Citations

AbstractSymptomatic hyperviscosity is a well‐established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity‐related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre‐empt hyperviscosity‐related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate‐analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time‐to‐initial therapy was 6.9 years and only 15% developed hyperviscosity‐related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity‐related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM‐directed therapy.

Abstract Introduction: Hyperdiploidy on FISH portends a good prognosis in myeloma. We compared hyperdiploidy determined by MFC to that by conventional FISH. Methods: We studied 1711 patients with plasma cell disorders who had simultaneous FISH and DNA index testing. Monotypic plasma cells in bone marrow are identified by MFC with antibodies to CD19, CD38, CD45, CD138, kappa and lambda; followed by staining by DAPI. DNA index is determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. Plasma cells with DNA content index of <0.95 are hypodiploid and G0/G1 DNA content index of >1.05 are considered hyperdiploid. Results: Distribution DNA index and FISH results are described in Table 1. Sensitivity and specificity of DNA index by hyperdiploidy was 86% and 83%. Cohen's Kappa coefficient for concordance was 0.69. Sensitivity increased to 94% for those with 2 or more trisomies and 97% for 3 or more trisomies. Of the 104 patients with trisomy and non-hyperdiploid DNA index, 62% patients had monosomy (mono) or deletion (del) 13q. Overall, DNA index was lower in patients with mono 13/del 13q (1.01; 0.97-1.11) compared to those without (1.07; 1.0-1.19), p<0.001. After excluding patients with mono 13/del 13q, sensitivity and specificity of hyperdiploidy by DNA index were 92% and 82%, kappa = 0.73. Hyperdiploidy was seen in 55% of 272 patients with newly diagnosed myeloma. Sensitivity and specificity were 88% and 93%, kappa = 0.78. After median follow-up of 2.3 yrs, those with hyperdiploid DNA index had better progression free survival at 2,3 and 5 years, 62%, 45% and 21% compared to 50%, 33% and 13% in non-hyperdiploid group, p=0.05. Median overall survival (OS) was not reached; estimated 2, 3 and 5 year OS was 83%, 76% and 63% vs. 76%, 64% and 44%, respectively; p=0.08. Conclusions: DNA index by MFC is a rapid method to determine hyperdiploidy, with potential for replacing trisomy testing by FISH, especially when coupled with monosomy FISH probes. Hyperdiploid N=768 n/N (%)Diploid N=762 n/N (%)Hypodiploid N=78 n/N (%)P1P2Any trisomy 619/765 (81)96/758(13)8/76 (11)<0.001<0.001One chromosome42587733191429-111362Others12204Two chromosomes8525-Three or more chromosomes492131Any translocation124/744 (17)566/748 (76)53/74 (72)<0.001<0.001t(4;14)106313t(11;14)2240127t(14;16)5325t(14;20)38-t(6;14)8104Unknown partner76524Trisomy + Translocation95/743 (13)60/744 (8)6/74 (8)0.0090.002Monosomy 13/17 or deletion 13q/17p252/759 (33)295/744 (40)54/74 (73)<0.0010.0001Monosomy 13/Deletion 13q208/717 (29)282/718 (39)20/70 (29)Monosomy 17/Deletion 17p70/749 (9)50/735 (7)20/72 (28)P1= three groups; P2= hyperdiploid vs. non-hyperdiploid Citation Format: Surbhi Sidana, Nidhi Tandon, Dragan Jevremovic, Rhett P. Ketterling, Angela Dispenzieri, Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, William Morice, Curtis A. Hanson, Michael Timm, Patricia Greipp, Linda B. Baughn, David Dingli, Suzanne R. Hayman, Wilson I. Gonsalves, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A. Lust, S.Vincent Rajkumar, Shaji K. Kumar. Hyperdiploidy in plasma cell disorders using multi-parametric flow cytometry (MFC) vs. FISH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 655.

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. It is the second most common hematologic cancer, affecting nearly 30,000 people in the United States annually. Substantial progress has been made in the past fifteen years in the treatment of MM due to the approval of several new classes of drugs. However, patients inevitably relapse and become refractory to existing therapies. Hence, there is an immediate unmet need to develop novel therapies for MM based on a better understanding of the disease biology. Mutations in RAS have been found to occur in about 40% of newly diagnosed MM patients, with the frequency increasing to around 70% in relapsed/refractory patients. Such mutations are absent in patients with the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Clearly, RAS mutations contribute to both disease progression and relapse. However, targeting the MEK/ERK pathway has been unsuccessful in MM patients to date. Given the high frequency of RAS mutations in MM, we hypothesized that targeting this pathway could still be a promising strategy when combined with existing agents that have multifaceted mechanisms to promote tumor cell death, such as the recently approved histone deacetylase (HDAC) inhibitor LBH589 (panobinostat). Our results clearly demonstrate that low doses of LBH589 in combination with the MEK inhibitor AZD6244 induce BIM-dependent synergistic cell death in several MM cell lines and patient cells. Our studies also suggest that mutations in RAS/RAF could serve as a predictive biomarker for sensitivity to AZD6244/LBH589. RAS/RAF mutations appear to confer Mcl-1 dependence in MM cells, in part by driving up the phosphorylation of Mcl-1. The AZD6244/LBH589 combination is able to decrease the phosphorylation of Mcl-1 at several sites, which dissociates BIM-Mcl-1 complexes, ultimately leading to activation of the intrinsic apoptosis pathway. Additionally, we identified that wild-type RAS/RAF cells have relatively lower levels of phospho-Mcl-1, as well as higher levels of Bcl-2 and phospho-Bcl-2 when compared to mutated RAS/RAF cells. This seems to confer functional Bcl-2 dependence. Consequently, we found that wild-type RAS/RAF cells are sensitive to the BH3-mimetic ABT199 (venetoclax) when combined with LBH589. Through ongoing experiments, we hope to further confirm the mechanism of action of both these combinations, identify the particular HDAC that is required to be inhibited for the observed synergy, and validate RAS/RAF mutational status as a biomarker for predicting sensitivity to either combination. Our findings have broad therapeutic potential given the prevalence of RAS mutations in MM. Moreover, the ABT199/LBH589 combination could emerge as a targeted therapy for wild-type RAS patients, perhaps broadening the scope and capacity of Bcl-2 inhibition in MM. Citation Format: Kevin C. Miller, Jessica Haug, Teresa Kimlinger, Sanjay Kumar, Wilson Gonsalves, S. Vincent Rajkumar, Shaji K. Kumar, Vijay Ramakrishnan. HDAC inhibition in combination with MEK or BCL-2 inhibition as novel therapeutic strategies in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3909.

AbstractDetection of myeloma progression (PD) relies on serial 24‐h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24‐h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55‐312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24‐h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24‐h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.

SummaryThe optimal duration of induction therapy (IT) in transplant‐eligible multiple myeloma (MM) patients in not well defined, resulting in a wide variation in clinical practice. The objective of our study was to determine whether the duration of IT in patients undergoing upfront autologous stem cell transplantation (ASCT) has an impact on progression‐free survival (PFS) in the era of proteasome inhibitors and immunomodulatory drugs. A total of 596 patients who underwent ASCT at Mayo Clinic between 2007 and 2014 were included. The patients were divided into two cohorts based on the duration of IT: IT ≤ 4 and IT > 4 months. At a median follow‐up of 54·5 months from ASCT, the median PFS in the IT ≤ 4 group was 28 months [95% confidence interval (CI), 25–33], compared to 26 months in the IT > 4 group (95% CI, 24–31) [P = 0·605]. There was no significant difference in overall survival (OS) in the two groups (P = 0·904). The lack of impact of IT duration on PFS and OS was consistent in subgroups with high‐risk features at diagnosis (International Staging System III or high‐risk cytogenetics) and different depths of pre‐transplant response [≥very good partial response (VGPR) and <VGPR]. In conclusion, prolonging the duration of IT beyond 4 months does not impact survival in patients with newly diagnosed MM who complete a single line of IT followed by consolidation with ASCT.

AbstractResponse rates in newly diagnosed multiple myeloma have improved dramatically with the introduction of highly effective novel therapies. However, survival in patients achieving optimal responses to initial treatment can vary significantly, and new prognostic indicators are required to improve risk stratification. We investigated the relationship between time to plateau (TPlat) and survival in 1099 newly diagnosed patients treated with novel agents at our institution from 2005 to 2015.TPlatwas defined as time from initiation of first‐line therapy to best response to first‐line therapy. The medianTPlatwas 4.9 months (0.7‐58.6) and plateau duration was 1.8 years (0.2‐11.0). Patients who required > 120 days to achieve a plateau had longer modified overall survival (mOS) and progression free survival (mPFS) calculated from a landmark of best response (P < .001 for both comparisons). Statistically significant improvement in mOS was retained in subgroup analysis based on age and whether patients received upfront autologous hematopoietic stem cell transplantation (ASCT) (P < .001 for all comparisons). Our results suggest that patients who respond more gradually to initial therapy (TPlat > 120 days) experience longer survival compared to more rapid responders. Patients with a prolongedTPlatcould represent an “ongoing responder” phenotype that portends a survival advantage independent of treatment with upfront ASCT, depth of response, and biologic markers such as ISS stage and cytogenetic risk.

Key Points λ Light chain AL amyloidosis is associated with a shorter PFS and OS compared with κ. Light chain type predicts likelihood of organ involvement in AL amyloidosis.

Purpose Autologous stem-cell transplantation (ASCT) has been used in patients with immunoglobulin light chain (AL) amyloidosis for more than two decades. Early experience raised concerns regarding safety with high early-mortality rates. Patients and Methods We report 20 years of experience with ASCT for AL amyloidosis at the Mayo Clinic Rochester. In all, 672 consecutive patients receiving ASCT for AL amyloidosis were divided into three cohorts on the basis of date of transplantation (cohort 1, 1996-2002 [n = 124]; cohort 2, 2003-2009 [n = 302]; and cohort 3, 2010-2016 [n = 246]). Results The median age for the entire cohort was 59 years, with patients in cohort 3 being slightly older than those in the other two cohorts (60 v 58 v 54 years for cohorts 3, 2, and 1, respectively; P < .001). Fewer patients in cohort 3 had more than two organs involved (9% v 18% v 19% for cohorts 3, 2, and 1, respectively; P < .001). More patients received pretransplantation therapy in cohort 3 compared with earlier time periods (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). Hematologic response was higher in cohort 3 (84% v 79% v 69% for cohorts 3, 2, and 1, respectively; P = .002). Median overall survival for the entire cohort was 122 months and improved over time (not reached v 120 months v 75 months for cohorts 3, 2, and 1, respectively; P < .001). Treatment-related mortality declined over time (2.4% v 8.6% v 14.5% for cohorts 3, 2, and 1, respectively; P < .001). On multivariable analysis, conditioning dose, Mayo stage 2012, and hematologic response were independent predictors of survival. Conclusion ASCT is a highly effective therapy for AL amyloidosis. The improved survival and markedly reduced treatment-related mortality in eligible patients indicate that this will remain an important first-line option even in the era of treatment approaches that use novel agents.