Citations

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.

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]

AbstractMetaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

e19519 Background: NSMM is a rare subtype of myeloma that has not been well characterized in the era of novel agent induction therapy. Thus, we evaluated the clinical and cytogenetic features of patients with newly diagnosed NSMM evaluated at our institution. Methods: We evaluated all NSMM patients seen at the Mayo Clinic, Rochester from 2008-2017 based on the absence of a detectable monoclonal protein in their serum and urine electrophoresis and having a concurrent involved serum immunoglobulin light chain of less than 5 mg/dL. Survival analysis was performed by the Kaplan-Meier method and clinical and cytogenetic features were reported descriptively. Results: This cohort consisted of 30 consecutive patients with NSMM with a median age of 62 years (40-79) of which 16 (53%) were male. The median bone marrow plasma cell involvement was 70% (Range: 0 – 100). There were 3/25 (12%) patients who presented with a creatinine of 2 mg/dL or greater and 6/23 (26%) patients who presented with hypercalcemia (11 mg/dL or greater). The ISS classification of this cohort is as follows: Stage 1- 8 (36%) patients, Stage 2- 3 (14%) patients and Stage 3- 11 (50%) patients. There were 6 (21%) out of 28 patients with high risk cytogenetics (either del 17p, t(4;14), t(14;16) or t(14;20). The distribution of primary cytogenetic abnormalities among this cohort was as follows: t(11;14) – 16 (57%), t(4;14) – 1 (4%), trisomies – 6 (21%) and other - 5 (13%). The median overall survival (OS) for patients in this cohort was 59 months (95% CI: 34 – 64). In comparison to a control cohort of newly diagnosed secretory myeloma patients matched for age, gender and year of diagnosis in a 1:2 ratio, the median OS was worse for the NSMM cohort but this was not statistically significant (59 vs. 92 months, p = 0.257). Conclusions: Patients diagnosed with NSMM had a predisposition towards having a t(11;14) primary cytogenetic abnormality. In the era of novel agent induction therapy, they may have a survival outcome that may be worse than newly diagnosed secretory myeloma patients.

8039 Background: Treatment of MM has evolved significantly over the past decade, with increasing use of multi-drug combinations for initial therapy. In addition, supportive care approaches have also improved. We examined how these improvements have translated to survival outcomes in patients with newly diagnosed MM. Methods: Patients (n=3449) with a diagnosis of MM made between 2004 and 2017 and seen at Mayo Clinic within six months of the diagnosis, were included in this analysis. Patients were divided into three groups based on the year of diagnosis; group 1- 2004-07 (n=831), group 2-2008-12 (n=1161), and group 3-2013-17 (n=1457). Survival of the groups were estimated using Kaplan-Meier method, and compared using log rank test. Results: The median age was 64 years (22 to 96); 60% were male and 40% were female. 14% were >75 years, 33% were aged 65-75 and 53% were <65 years. The median overall survival for the whole cohort was 5.7 years (95%CI; 5.4, 6.3). The median OS for the groups 1, 2 and 3 were 3.9, 6.3 and NR, respectively; p<0.001. The 4-year survival estimates were 50%, 62%, and 75%, respectively. We then explored the improvements in patient subgroups. While all patients experienced improvements in OS over time, improvement in group 3 was most prominent for those >75 years. In patients <65 years, the 4-yr OS for groups 1, 2 and 3 were 57, 71, and 79% respectively. In patients 65-75 years of age, the 4-yr OS for groups 1, 2 and 3 were 48, 60, and 75% respectively. In patients >75 years, the 4-yr OS for groups 1, 2 and 3 were 24, 35, and 56% respectively. While patients with high-risk disease did not see as much benefit in the earlier period, substantial progress was seen in the last group. The 3-yr OS for patients with high-risk cytogenetics were 52, 55, and 73% for groups 1, 2 and 3 compared to 67, 75, and 85% for standard-risk cytogenetics respectively. 2067 patients were staged according to the International Staging System and the median OS for stages 1, 2 and 3 were 6.5, 4.6 and 2.4 in group 1; 9.2, 6.6 and 3.5 in group 2 and NR for any of the stages in group 3. Conclusions: The results confirm continued improvement in survival of newly diagnosed multiple myeloma patients, including elderly and high-risk MM.

8034 Background: Minimal residual disease (MRD) assessment in multiple myeloma (MM) has improved our ability to assess disease activity, resulting in more advanced prognostication. While MRD assessment remains confined to the bone marrow (BM) plasma cell population, serum studies including immunofixation (IFE) are required to complete response evaluation. The significance of those who are MRDneg yet have detectable monoclonal protein through IFE remains unclear. Methods: We retrospectively studied 256 MM patients who had MRD assessment via the Euroflow multiparametric flow cytometry on the BM with concomitant serum IFE testing. Patients who were MRDneg were included in the study. Outcomes included probability of disease progression (PD) at 1 year. The Cox-proportional hazards model was used to compare probability of PD among different groups. Time to progression (TTP) was calculated as the difference from date of MFC analysis to PD in months. Results: Among the entire cohort, 178 (70%) patients were MRDneg and median follow-up from MRD assessment was 6.3 months. Among these patients, 74 (42%) had a positive IFE at the time of MRD analysis. Within the MRDneg/IFEpos group, 31 (42%) patients remained IFEpos after a median follow up of 5.5 mo from initial MRD/IFE testing while 34 patients eventually became IFEneg after a median of 2.8 mo with no subsequent IFE available in 9 patients. The 1 year probability of PD in the MRDneg/IFEneg group was 20% compared to 41% in the MRDneg/IFEpos group (P < 0.01, Wilcoxon test). When comparing subsequent IFE status in those who were MRDneg/IFEpos, those who remained IFEpos had a trend towards shorter TTP compared to patients who later became IFEneg. Conclusions: Persistent monoclonal protein in the face of MRD negativity predicts for a shorter TTP. This likely reflects persistent disease that was not sampled on the BM aspirate in many of these patients compared to those who eventually become IFEneg with a trend towards longer TTP owing to the prolonged half-life and therefore clearance of M protein. This supports the current strategy of assessing for MRD at the time of suspected complete response to reduce the chance of positive MRD tests and thus avoidance of multiple BM exams.

8031 Background: Our prior studies identified the prognostic significance of ≥400 cPCs/150,000 analyzed events quantified by MFC in NDMM. We evaluated if a similar quantification of cPCs using MFC can add prognostic value to the current R-ISS classification of NDMM pts. Methods: We evaluated all NDMM pts seen at the Mayo Clinic, Rochester from 2009-2017 who had their peripheral blood samples evaluated by 6-color MFC prior to therapy. The cPCs detected were reported as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 566 consecutive pts with NDMM with a median age of 66 years (27-95). The distribution of the R-ISS classification of this cohort is as follows: Stage 1- 128 (23%) pts, Stage 2- 369 (65%) pts and Stage 3- 69 (12%) pts. The median number of cPCs was 59 (0-46,412) / 150,000 events. The median time-to-next-treatment (TTNT) and overall survival (OS) for pts with ≥400 cPCs (n = 140, 25%) was 19 months and 46 months compared with 34 months and 77 months for those with < 400 cPCs respectively (n = 426, 75%) (p < 0.001 for both). The median TTNT and OS for pts based on their R-ISS classification as well as with and without the presence of ≥400 cPCs by MFC was as follows in the following Table. Conclusions: Quantifying ≥400 cPCs/150,000 analyzed events by MFC can potentially upstage the R-ISS classification of a subset of NDMM pts with stage I and II disease and identify those pts with a worse than expected survival outcome.[Table: see text]

8019 Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF > 200 pg/ml, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.