Gertz, Morie A.

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 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.

Abstract Abstract 1364 In light chain (AL) amyloidosis, as well as in multiple myeloma, response to treatment is increasingly being used as a surrogate endpoint in clinical trials. In 2005 a consensus statement of the International Society of Amyloidosis (ISA) established the criteria for hematologic and organ response. Since then, several studies emphasized the prognostic relevance of the measurement of the amyloidogenic precursor, the circulating free light chain (FLC). Moreover, it was reported that patients who with treatment achieved decreases in the cardiac biomarker N terminal natriuretic peptide type B (NT-proBNP) had longer survival, although echocardiographic criteria of response were not attained. The ISA Consensus Panel reconvened in 2010 to update hematologic and organ response criteria. The panel felt that any new criteria should be validated in a large patient population. Thus, we systematically gathered from 7 referral centers in Europe and in the United States a cohort of 649 patients with systemic AL amyloidosis who had been evaluated for hematologic and organ responses at diagnosis and 6 months after treatment initiation, excluding patients who died earlier. At diagnosis, 430 patients (66%) had heart involvement, 377 (58%) had NT-proBNP ≥650 ng/L, 455 (70%) had renal involvement (95, 15%, with glomerular filtration rate <30 mL/min) and 100 (15%) had liver involvement. Two-hundred eighty-nine patients (44%) were treated with melphalan and dexamethasone, 118 (18%) received thalidomide based therapy, 73 (11%) underwent autologous stem cell transplant, 35 (5%) were treated with regimens including lenalidomide, 20 (3%) received bortezomib-based therapy, and the rest received other alkylating agents, nucleoside analogues or dexamethasone. The median follow-up of living patients was 24 months, and 233 patients (34%) died. The ability of response criteria to identify patients who died was compared by evaluating the areas under Receiver Operator Characteristic curves based on death at 1 year, and by calculating the Harrell C statistic and the Royston explained variation. Survival was calculated from the time of evaluation of response. We maintained the category of complete response (CR: negative serum and urine immunofixation, normal FLC kappa/lambda ratio and normal marrow studies) and examined candidate criteria for partial (PR) and very good partial responses (VGPR), based on percentage changes or absolute values achieved after treatment of involved (amyloidogenic) FLC (iFLC), and alternatively on the difference between iFLC and uninvolved FLC (dFLC). With respect to cardiac response and progression, NT-proBNP-based criteria were defined as a decrease or an increase of both >30% and >300 ng/L, and a threshold of evaluability based on NT-proBNP baseline level >650 ng/L was chosen. The most powerful criteria for PR were those based on dFLC percent decrease, and a 50% cutoff was preferred because of easier clinical use. Among candidate criteria for VGPR, the best were based on iFLC absolute value achieved after therapy, but the performance of those based on dFLC absolute value was only slightly lower. Therefore, a definition of VGPR based on dFLC (<40 mg/L) was adopted for the sake of harmonization with the dFLC-based definition of PR. The adopted hematologic response criteria and their prognostic significance are reported in Table 1. These criteria identified 4 groups with significantly different survivals (Figure 1). Also the proposed criteria of NT-proBNP response and progression were significantly associated with survival (Figure 2). Our 2010 revised consensus criteria for hematologic response include maintenance of the definition of CR, and with use of dFLC re-casting the definition of PR and introducing a VGPR category, and for cardiac response and progression introducing the use of changes in NT-proBNP levels. In a further analysis we will address the definition of measurable dFLC at baseline and evaluate the applicability of the response criteria to earlier evaluation of response. The revised criteria improve the framework for clinical research in AL. Disclosures: Off Label Use: Thalidomide, lenalidomide, bortezomib for systemic AL amyloidosis. Dispenzieri:The Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria.

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.

AbstractIntroductionAmyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild‐type ATTR) throughout the body. Two new therapies—inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy—received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR.MethodsA PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR.ResultsUntil recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early‐ and late‐stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early‐stage disease, and tafamidis, indicated for the treatment of early‐stage disease in Europe, or diflunisal, a nonsteroidal anti‐inflammatory drug that is used off‐label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities.ConclusionsImportant differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.