Search

e20043 Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.

8029 Background: Histone deacetylase (HDAC) inhibitors (HDI) have a therapeutic niche in multiple myeloma (MM) due to their ability to salvage proteasome inhibitor and immunomodulatory drug responsiveness in refractory patients, thus raising interest in this therapeutic class. Selective HDI may further improve therapeutic efficacy. Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11-/-) or targeted to the B cell lineage (CD19Cre.HDAC11-/-). Molecular and pharmacologic means were used to impair HDAC11 in established MM cell lines. Viability was measured by activated caspase-3, Annexin/PI (A/PI) staining, and CCK-8 viability assay. Subcellular localization changes induced by HDI and identification of the novel binding partner IRF4 were assessed by proximity ligation assay (PLA). Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. In addition, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11-/-mice suggests activity inherent in B cells rather than via externally derived signals. Quisinostat (QS), an HDI with enhanced HDAC11 selectivity, showed dose-dependent cytotoxicity in 10 MM cell lines (EC50 1-10nM). This activity was synergistic with bortezomib (BTZ) and carfilzomib (CFZ) in RPMI-8226 cells, while synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Exposure of RPMI-8226 cells to QS decreased detection of nuclear, but not cytosolic, HDAC11. Targeted siRNA–mediated silencing of HDAC11 in RPMI-8226 cells activated caspase-3 and reduced viability by A/PI staining. PLA of MM cell lines showed a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, unmasking a potential mechanism for HDAC11-induced cytotoxicity in MM. This interaction was disrupted by QS. Conclusions: We show that HDAC11 inhibition reduces MM cell survival in vitro. Furthermore, we identify IRF4 as a binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM survival.

8013Background: SEL, an oral, first-in-class inhibitor of XPO1 showed activity in clinical trials for hematologic malignancies. SEL inhibits DNA damage repair and exhibits marked synergy with doxor...

8579 Background: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM) (Colla, Leukemia 2010). Evofosfamide (EVO; formerly TH-302) is a nov...

8608 Background: SP can occur in bone (SPB) or in extramedullary sites (EMP) and generally accounts for ~ 3-5% of plasma cell dyscrasias. Up to 50% of SPB and 15% of EMP will progress to multiple myeloma (MM). We evaluated the utility and prognostic significance of positron emission tomography (PET) imaging and SFLC ratio (sFLCr). Methods: We retrospectively reviewed electronic medical records of patients with SP evaluated at Moffitt Cancer Center between 1990-2012. The diagnosis of SP was per IMWG criteria (BJH 2003, 121:749) (biopsy proven single site, negative skeletal survey, bone marrow biopsy with no more than 10% plasma cells). Initial and post therapy sFLCr as well as PET findings were correlated with progression to symptomatic MM (PFS). Radiation therapy (XRT) was at the discretion of the treating physician. Results: 135 patients were identified and 91 (67%) were males. The median age was 58 years (range 20-82). Consistent with prior reports, the PFS of the entire cohort was 43 months (95% CI 17.8-70). 23 patients had PET prior to progression. All patients had uptake in the primary lesion (except 4 who had resection of the primary). 8 patients had additional PET findings in other bony structure (PET+), and 15 did not (PET-). 2 and 6 of the PET- and PET+ patients progressed (median PFS Not reached (NR) vs. 8.1 months, p=0.021) respectively. Of the 49 patients with available sFLC data, 32 had an abnormal ratio (17 progressed) and 17 patients had a normal ratio (2 progressed). Abnormal baseline sFLCr was associated with progression (median PFS 19 months vs NR, p=0.012). Post XRT, 44 patients had an available sFLCr, of which 23 had an abnormal ratio and 21 a normal ratio. A persistent serum/urine m spike after XRT was associated with progression to MM (median PFS 20.8 months vs NR, p

e19516 Background: Though cumbersome, a 24-hour urine collection remains crucial for diagnosis and monitoring in plasma cell dyscrasias (PCD). Nephrology guidelines recommend replacement of 24-hour urine collection with spot urine protein/creatinine (Pr/Cr) ratio for proteinuria. Only limited data exist on accuracy of spot urine Pr/Cr ratio in PCD. Methods: From 04/2012 to 01/2013, a total of 67 PCD patients were prospectively enrolled. Oliguria or dialysis were considered ineligible. Spot urine was collected on the day of 24-hour urine collection. Spot urine Pr/Cr ratios were compared to 24-hour urine on (1) total protein and (2) monoclonal protein (M-spike). Results: Fifty-two of 67 patients were evaluable (missing samples in 9; no Pr/Cr ratios in 4; protein below the level of detection in 2). A median age was 66 (range, 36 - 82), 62% were male, and 81% were Caucasian. Primary diagnoses were myeloma (n=47), amyloidosis (n=2), plasmacytoma (n=2), and MGUS (n=1). Comorbidities included hypertension (58%), chronic kidney disease (27%), diabetes (19%), and congestive heart failure (2%). A median serum creatinine was 0.9 mg/dL (range, 0.5 - 5.1). A median spot urine Pr/Cr ratio was 140 mg/g creatinine (range, 32 - 21,447), a median 24-hour urine protein was 130 mg (range, 31 - 15,092: n=49), and a median urine M-spike was 1.9 mg (range, 0 - 8,099). Most spot urine samples were collected in the morning (65%). There were strong correlations between (1) spot urine Pr/Cr ratio and 24-hour total urine protein (Spearman correlation coefficient=0.91, p < 0.0001), and (2) spot urine Pr/Cr ratio and 24-hour urine M-spike (Spearman correlation coefficient=0.73, p < 0.0001). The timing of spot urine sample collection had no significant effect (p = 0.274 by Wilcoxon rank-sum test). Conclusions: Spot urine Pr/Cr ratio strongly correlates with proteinuria measured in 24-hour urine collection and may predict the quantity of urine M-spike in non-oliguric PCD population. Spot urine Pr/Cr ratio may be useful as a monitoring tool for estimation of proteinuria. The study is ongoing and updated result will be provided.