patient revealed trisomy 3 and 7. No abnormalities were seen at 11q13 (CCND1), 17p13 (p53) or translocations involving 14q32 (IGH). Thrity-eight total karyotypes analyses were attempted, though two showed an insufficient number of suitable metaphases. Of the 36 karyotype analyses, 31 were normal, 2 displayed characteristic plasma cell anomalies (hyperdiploid with structural anomalies), 2 treated patients displayed del20q anomalies and 1 patient had a constitutional 13;14 translocation. Conclusion: We are the first to report del13 as a possibly common abnormality in POEMS syndrome, detected by cIg-FISH in 5 of 9 (55%) samples with sufficient plasma cells, similar to the rate observed in MM and MGUS. The lack of abnormalities at 14q32 (IgH locus) is in contrast to MM and MGUS. Abnormal karyotypes, consistent with dividing plasma cells, are rare in POEMS, observed in only 2 of 36 (5.5%) cases. These observations could possibly lend insight into all three disorders. No significant financial relationships to disclose.

8108 Background: 2-methoxyestradiol (2ME2) is a natural endogenous product of estradiol metabolism with anti-angiogenic and anti-neoplastic properties that has demonstrated activity against multiple myeloma cell lines and xenografts in immunocompromised mice. We report results of the first phase II clinical trial of 2ME2 in pts with relapsed and plateau phase myeloma. Methods: This trial was designed with a one-stage design to accrue 60 pts in the setting of relapsed and plateau phase myeloma. 2ME2 was administered orally at a dose of 1000 mg daily. After the first 39 pts were accrued, based on the results of ongoing phase I trials, the dose of 2ME2 was increased to 800 mg twice daily for the remaining patients. Pts who were already on study at that point were also allowed to escalate their dose to 800 mg twice daily. The primary endpoint was overall response rate. Responses were assessed using Eastern Cooperative Oncology Group criteria. Results: Sixty patients were treated at Mayo Clinic and Dana Farber Cancer Institute. Median age was 60 years (range, 28–99). Thirty-one patients had relapsed/refractory myeloma and 29 patients had plateau phase myeloma. Median number of prior therapies was 4 including stem cell transplant (48%), thalidomide (62%), bortezomib (6%) and lenalidomide (3%). Therapy was well tolerated. Adverse events were anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flashes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most toxicities were mild (grade 1–2). Estimated progression-free survival rates for all pts at one, two, and three years are 24%, 16%, and 9% respectively. Three pts with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months. Response assessment is ongoing; so far, whilst no partial responses have been seen, prolonged stable disease has been observed in 3 pts (5%). Conclusions: 2ME2 is a novel agent that appears to be safe and well tolerated. Although no responses have been seen, prolonged stable disease in some pts is promising. Preliminary pharmacokinetic data indicate that the dose of 2ME2 used in this study may be inadequate, and a new formulation with significantly better bioavailability will be tested soon in this patient population. No significant financial relationships to disclose.

8105 Background: IL-6 is the central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. A Phase II trial was completed using IL-1ra, which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with smoldering/indolent MM (SMM/IMM). These patients are at the greatest risk for progression to active MM and most likely to benefit from anti- cytokine therapy. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. A total of 47 patients received 100 mg of IL-1ra SQ qd for 6 months unless clinical progression occurred. Responding patients were allowed to continue on therapy with IL-1ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1ra in non-responding patients. The primary endpoint was progression-free survival (PFS). Results: The 47 patients were at high risk for progression to active MM with 98% having ≥ 10% plasma cells, 89% generating IL-1 levels consistent with myeloma (≥ 1.0), and 32% having bone lesions. All 47 patients received IL-1ra initially and 25/47 subsequently received IL-1Ra/Dex. For the group of 47 patients, the median overall progression-free survival was 37.5 months. Three patients achieved a minor response (MR) to Anakinra alone; 5 pts achieved a PR and 4 patients an MR after addition of Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI; a marker of myeloma cell growth) on Anakinra alone which paralleled a decrease in the high sensitivity CRP (a marker of serum IL-6 levels). The median PFS for patients without (n=12) and with (n=35) a ≥ 15% decrease in their baseline hsCRP was 6 months and > 3 yrs, respectively (p=0.002). Conclusions: In SMM/IMM patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-1ra ± Dex) results in an increased PFS in patients that demonstrate a ≥15% reduction in the baseline CRP compared to those that do not respond. No significant financial relationships to disclose.

8022 Background: Autologous stem cell transplant (ASCT) is the standard approach for eligible patients (pts) with multiple myeloma (MM). The median time to relapse after early ASCT is 2–3 yrs and overall survival (OS) is 4–5 yrs. Though various risk factors have been identified for early relapse, the outcome of this group of pts is not clearly described. With the advent of newer therapies, it is important to understand the natural history of MM in these pts to design treatment strategies. Methods: A total of 432 pts with MM, undergoing ASCT within 12 months (mos) of diagnosis, with a minimum follow up of 12 mos were studied. Clinical and laboratory data were obtained from a prospectively maintained database and clinical records. Pts were divided into 2 groups: early relapse (relapse <12 mos from ASCT) and late relapse (either relapsed >12 mos after ASCT or disease free at last follow up). Results: There were 94 pts (22%) in the early relapse group and among the late relapse group (N=338), 171 had relapsed beyond 12 mos and 167 were disease free at last follow up. The median time to ASCT was similar in all groups. The early relapse group had a significantly shorter median OS from diagnosis (23.9 vs. 82.2 months; P < 0.001) and from transplant (17.6 mos vs. not reached; P < 0.001). The median OS from relapse was 7.9 mos in this group compared to 39.6 months for the rest. In univariate analysis, elevated CRP, high BM plasma cell%, labeling index (PCLI) >1%, abnormal cytogenetics, presence of circulating PCs at harvest and lack of CR from ASCT predicted for early relapse. In multivariate analysis, an elevated PCLI (RR=2.9; P=0.002) and failure to achieve CR (RR 2.7; P=0.002) was associated with early relapse. Conclusions: Pts who relapse within 12 mos of an ASCT have a very short survival and should be offered trials evaluating novel therapies and combinations. Survival figures from this study represent the benchmark for the comparison of novel approaches in this population. Pts with poor prognostic factors have a short PFS after ASCT and should be considered for alternative approaches. Inability to achieve CR appears to predict shorter PFS and clinical trials evaluating maintenance therapy should be offered in these pts. No significant financial relationships to disclose.

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.

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.

Key PointsPatients with an abnormal sFLC ratio because of LC suppression have outcomes similar to those with a normal ratio. sFLC ratio has prognostic value in patients achieving CR who have an absence of clonal BMPCs assessed by MFC.

AbstractOur prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R‐ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009 to 2017. Those patients that had ≥5 cPCs/μL and either R‐ISS stage I or stage II disease were re‐classified as R‐ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥5 cPCs/μL at diagnosis was as follows: R‐ISS I (N = 110) ‐ 40 months and not reached; R‐ISS II (N = 69) ‐ 30 and 72 months; R‐ISS IIB (N = 96) ‐ 21 and 45 months and R‐ISS III (N = 281) ‐ 20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R‐ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.