Lacy, Martha Q.

Abstract Abstract 1802 Poster Board I-828 Background Heterogeneity in multiple myeloma (MM) leads to disparate outcomes with a wide variation in overall survival (OS). Based upon the evidence predominantly gathered from newly diagnosed patients treated with standard chemotherapy and/or transplantation, the current Mayo (mSMART) prognostic model uses a combination of metaphase cytogenetics, fluorescence in-situ hybridization (FISH) and plasma cell labeling index (PCLI) for risk-stratification at diagnosis of MM. The objective of our study was to evaluate the significance of this stratification model in the era of novel therapies, and to assess the independent prognostic value of each of the components in the model. Methods Data were abstracted from a cohort of 1556 consecutive patients with MM who presented to our institution between January 1999 and March 2009 within ninety days of diagnosis of MM A total of three hundred and eighty six patients had been evaluated with conventional cytogenetics near diagnosis in addition to interphase FISH. Out of this cohort, three hundred and sixty six patients had availability of all the three tests, including the slide-based PCLI. High-risk MM was defined as presence of any one or more of the following: cytogenetics: hypodiploidy, monosomy of chromosome 13 or deletion 13q ; FISH: deletion of p53 (locus 17p13) or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23); PCLI ≥3%. Survival estimates were created using the Kaplan-Meier method and compared by log-rank tests. The impact of each of the three tests was assessed by a multivariate (MV) analysis using Cox proportional hazards model. Results The median OS of the cohort of 366 patients was 65 months from presentation. One hundred and twelve (31%) patients were deemed high risk by any one or more of the three tests: Metaphase cytogenetics, FISH or PCLI (current mSMART definition of high-risk MM). The median OS of high risk patients was 52 months versus 71 months for standard-risk (P=0.007). We then studied the prognostic value of the three tests separately. Patients classified as high risk by FISH had a median OS of 35 months versus 65 months for the standard risk, HR= 2.3, P<0.001. Similarly, cytogenetics alone was also able to classify patients into high and standard risk with a comparable HR of 2.1 (P=0.008, median survival 37 vs. 64 months). In contrast, PCLI did not have a significant prognostic value (HR =1.41, P=0.32). This was confirmed on multivariate analysis in a model that included all 3 tests. FISH (HR=2.36, P=0.001) and cytogenetics (HR=1.99; P=0.017) emerged as independent determinants of prognosis in the multivariable analysis, while PCLI (HR=1.03, P=0.93) did not provide additional prognostic value. We then examined whether the prognostic value of FISH contributed additionally in patients classified into high and standard risk by conventional cytogenetics, and vice versa. Those classified as high risk by cytogenetics (n=44, 11 %), were further categorized into 2 groups by additional prognostic information obtained by FISH (median survival 18 vs. 52 months; P=0.005). Similarly, those classified as standard risk by cytogenetics (n=342, 89 %), were further categorized into 2 groups (median survival 52 vs. 71 months; P=0.017) by additional FISH-based stratification. Similarly, high-risk patients defined by FISH (n=65, 17 %) were further classified into 2 groups with significant difference in median OS (18 vs. 52 months, P=0.004), based on the presence or absence of high-risk features on cytogenetics. In contrast, no additional prognostic information was gained by cytogenetics in patients who were stratified as standard risk by FISH alone (n=321, 83%). Conclusion Our study validates high risk features defined by FISH and conventional cytogenetics in the mSMART risk stratification model among patients treated after the introduction of novel therapies. Either test identifies a high risk cohort with a hazard ratio of approximately 2 (median survival ∼37 versus ∼65 months). In patients known to have high risk disease by one of the two tests, knowledge of the other appears to add additional prognostic value. Disclosures Fonseca: Amgen, BMS, Celgene, Otsuka, Genzyme and Medtronic: Consultancy. Gertz:celgene, millennium: Honoraria. Dispenzieri:celgene: Research Funding. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 946 Background: The emerging therapies directed at the plasma cell clone have dramatically increased overall survival (OS) for both myeloma and amyloidosis patient populations. As more treatment trials are done in patients (pts) with AL, benchmarks for outcomes among previously treated AL pts are required, especially for those pts who are not candidates for high-dose chemotherapy with peripheral blood stem cell transplantation (ASCT). Inadequate information is available about the number of non-transplant pts who go on to receive second line treatment for AL amyloidosis. Methods: To ascertain the outcomes of pts who did not receive ASCT as primary therapy but who required a second line of therapy, we reviewed the experience of pts seen at Mayo Rochester between 1990 and 2010 according to an IRB approved retrospective review protocol. 1828 pts had their first Mayo visit for AL during this time period. Pts were excluded from this study for the following reasons: 571 had upfront transplant; 907 pts had received only one line of treatment for their amyloid; 91 had longstanding other associated malignancy [Waldenstrom's macroglobulinemia (8), lymphoma (15), CLL (6), multiple myeloma (62)]; and 93 had inadequate follow-up information. One-hundred and sixty-six pts received 2 or more lines of therapy for their AL amyloid and are the subject of these analyses. Statistical analyses were done using JMP statistical software (SAS, Carey, NC). Results: Of the 166 pts, the median age was 64 years (range 34, 84). 49% were male. Baseline organ involvement was as follows: cardiac 84/166 (50%); renal 118/166 (71); liver 23/166 (13.8%); peripheral nerves 19/166 (11.4%); and gastrointestinal 14/166(8.4%). Thirty-one percent (52/16) had both cardiac and renal involvement. Only 73 pts had cardiac biomarkers (NT pro BNP and Troponin T) done at baseline. Of these pts, 26% were stage 1, 49.3% were stage 2, and 24.6% were stage 3 according to original Mayo cardiac biomarker staging system. By inclusion criteria definition, all 166 pts received 1st and 2nd line therapies; 53 (32%) pts received 3rd line of treatment; 20 (12%) received 4th line of treatment; and 10 (6%) received 5th line of treatment. For first line therapy, the most common drugs given either singly or in combination were corticosteroid (147/166; 88.5 %), alkylator (99/166; 59.6%), IMID (34/166; 20.4 %), and bortezomib (19/166; 11.4%). The median time from diagnosis to 2nd line therapy was 10.3 months. Second line regimens received included: corticosteroid, 108/166 (65.1%); alkylator, 76/166 (45.8 %); IMID, 46/166 (27.7%); and bortezomib, 46/166 (27.8%). The median time from diagnosis to 3rd line therapy was 19.8 months. For the 53 pts who received 3rd line treatment, regimens included: corticosteroid, 41/53 (77.3%); IMIDs, 17/53 (32.1%); alkylator, 17/53 (32.1%); bortezomib, 12/53 (22.6%). The median time from diagnosis to 4th line therapy was 31.8 months. For the 20 pts receiving 4th line treatment, regimens included: corticosteroids, 15/20(75%); alkylator, 12/20 (60%), bortezomib, 7/20 (35%); and IMIDs, 4/20(20%). Eighty-three pts have died. The 1 year mortality of our study population was only 8%. The median follow-up of surviving pts was 47.6 months. Figure 1 demonstrates Kaplan-Meier estimates of overall survival (OS) from initiation of each successive therapy. The median OS from initiation of 1st, 2nd, and 3rd lines of treatment were 65, 49.5 and 36.7 months respectively. The median OS after the 4th line of treatment was not reached. The 4 year OS rates from initiation of 1st, 2nd, 3rd and 4th lines of therapy were 58%, 50.8 %, 50 % and 53.4% respectively. Conclusion: Outcomes among relapsed or refractory AL pts are better than what one might expect. Multiple publications have demonstrated that the 1 year mortality of newly diagnosed AL is in the vicinity of 40%. Thereafter, the rate at which pts die dramatically decreases. Our study provides explicit data characterizing the fate of pts unfortunate enough to require additional therapy but fortunate enough to survive past the exceedingly high risk period of death that occurs within 6–12 months of diagnosis. These data provide useful information for benchmarking future trials for treatments of AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 194 Background: Immunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Recently, we demonstrated that CRBN expression is the major mediator of IMiD action operating at least in part via interferon regulatory factor 4 (IRF4), however the clinical significance of this finding remains unclear. Methods: To better understand clinical impact, we retrospectively reviewed 148 MM patients whose tumor cells were tested for CRBN expression by Gene Expression Profiling (GEP) prior to treatment with an IMiD containing therapy. Results: GEP studies show no significant differences in CRBN expression between MGUS, smoldering MM (SMM), untreated symptomatic MM and normal plasma cells. However, differences were observed between MM cell lines of varying drug sensitivity to IMiDs and between other B-cell Neoplasia (eg low grade lymphoma has higher levels). Within the genetic subtypes of MM, levels were significantly higher for hyperdiploid patients (median 1.26) as opposed to significantly lower levels for TC class D2 (median 0.76) and average for the 4p16 (median 0.97). We next screened the University of Arkansas Medical School (UAMS) GEP database of MM patients treated with combination therapies and did not find significant correlation between CRBN expression and survival in this multi-agent regimen. We then focused on patients that received only single agent IMiD therapy with low dose dexamethasone. Review of the twelve lowest expressing patients demonstrated a lack of response to IMiDs in any patient. Finally we analyzed 53 relapsed or relapsed/refractory patients treated homogeneously in a study with pomalidomide 2–4mg daily and weekly dexamethasone 40mg. CRBN levels were assessed prior to therapy initiation. Response rates varied significantly based on gene expression level. The percentage of patients that demonstrated at least a partial response was 0% for CRBN <0.81, 19% for CRBN expression of 0.81–0.90, and 33% for CBN expression >0.9. Significant differences in PFS (3.0 months vs. 8.9 months, p = 0.0006) and in OS (9.1 months vs. 27.2 months, p = 0.01) were observed when the lowest quartile of CRBN expression was compared to the top three quartiles. Values used for the cut offs are as follows: (25%: 0.889687; 50%: 1.026542, 75%: 1.211133). While this study demonstrates a positive correlation between CRBN expression and response to pomalidomide and dexamethasone, an important caveat with respect to PFS and OS is that CRBN mRNA level is primarily a reflection of the number of copies of CRBN. Since focal deletions are uncommon, this mostly reflects chromosome 3p copy number. Since trisomy 3 is common in hyperdiploid, good prognosis disease, CRBN not only is required for IMiD function but higher levels also serve as a surrogate for low risk disease. Optimal gene expression cut offs for survival were determined using the Contal and O'Quigley method. The optimal cut point for PFS was 1.18443 and for OS was 1.17816. Conclusion: In summary, this study demonstrates, for the first time, a clinical correlation between CRBN expression and response to IMiD and dexamethasone therapy. CRBN expression is also predictive of survival outcomes and when quantified prior to therapy could potentially be utilized as a predictive biomarker for response to an IMiD based treatment. Disclosures: Stewart: Celgene: Consultancy, Honoraria.

Abstract Abstract 1988 Background With the utilization of novel agent-based combination therapies and autologous stem-cell transplantation (ASCT) in multiple myeloma (MM), the rigorous response category of stringent complete remission (sCR) in the international uniform response criteria is increasingly becoming attainable. In addition to the standard criteria for complete remission (CR), sCR requires normalization of the free light chain ratio and disappearance of clonal cells as determined by the marrow immunofluorescence or immunohistochemistry. We have previously validated the new response category of sCR created in by the International Myeloma Working Group and demonstrated that sCR represents a deeper level of response, translating into a superior OS. Herein we report the survival outcomes of patients attaining sCR or standard CR, from a 2-year landmark after ASCT in a cohort of patients with extended follow-up. Additionally, we report the outcome of patients who remained in sCR for at least 6 months (sustained-sCR) after ASCT. Patients and Methods Maximal response rates of four hundred and forty-five consecutive patients who underwent ASCT within 12 months of diagnosis of MM were determined. The population achieving varying degrees of complete remission (n=237) is the focus of this study. We performed a landmark analysis 2 years after ASCT to ensure that all the patients attaining at least CR had sufficient time to reach the response levels being studied. Patients were categorized as having sustained sCR (sus-sCR) if the duration of sCR was at least 6 months. Overall survival (OS) was estimated by the Kaplan Meier method and the survival curves were compared by log-rank test. Results The median follow-up of the entire cohort was seventy-seven months (95% CI: 73–82 months). The sCR rate after ASCT was 24% (n=109). Median time to progression (TTP) of patients attaining sCR was 50 months from ASCT, and median overall survival (OS) is not reached, in contrast to those attaining standard CR (n=37, TTP=20 months, OS=81 months) or near CR/nCR (n=91; TTP= 19 months, OS=60 months, p<0.0001 for both TTP and OS). OS of patients surviving at least 2 years from ASCT (Figure 1a) continued to remain superior for those attaining sCR (n=105, median: not reached) versus 70 months for the CR group (n=32; p=0.004). Among patients achieving sCR (n=109), OS of patients with sus-sCR (n= 75) at 6 months from ASCT is not reached (5-year OS=91%, 7-year OS=86%) versus median OS of 66 months (5-year OS=49%, 7-year OS=37%; p<0.0001) for those who had non-sustained-sCR (n=34) after ASCT (Figure 1b). Conclusion In our landmark analysis of patients with MM who survived at least 2 years from ASCT, those attaining sCR have a markedly superior outcome compared to those attaining standard CR. However, among patients attaining sCR, those with sustained sCR of 6 months or greater had the best outcome. Myeloma trials reporting response rates should identify patients achieving sCR and CR separately owing to markedly disparate outcomes of the two categories. Disclosures: No relevant conflicts of interest to declare.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Abstract Introduction. Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular antitumor immune responses and tumor selectivity. VV1 also contains the human sodium iodide symporter (NIS) as an imaging gene. We report here the novel use of virus-encoded IFNβ as a PD marker using correlative data from three Phase I trials of VSV-IFNβ-NIS in patients with refractory cancers (n=46). Methods. 46 patients with solid tumors (n=34) and hematological malignancies (n=12) received 1 dose of VV1 either intratumorally (ITu) or intravenously (IV) at doses ranging from 3 x 106 to 5 x 1010 TCID50. Plasma IFNβ levels were collected pre-treatment, 4 hours post-infusion, Day 2 (24-hour), Day 3, 8, 15 and 29 (IT only). Samples were processed using a standard IFNβ specific ELISA kit. Results. ITu dose escalation is complete with 27 patients treated and no DLTs. IV escalation is ongoing at 5 x 1010 TCID50 with 19 patients treated to date. In the ITu study, plasma IFNβ levels at 24h were undetected at the lowest dose levels (up to 1 x 107 TCID50), and became detectable from 3 x 107 TCID50. In the IV patients, IFNβ was detectable at all dose levels (5 x 109 through 5 x 1010 TCID50) with the highest peak and longest duration in a patient with metastatic endometrial cancer coincident with shrinkage of multiple tumors. The IFNβ produced by virus-infected cells can be differentiated from the acute innate antiviral responses by magnitude of response and AUC as the majority of the inflammatory cytokines returned to baseline by 48h. Peak IFNβ levels were variable between patients, likely reflecting heterogeneity in tumor susceptibility to VV1, ranging from 1.4pg/mL to 656pg/mL across 6 patients (mean 153pg/ml) at the highest ITu dose. Plasma IFNβ 24 hours post-therapy of &gt;20pg/mL appears to predict for RECIST 1.1-evaluated SD vs PD, p=0.048 in the ITu patients. Peak IFNβ ranged from 18 to 1700 pg/mL across 9 patients (mean=442pg/ml) at 1.7 x 1010 in the IV study. Peak IFNβ was highest in two cases of endometrial cancer (1500 and 1700 pg/ml). The patient with the highest IFNβ levels on the IV trial showed 16.7% tumor shrinkage at the first tumor evaluation. SPECT imaging, which shows location of viral replication, was positive in 50% of ITu injected tumors, also validating of VV1 infection of target cells. To date, SPECT images were negative in the IV trial despite IFNβ positivity, reflecting IFNβ as a more sensitive PD marker of viral infection. IHC staining of tumor biopsies collected pre-treatment and 1 month after VSV showed increased numbers of CD3, CD8, CD68, PDL1 or PD1 in some injected or noninjected tumors. Other immune markers and tumor gene signatures are also being evaluated. Conclusions. Plasma IFNβ has emerged as a simple and convenient biomarker of viral replication in tumors. IFNβ will be used in future studies as a PD marker to assess the impact of immune-modulating combination drugs with VV1. Citation Format: Timothy P. Cripe, Jamie Bakkum-Gamez, Jaime R. Merchan, Martha Q. Lacy, Manish R. Patel, Steven Powell, James Strauss, Lianwen Zhang, Toshie Sakuma, Memy Diaz, Nandakumar Packiriswamy, Deepak Upreti, Bethany Brunton, Dragan Jevremovic, Stephen J. Russell, Alice Bexon, Kah-Whye Peng. Rational design of an oncolytic virus permits use of interferon beta as a pharmacodynamic marker for clinical application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT090.

Summary Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis ( n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.