Kumar, Shaji

e20510 Background: pPCL is a rare and aggressive form of multiple myeloma (MM) with dismal survival outcomes compared to the remainder of MM patients. Several studies have validated the optimal cutoff for defining pPCL to be >5% circulating plasma cells (cPCs) on a peripheral blood smear due to equally poor outcomes in this less restrictive cohort. We evaluated the clinical outcomes and cytogenetic features of patients diagnosed with pPCL at our institution that were treated with novel agent induction therapies. Methods: We evaluated patients with pPCL diagnosed between 2000 – 2018 (using the 5% cut off) at Mayo Clinic, Minnesota. Data was extracted from a prospectively maintained database and from the review of electronic medical records. Patients were categorized as having high risk (HR) cytogenetics if any of the following abnormalities were present: del 17p, t(4;14), t(14;16) or t(14;20). Chi-square tests and Fisher exact tests were used to compare differences between sub-groups. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 67 patients with pPCL with a median age of 62 years (range: 34-91) of which 33 (46%) were male. The median follow up was 46 months (95% CI: 41 – 90). The median bone marrow plasma cell involvement was 84% (Range: 10 – 100) and the median cPCs percentage on the peripheral blood was 23% (range: 5 - 93). Data on primary cytogenetic abnormalities were available in 60 (85%) patients and the distribution was as follows: t(11;14) – 27 (45%), t(4;14) – 5 (8%), t(14;16) – 8 (13%), t(14;20)- 3(5%) and del 17p- 15(25%). All patients received novel agent induction therapy with 36 (54%) having received autologous stem cell transplant and 4 undergoing an allogeneic stem cell transplant. The median time to next therapy (TTNT) and overall survival (OS) for all patients was 13 months (95% CI: 9 – 17) and 24 months (95% CI: 19 – 40) respectively; 16 months and 51 months for standard risk (SR) vs. 10 months and 19 months for HR (P = 0.005 for OS), when stratified by cytogenetic risk. There were only 17 (31%) patients who were alive for ≥48 months since diagnosis (i.e. twice the median OS of this cohort); The absence of high risk cytogenetics (P = 0.049) and non-elevated LDH level (P = 0.047) at diagnosis predicted for achieving this survival goal. Conclusions: The outcomes of patients diagnosed with pPCL remain poor despite the use of novel agent induction therapy. However, some patients appear to do better than expected and this phenomenon may be influenced by the presence of HR cytogenetics.

e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with light chain (AL) amyloidosis. Mayo 2012 stage and increased plasma cell percentage (%PC) are known predictors for survival. Increased beta-2 microglobulin (B2M) predicts survival in patients with multiple myeloma. However, its prognostic effect in patients with AL amyloidosis undergoing ASCT is not known. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and were treated with ASCT between July-1996 and September-2017. Patients with creatinine > 1.2 mg/dL were excluded, as that affects B2M levels. The receiver operator curve was used to determine the best cutoff for B2M in predicting survival and was 2.5 mcg/mL. Baseline characteristics were compared between patients with B2M > 2.5 and ≤2.5. Progression-free survival (PFS) was defined as time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from ASCT to death of any cause. Univariate and multivariate analysis were done for OS. Results: Five-hundred patients were identified and 222 (44%) had a B2M > 2.5. These patients were more likely to be > 65 years old (32% vs. 17%, P = 0.0001), have Mayo 2012 stage III/IV (33% vs. 8%, P < 0.0001), have ≥3 organs involved (25% vs. 14%, P = 0.001), and have ≥10% PCs (56% vs. 40%, P = 0.0002) compared to patients with B2M ≤2.5. The median PFS and OS were shorter in patients with B2M > 2.5 (median PFS: 64 vs. 80 months, P = 0.03); (median OS: 104.9 vs. 175.5 months, P < 0.0001). On univariate analysis, predictors for OS included age > 65 (HR: 1.6, P = 0.001), Mayo 2012 stage III/IV (HR: 3.3, P < 0.0001), ≥3 organs involved (HR: 1.3, P = 0.06), ≥10% PC (HR: 1.5, P = 0.004), melphalan conditioning 200mg/m2 (HR: 0.28, P < 0.0001), and B2M > 2.5 (HR: 1.8, P < 0.0001). In a multivariate analysis, only Mayo 2012 stage III/IV (HR: 1.8, P = 0.006), melphalan conditioning 200mg/m2 (HR: 0.35, P < 0.0001), and B2M > 2.5 (HR: 1.7, P = 0.01) remained independent predictive of OS. Conclusions: Beta-2 microglobulin > 2.5 is an independent predictor for OS in AL amyloidosis patients undergoing ASCT and should be routinely measured.

8550 Background: Waldenström Macroglobulinemia (WM) is a rare lymphoplasmacytic malignancy characterized by the presence of a recurrent point mutation in the MYD88 gene (MYD88L265P) in 80-95% of cases. Patients with MYD88WT genotype comprise a small subset that responds poorly to ibrutinib and other Bruton tyrosine kinase inhibitors. We examined the characteristics and outcome of WM patients with MYD88WT genotype predominantly treated with non-BTK inhibitor based therapies. Methods: Patients with a diagnosis of WM seen at Mayo Clinic, Rochester, between 1996 and 2018 were included. Their characteristics and outcomes were assessed from the time of active disease. Marrow MYD88 genotyping was assessed with an allele specific PCR assay (analytic sensitivity 1%). Categorical and continuous variables were compared using Chi square and Wilcoxon tests, respectively. Time-to-event analyses were performed using Kaplan Meier test. Results: Of 986 patients with active WM, MYD88 genotype data were available in 331 (34 %) patients; 72 (22%) and 260 (78%) patients harbored MYD88WT and MYD88L265P genotypes, respectively. The median follow-up was 5.8 years (95% CI: 5.0-6.5 years) from active WM; 6 years MYD88WT vs 5.4 years for MYD88L265P cohort. Median age was 63 years and 66 years in the MYD88WT and MYD88L265P cohorts, respectively (p = 0.07) with 46% and 53% patients being ≥65 years of age, respectively (p = 0.36). Pre-treatment marrow lymphoplasmacytic (LPL) infiltrate (median 40% for MYD88WT vs 60% for MYD88L265P; p = 0.001) and beta-2 microglobulin (median 3 µg/mL for MYD88WT vs 3.9 µg/mL for MYD88L265P; p = 0.02) were lower in the MYD88WT compared to the MYD88L265P cohort; other laboratory parameters at active disease were comparable. Per IPSSWM prognostic criteria, MYD88WT had fewer patients in the high risk group (18% for MYD88WT vs 42% MYD88L265P; p = 0.03). Patients with MYD88WT had higher likelihood of histological transformation [18% for MYD88WT vs 4% for MYD88L265P; odds ratio 5.8 (95% CI: 2.5-13.5; p < 0.0001)]. Among patients with treatment data available, only 35 (11%) patients received ibrutinib. The 5-year overall survival (OS) from active disease was comparable (85% in MYD88WT vs 82% in MYD88L265P cohort; p = 0.7). Conclusions: MYD88WT genotype in WM is associated with lower marrow LPL infiltration, lower likelihood of high-risk IPSSWM categorization and a higher likelihood of histological transformation in comparison to MYD88L265P mutant subpopulation. MYD88 genotype does not affect the OS from active disease in predominantly non-BTK inhibitor treated patients.

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( < 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p < 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [Table: see text]

8542 Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of leukemia-associated somatic mutations in clonally expanded hematopoietic stem cells with a VAF of ≥2%. CHIP has been associated with myeloid malignancies and increased all cause mortality largely from atherovascular disease. The prevalence and impact of CHIP in patients with myeloma (MM) is yet to be defined. Aims: Evaluate the prevalence and significance of CHIP in 101 lenalidomide exposed patients with multiple myeloma. Methods: 101 MM patients, the majority exposed to > 2 years of lenalidomide (Len), with stored mononuclear blood samples were identified for Next Generation Sequencing (NGS) using a panel encompassing 42 gene mutations associated with CHIP. Electronic medical records were reviewed and outcomes of secondary malignancy, macrocytosis, thrombosis and mortality were extracted. Results: Thirty of 101patients were found to have CHIP with the most frequent mutations: DNMT3A (12%), TET2 (5%), and TP53 (4%). One third of patients with CHIP had > 1 mutation (37%). At 68 months median follow up over a quarter of patients experienced thrombosis (31%) and 13% developed subsequent malignancy/premalignant condition including myelodysplastic syndrome (3%). There was no significant difference in age, gender, duration of Len prior to NGS testing, thrombosis complication, or survival in those with versus without a CHIP mutation. At last F/U 30% had died, 25% remained on therapy, 27% were on maintenance therapy and 11% were on observation alone. Conclusions: CHIP mutations are common in plasma cell neoplasms, with 30% of patients in this study retrospectively found to have CHIP mutations by NGS testing. CHIP mutations have been associated with cardiovascular events and malignancy development, however no associations were identified in this small study. Limitations to this study include small sample size, retrospective nature and duration of follow up. Further study of this very common finding in MM patients regarding timing of development and subsequent impact of these mutations could help risk stratify and inform therapy selection. [Table: see text]

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]

8515 Background: AL is a clonal plasma cell (PC) disorder causing multiorgan dysfunction from amyloid fibril deposition. While bortezomib (B) induction has been used prior to AHCT recently, AHCT without prior induction has been a common practice. The primary objective of this study was to compare outcomes of AL patients who proceeded to AHCT without induction to those receiving pre-AHCT induction with B. Methods: Outcomes of 426 systemic AL AHCT recipients between 2014-2018 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were reviewed. Patients receiving induction with therapy other than B, AHCT occurring > 9 months after diagnosis, no documented AL end-organ involvement, myeloma-defining events and conditioning other than melphalan (MEL) monotherapy were excluded. Multivariate analysis (MVA) was conducted to identify prognostic factors associated with relapse, PFS and overall survival (OS). Results: 286 patients received B induction therapy vs 140 patients receiving no induction. Age, gender, number and type of organs involved, and AL AHCT center volume were similar between the groups. Patients receiving induction had greater PC burden compared with no induction (PC ≥ 10%, 41% vs 11%, p < 0.01). Induction was B, cyclophosphamide and dexamethasone (D) in 83% followed by B, lenalidomide and D (10%) or B+D (7%). Median follow-up was 24.9 months. At 2 years, B induction vs. no induction was associated with 13% (95% CI 10-17%) vs 22% (95% CI 15-30%) relapse risk (p = 0.03); 83% (95% CI 79-87%) vs 74% (95% CI 66-81%) PFS (p = 0.04); 93% (95% CI 90-95%) vs 94% (95% CI 89-97%) OS (p = 0.7). On MVA, the B induction group had improved PFS (HR 0.46, 95% CI 0.3-0.7, p < 0.001) with similar OS (HR 0.6, 95% CI 0.3-1.2, p = 0.1) compared with no induction. Creatinine < 2 mg/dl (HR 0.55, 95% CI 0.3-0.9, p = 0.02) and Karnofsky score ≥90 (HR 0.51, 95% CI 0.33-0.78, p < 0.01) were also associated with improved PFS. MEL dose < 180 mg/m2 was associated with inferior PFS (HR 2.17, 95% CI 1.31-3.61, p < 0.01) and OS (HR 3.6, 95% CI 1.5-8.6, p < 0.01). No deaths were seen in the first 100 days post-AHCT. At last follow-up, 32 deaths occurred, 26 (81%) due to AL. Conclusions: Compared with prior CIBMTR analyses, B induction use has increased in AL AHCT recipients and a higher PC burden was the only clinical determinant. Furthermore, B induction was associated with lower relapse and improved PFS at 2 years with no OS difference despite higher proportion of patients with > 10% PC, which has been associated with poor outcomes.

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

e19112 Background: We sought to study the longitudinal QOL, financial burden and perception of care (PoC) in patients with multiple myeloma (MM) or lymphoma (LYM) enrolled on CTs vs. those receiving standard care (Non-CT). Methods: QOL was evaluated using the FACT-G questionnaire (baseline, 1, 2, 3, 6 & 12 months). Financial burden was evaluated using 10 questions adapted from the MEPS survey and PoC was evaluated using 6 questions adapted from the CAHPS survey (baseline, 3, 6 & 12 months). Results: 35 (28%) of 123 enrolled patients were treated on CTs. Demographics, QOL and financial burden are shown in the Table. Baseline QOL scores were similar in CT vs non-CT groups. Age, gender and self-reported performance status were significantly associated with baseline QOL, while lines of therapy & cancer type were not. There were no significant differences in change in QOL vs. baseline in patients treated on CTs vs. non-CTs at 1, 2, 3, 6 and 12 months from baseline, including the total FACT-G score and the subdomains of functional, physical, emotional and social well-being. Within each group, there was a decline in QOL over the first 3 months, specifically physical WB, which gradually returned to baseline. Baseline answers to financial burden questions were similar, except patients on CTs reported less need for taking extended time-off from work (22% vs. 46%, p = 0.02). The only statistically significant difference in individual Qs over 1 year was ‘worry about having to pay large medical bills’ at the 6-month timepoint (CT: 0%, non-CT: 52%, p = 0.01). Using a composite score from 4 MEPS questions, financial burden over time was lower in the CT group, though the differences were not statistically significant. There were no significant differences in PoC at baseline, 3, 6 and 12 months in the two groups based on answers to each of the six questions adapted from the CAHPS survey. Conclusions: Over 1 year, patients on CTs experienced a similar QOL and perceived their care to be similar as non-CT patients. Financial burden was lower in the CT group, though differences were not statistically significant. [Table: see text]

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.