Baudi, Francis K.

Introduction: Uniform assessment of response to treatment is crucial to managing myeloma and developing new therapies. Measurement of the monoclonal protein (s) secreted by the myeloma cells forms the cornerstone of disease assessment in MM and has primarily been performed by electrophoretic methods in the serum and urine, as well as assessment of free light chains in the serum. According to international myeloma working group (IMWG) guidelines, serial serum-free light chain (sFLC) is included in MM response assessment to define stringent complete response and for evaluating partial response (PR) or progressive disease (PD) in non/oligo-secretory MM. This study aims to determine the added value of serial sFLC measurements in monitoring response and progression in MM with measurable disease by comparing the kinetics of FLC with M spike measured by electrophoresis in serum or urine. Methods: This retrospective observational study included newly diagnosed MM patients evaluated at Mayo Clinic in Rochester between 2011-2021. All patients had measurable sFLC (involved FLC level ≥ 10mg/dL, with abnormal sFLC ratio) along with measurable M-protein by serum or urine protein electrophoresis at diagnosis. Serial measurements of sFLC and M-protein by electrophoresis (sPEP/uPEP) were prospectively collected from the electronic medical records at different time points. FLC-response and FLC-PD were evaluated based on IMWG criteria. Results: The study cohort included 839 patients, 52% with measurable M protein by electrophoresis in serum, 27% in both serum and urine, and 21% in urine-only. A significant association was observed between sFLC and electrophoretic response during the induction and at the time of best response (p <.001). Serum FLC showed a comparable response rate of 98% (≥ PR) at the time of best electrophoretic response (p <.001). Ninety-nine percent of early FLC responders eventually achieved an overall response by sPEP/uPEP (p <.001). In the urine-only group, 99% achieved at least a PR by uPEP, and all showed at least a PR based on sFLC. We observed comparable median percentage changes in serial dFLC and urine M-protein, with parallel trends (p <0.001). The correlation coefficients between the change of sFLC and urine M-protein showed a moderate/strong correlation with coefficients (r) of 0.791, 0.597, 0598, 0.545, after cycles 1, 2, 3, 4, respectively, (p < .001). The response for all cohorts was detected earlier by dFLC (median time 1.1 months, 95% CI: 1.06-1.17), in comparison with serum M-protein (1.5 months, 95% CI: 1.40-1.62) and urine M-protein (2.8 months, 95% CI: 2.42-3.10) with p < .001. In the urine-only group, earlier detection of response by dFLC (1.1 months, 95% CI: 1.00-1.2) was observed, compared to urine M-protein (2.4 months, 95% CI: 2.00-2.7) (p <.001). After a median follow-up of 52 (IQR 27.6, 72.3) months, 56% had PD: 62% by s-FLC, 56% by serum M-protein, and 24% by urine M-protein. Among patients with PD by uPEP, all except one patient met sFLC-PD. Within patients with PD, sFLC was the only detectable tumor marker in 12% of cases at the time of the second line of treatment. After four cycles of induction, there was no difference in PFS between VGPR response determined by sFLC, sPEP, and uPEP (p =0.538). The median second-PFS for patients with onlysFLC-PD was similar to those with urine M-protein PD with or without sFLC-PD (HR 1.28, 95% CI =0.77-2.13. p 0.334). However, the median overall survival (OS) from the first relapse was significantly better for patients with onlysFLC-PD than those with urine M-protein PD (HR 1.87, 95% CI =1.07-3.27. p 0.026). Conclusions: In this study, achieving sFLC-VGPR has a similar impact on PFS as electrophoretic-VGPR after induction, indicating that serial sFLC can potentially replace the requirement for urine M-protein response (< 100mg in 24-hours urine) as part of the electrophoretic-VGPR criteria, as required by IMWG. A similar response rate between sFLC and urine paraprotein confirms the current cutoffs (90% for urine and 50% for dFLC for VGPR) used for response categories for s-FLC. We also observed that in 12% of patients with PD, sFLC was the only marker of progression, highlighting the value of serial s-FLC in monitoring relapse. In conclusion, our study supports the integration of serial sFLC measurements for monitoring response and progression in MM, even with electrophoretic measurable disease.

8603 Background: Steroids, primarily dexamethasone (Dex), remains an integral part of the therapy for myeloma. Prior to the advent of novel agents, Dex as a single agent was demonstrated to produce overall response rates of around 50%. The toxicity associated with pulsed high dose Dex has led to this approach being abandoned. This study investigates whether responsiveness to Dex correlates with biological qualities of the plasma cell clone that predicts outcome. Methods: We identified from our prospectively maintained database, patients with newly diagnosed myeloma, who were seen at Mayo Clinic within 30 days of diagnosis and were treated with single agent Dex. The M-protein measurements and responses were assessed using the IMWG criteria. Results: 182 patients seen between March 1998 and June 2007, initially treated with single agent Dex for at least 4 weeks, were included in the analysis. The median age at diagnosis was 63 (range; 39–81) and 59% were male. The actuarial median survival for the entire group was 55 months. The median duration of Dex therapy was 15 weeks (range; 4–193). Ninety one (50%) had a partial response or better and 11 (6%) were not evaluable, with the remaining patients (44%) having less than PR or progression. 10 patients (5%) achieved a VGPR or CR. The median overall survival from diagnosis for the 91 responders was 75 months compared to 71 months for the remaining patients; p = 0.6. There was no correlation between baseline disease characteristics and Dex responsiveness. One hundred thirty (70%) patients proceeded to an autologous SCT after a median of 15 weeks (range 1–46 months) of Dex. While the median overall survival was longer among the group of patients who underwent SCT, among either group, there were no survival benefit between those with a PR or better to Dex compared to the rest. Conclusions: Among this group of patients with newly diagnosed myeloma treated with single agent Dex, failure to respond to Dex induction therapy did not impact overall survival. Failure to respond to single agent steroid does not have an adverse impact on outcome in newly diagnosed myeloma. [Table: see text]

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Abstract BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

Abstract Background: Both MM specific and patient specific parameters place patients at risk for death. Patient frailty has been delineated primarily by age and ECOG performance score (PS) and secondarily with creatinine, eGFR, and the International Staging System (ISS), which reflect both renal function and disease burden. In an attempt to improve upon these commonly used measures, a frailty score for elderly patients that combines functional status [Activity of Daily Living (ADL) and Instrumental Activity of Daily living scores], comorbidities [Charlson comorbidity index (CCI)] and age has been developed by the IMWG. Incorporation of these tools into a busy clinical practice is challenging due to time constraints. Therefore, the identification of frail patients with an easily applicable, rapid and objective tool remains a challenge and an unmet need. A reliable, non-invasively assessable, biochemical marker of frailty would be an ideal tool to identify patients at higher risk of death. It was our goal to determine the role of NT-proBNP, a well-established cardiovascular risk biomarker, as a marker of frailty in patients with MM and in predicting overall survival (OS). Methods: Patients were elegible for this retrospective study if they were seen at the Mayo Clinic, Rochester, MN within 30 days of their myeloma diagnosis during the interval between 1/1/2007 and 12/31/2011. As part of the Mayo Clinic registration, all patients complete forms containing their past medical history, symptoms, and ADLs. Data from that first visit was abstracted and used to calculate a CCI. We excluded all patients with a concomitant diagnosis of light-chain AL amyloidosis. NT-proBNP concentration was measured in frozen sera collected within 30 days of diagnosis. NT-proBNP assay was run on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). We evaluated the prognostic role of NT-proBNP and these indices on OS using the Kaplan-Meier method. Results: Among the 351 consecutive patients satisfying entry criteria, median age was 65 years (range 22-95), 33% were ≥70 years, and 56% were male. Twenty-eight percent were ISS stage III, 13% had a creatinine ≥2 mg/dL, 19% had PS ≥2, and 11% had ADL score ≥2, and 30% CCI ≥2. The median value of NT-proBNP was 109 ng/L (interquartile range: 30-375 ng/L). NT-proBNP concentrations differed in the three ISS stages (median: 122 ng/L stage I, 190 ng/L stage II and 1822 ng/L stage III, P<0.0001). Median OS was 5.6 years. The best cutoff of NT-proBNP predicting OS at one year was 301 ng/L (sensitivity: 57.88%, specificity: 74.29%; AUC=0.668) and distinguished two groups with different OS (median not reached vs. 35 months, P<0.0001). Variables predictive for OS are shown in the Table and included PS, age, CCI, ISS, NT-proBNP. On multivariate analysis, ISS and NT-proBNP were independent of each other as long as age, PS and/or CCI were excluded from the model. NT-proBNP withstood these clinical variables better than did ISS (data not shown). We built two different models (table). In model 1, NT-proBNP >301 ng/L was an independent predictor of survival while age ≥70 and PS ≥2 and CCI were not significant. However, if we considered ISS stage instead of NT-proBNP in the same model, ISS stage was not significant. Conclusions: In this unselected cohort of patients with newly diagnosed multiple myeloma, NT-proBNP was a useful predictor of survival independent of age and PS. The threshold of 301 ng/L is remarkably similar to the well-established cutoff for heart failure of 300 ng/L. NT-proBNP outperformed the CCI and the ISS as risk factors. NT-proBNP is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple means of determining patient frailty in a busy clinical practice. Table. Results of univariate and multivariate analysis of various prognostic factors (NS, not significant; NI, not included). Univariate Multivariate Multivariate RR (95% CI) P Model 1 P Model 2 P PS ≥2 3.4 (2.4-4.8) <0.0001 2.5 (1.7-3.6) <0.0001 2.8 (1.9-4.0) <0.0001 Age ≥70 2.7 (1.9-3.6) <0.0001 2.1 (1.5-2.9) <0.0001 1.9 (1.3-2.7) 0.0003 CCI >=2 1.9 (1.4-2.6) <0.0001 NS NS 1.5 (1.0-2.0) 0.03 ISS stage 1.1 (1.1-1.8) 0.0004 NI NI NS NS NT-proBNP >301 ng/L 2.3 (1.7-3.2) <0.0001 1.6 (1.1-2.2) 0.007 NI NI Disclosures Merlini: Janssen-Cilag: Honoraria; Prothena: Honoraria; Millennium-Takeda: Honoraria; Pfizer: Honoraria. Kumar:Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria.