Citations

8092 Background: High dose therapy and autologous stem cell transplant (SCT) remain an integral part of the treatment of multiple myeloma (MM). Despite the introduction of several new drugs, disease relapse remains inevitable and a second SCT often allows continued disease control. Methods: We examined the outcomes in 105 patients (pts) undergoing a second SCT (SCT2) for relapsed MM, from among 1033 pts receiving initial transplant between 1994 and 2009. Patients receiving an allogeneic SCT post SCT2 were not included in the survival analysis. Results: Median (range) age at SCT2 was 60 yrs (35-74) and the time between SCTs was 46 mos (10-130). The median follow-up was 5 yrs from SCT2. The median (range) number of regimens between the two SCTs and from diagnosis was 2 (0-7) and 3 (1-11), respectively. Conditioning regimen was Mel 200 in 85 (81%) pts. Median (range) CD34 cells infused was 4.6 (2.5-25 million/kg). Hospitalization was required for 53 pts (50%), median hospital stay was 7 days.. Median time to ANC of 500 and platelets of 50,000 were 13 and 16 days, respectively. Treatment related mortality was seen in 5 (5%) pts. A partial response or better was seen in 95 (90%) pts, including a stringent CR in 10%, CR in 19%, and VGPR in 21%. Stable disease or progression was seen in 7 pts and 3 pts died prior to disease assessment. The median (95% CI) PFS and OS after SCT2 were 10.4 (8, 14) and 33 (28, 51) mos, respectively. The median OS was not reached and 33 mos respectively, for those obtained a CR and those with <CR, P=0.03. FISH pre-SCT2 was available for 73 pts; the PFS and OS were not affected by the presence of high-risk MM. In multivariate analyses, shorter duration of response to SCT1, higher plasma cell (PC) labeling index at SCT2, more regimens used prior to SCT2 all predicted shorter PFS and OS post SCT2. Lack of CR to SCT2 was also significantly associated with shorter PFS. Conclusions: Second SCT is an effective therapy for eligible pts relapsing after other treatments. It provides a meaningful duration of response and appears to be well tolerated. Pts with longer duration of response to first transplant and those achieving a CR appear to have maximum benefit.

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

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.

AbstractHistological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high‐grade lymphoma, with median time‐to‐transformation of 4.5 (range 0‐21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non‐transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1‐23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time‐to‐transformation (HR 7.9 [95%CI: 2.3‐27; P = .001]), with a 5‐year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8‐6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time‐to‐transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

Abstract Background: Venous thromboembolism (VTE) contributes to significant morbidity, mortality, and socioeconomic burden. Though male sex is a known risk factor for recurrent VTE, there is a paucity of literature regarding sex-based sociodemographic differences as well as differences in VTE outcomes including hospital length of stay and mortality rates. Methods: We conducted a retrospective analysis from the National Inpatient Sample (NIS) database from 2012-2013. Inclusion criteria were age 18 years and older and primary discharge diagnosis of VTE Sociodemographic features and medical comorbidities were analyzed, as were hospital length of stay and in-hospital mortality rates. Results: 107,896 patients in the NIS, representing a national estimate of 539,480 patients hospitalized for VTE between 2012 and 2013, met inclusion criteria. 53% were female and 47% were male. Mean age was 63 years and on average women were older than men (65 years versus 62 years, p<0.001). There were significant differences between men and women with respect to race, primary insurance payor, and VTE location as well as medical comorbidities (Table 1). Median overall length of stay (LOS) was 4 days and in-hospital mortality rates were 2.1%. Female sex was associated with a small but significantly longer hospital LOS (RR 1.04, CI 1.03-1.05, p<0.001) which was also seen in subgroup analyses of lower extremity DVT (RR 1.05, CI 1.03-1.06, p<0.001) and pulmonary embolism (RR 1.03, CI 1.02-1.05, p<0.001) but not upper extremity (RR 1.04, CI 0.96-1.12, p=0.36). There were no significant sex-based differences in in-hospital mortality (2.2% in women versus 2.1% in men, p=0.15). In a multivariate model correcting for sociodemographic differences and medical comorbidities, there were no significant differences between women and men with respect to hospital LOS or in-hospital mortality (Table 2). Conclusion: We used data from the NIS to study a large number of patients hospitalized for VTE, and identified several sex-based disparities in sociodemographic factors and location of VTE. However, in a multivariable analysis correcting for these factors, sex was not associated with significant differences in hospital LOS or inpatient mortality rates. Disclosures Kapoor: Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.