Janakiram, Murali

Abstract Background/Introduction Patients with multiple myeloma (MM) are at increased risk of developing AL amyloidosis. It was determined by screening fat pad and bone marrow biopsy that 38% MM patients had amyloidosis at time of diagnosis and the majority were asymptomatic (1). However, whether amyloidosis-related echo features in MM affect survival remains unknown (1, 2). Purpose The goals of our study are to: 1) characterize prevalence of amyloidosis-related echo features in patients with multiple myeloma, 2) investigate whether decrease in longitudinal strain affect survival outcomes. Methods Patients diagnosed with MM between Jan 1, 2000 and Dec 31, 2017 at our institution were identified through Clinical Looking Glass. Those with echo within 1 year after myeloma diagnosis and left ventricular ejection fraction (LVEF) greater than 40% were included. Global longitudinal strain (GLS) and LVEF measurements were done using EchoGo (Ultromics, Oxford, UK). The average of GLS obtained from apical 4-chamber and apical 2-chamber views was used for analysis, with decreased GLS defined as absolute value less than 18%. Statistical analysis was conducted with STATA13, using Chi square test and Kruskal-Wallis for univariable analysis and Cox regression model for survival analysis. Results From a total cohort of 909 patients, 252 met inclusion criteria, of which 59 (23.4%) patients had decreased average GLS (see Table 1). Patients' mean age was 63±11 years, 44.8% were male and most were Black (42.7%) and the rest Hispanic (33.3%) and White (7.9%). Median follow up time was 4.25 years. The group with decreased GLS had lower percentage of females (22% vs 51.8%, p<0.01), higher percentage of previous MI (11.9% vs 1.6%, p<0.01) and more prior diagnosis of heart failure (20.3% vs 1.6%, p<0.01). Among patients with decreased GLS, five-year mortality rate was 63.3% compared to 46.0% in those with preserved GLS (p<0.036). Median survival time was 3.9 years among those with reduced GLS and 4.3 years in those without (see Figure 1; p<0.01). Reduced GLS correlated with decreased survival (HR 1.6, p=0.03) even after adjusting for demographic variables (age, gender, race), history of MI, history of CHF, Charlson comorbidity index, myeloma RISS stage, and LVEF (≥50% vs 40–50%). Forty-seven (18.6%) patients had end diastolic inter-ventricular septum (IVSd) thickness ≥1.2cm. Median GLS in patients with increased IVSd thickness was 19% compared to 21% in those without (p=0.01). Nine patients had the apical sparing strain pattern for amyloidosis. Total of 158 patients had bone marrow specimen stained with Congo-red with 7 (4.4%) testing positive. Median GLS was 19% in the group staining positive for Congo-red compared 21% in the group with negative stain (p=0.03). Conclusions Decrease in GLS on baseline echo correlates with increased mortality in patients with MM and may be due to subclinical cardiac amyloidosis. Funding Acknowledgement Type of funding sources: None.

AbstractWe studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008–2017 to develop a prognostic model to predict outcomes. High‐risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high‐risk cytogenetics [hazard ratio, (HR) 1·68 (1·3–2·17)] and pre‐AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33–2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07–1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three‐category system with low risk (0–3), intermediate risk (4–8) and high risk (9–10) showed 3‐year progression‐free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52–63) vs. 49% (95% CI: 43–56) vs. 31% (95% CI: 12–51), P < 0.001 respectively, and 3‐year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84–91) vs. 81% (95% CI: 76–86) vs. 64% (95% CI: 39–80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

TPS8052 Background: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), present in approximately 20% of cases. MM cells with t(11;14) usually have a favorable high BCL-2 level and inferior outcomes compared to standard risk MM. Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in MM cell lines and primary samples. VEN has single agent activity in relapsed/refractory MM (RRMM) with an acceptable safety profile, especially in t(11;14) MM; however, non- t(11;14) MM patients may benefit from single agent VEN and VEN incorporated in multi-agent RRMM regimens. Dexamethasone (d) promotes Bcl-2 dependence in MM resulting in sensitivity to VEN and this combination with bortezomib (Vd-VEN) has an acceptable safety profile with high response rates in heavily pre-treated MM. Combination therapy with daratumumab and bortezomib (DVd) has become a standard of care in RRMM. Our hypotheses are that the addition of VEN will improve upon this standard and be most effective in the t(11;14) positive subset. Methods: Eligibility criteria include RRMM with measurable disease, not bortezomib refractory, platelet count > 100K. t(11;14) is an integral biomarker with status (positive or negative) established at registration. After a Ph1 study to determine the recommended phase 2 VEN dose, patients are randomized to DVd +/- VEN [stratified by prior lines of therapy and R-ISS]. The primary Ph2 objectives are to compare 8-cycle minimal residual disease (MRD) negative rate and to inform the role of t(11;14) as a biomarker. The Ph2 design proposed by Freidlin et al. follows a decision algorithm as outlined in the table below. Simulations were run to establish an optimal sample size given various parameters including biomarker prevalence and power to make appropriate decisions for a Ph3 design. Target Ph2 accrual is 240 patients with a 1/3 positive:2/3 negative t(11;14) split. Clinical trial information: NCT03701321. [Table: see text]