Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study

8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time < 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383

Time to Relapse and the Patterns of Relapse Are Prognostic for Post-Relapse Survival after CD34+-Selected Allogeneic Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Allogeneic hematopoietic stem cell transplantation (HCT), defined by its underlying graft-versus-multiple myeloma (MM) effect, is a potentially curative approach for high-risk pts. However, relapse remains the main cause of treatment failure. Predictors for post-relapse survival after HCT are not well characterized, and we hypothesized that the time to relapse and the patterns of relapse are prognostic for post-relapse survival. Methods: All pts with MM who underwent a CD34+-selected alloHCT at Memorial Sloan Kettering Cancer Center on protocol (NCT 01131169/01119066) or off study from 01/2010 to 12/2017 and progressed after alloHCT were included. Pts were conditioned with busulfan (0.8 mg/kg x 10), melphalan (70 mg/m2 × 2), and fludarabine (25mg/m2 × 5). The K-M method was used to estimate OS post-HCT relapse. Significant predictors were considered in a Cox model. Results: Of the 115 transplanted pts, 60 (52%) relapsed and were analyzed. The median age was 56 yrs (35- 66), 62% male and 82% with high-risk cytogenetics (CG). KPS was ≥ 80 in 100% and ≥ 90 in 52%. Pts received a median of 4 lines of therapy pre-HCT (1-10), with 88% achieving at least a partial response (PR) prior to alloHCT. All pts had received at least one autoHCT. Of the 38% who received a planned or preemptive post-HCT therapy, 13 received DLI and 10 other strategies. Relapse was characterized as very early (24 mo, 22%). At relapse, 27% presented with extramedullary disease (EMD). Median post-relapse OS was significantly different for pts who relapsed very early, early, or late; 4 mo, 17 mo, and 72 mo, respectively (p = 0.002). Age ≥55, relapse with EMD, lower KPS, <PR prior to HCT, <PR by day 100, and no maintenance were also prognostic for worse post-relapse OS in univariate analysis. There was no significant difference for post-relapse OS for number of lines, high-risk CG, or era of alloHCT. In multivariate analysis adjusting for sex and age, risk factors for worse post-relapse OS included very early (HR 4.4, 95%CI 1.4-13.5) or early relapse (HR 2.5, 95%CI 1.4-13.5), relapse with EMD (HR 5.2, 95%CI 2.1-12.9), and lack of DLI as planned post-HCT therapy (HR for DLI compared with no DLI = 0.11, 95%CI 0.01-0.9). Conclusion: For this very high-risk group of MM pts, differences in time to relapse after alloHCT define very distinct post-relapse survival patterns. Very early relapses were associated with greater chemoresistance and dismal prognosis. In contrast, the median post-relapse OS for late relapses was 6 yrs, suggesting different underlying disease biology and/or host/donor characteristics. Similar to the post-auto setting, relapse with EMD conferred poor prognosis. Of note, post-relapse OS was superior for pts who received a DLI as planned post-HCT therapy prior to relapse. Efforts to characterize optimal post-relapse therapeutic strategies and mechanism(s) driving relapses are ongoing

Evaluating serum-free light chain ratio as a biomarker for multiple myeloma

8047 Background: In 2014, the definition of multiple myeloma was updated to include serum free light chain (FLC) ratio ≥100 as a myeloma defining biomarker, based on retrospective data indicating a 2-year progression rate of 80% and a median time to progression (TTP) of 12 months associated with this marker. However, two recent studies have reported lower 2-year progression rates, 30-44%, and longer median TTP of 40 months in patients with FLC ratio ≥100. Because of the disparity in risk prediction by FLC ratio across studies, we were motivated to assess the risk of progression in patients with SMM and a FLC ratio ≥100. Methods: We performed a retrospective analysis of patients diagnosed with SMM at Memorial Sloan Kettering Cancer Center between January 2000 and December 2017. Diagnosis of SMM and progression to MM was defined according to the International Myeloma Working Group (IMWG) criteria at the time of diagnosis. Kaplan-Meier method was used to assess TTP and generate survival curves, with log-rank test for comparison between groups. Results: A total of 438 patients were included in the study, with a median follow-up time of 52 months. While all patients with a FLC ratio ≥100 (n = 66) had elevated involved FLC levels, 35 (53%) had an involved FLC concentration > 100 mg/L. Per current diagnostic criteria, we only included patients with an involved FLC concentration > 100 mg/L in the FLC ratio ≥100 group, and found a median TTP of 31 months (95% confidence interval [CI] 16-59 months) and a 2-year progression rate of 49% (CI 28-63%). In a sensitivity analysis including all 66 cases with FLC ratio ≥100 (independent of involved FLC concentration), we found the median TTP to be 41 months (CI 30-72 months), compared to 101 months for those with a FLC ratio 4 years, among whom 12 patients had an involved FLC level > 100 mg/L. Ten patients (7 with involved FLC level > 100 mg/L) were followed over a period ranging from 4 to 8.5 years before eventually progressing, and 12 patients (5 with involved FLC level > 100 mg/L) were followed between 4 and 8 years and did not progress during the study period. Conclusions: While FLC ratio ≥100 is associated with a high risk of progression in patients with SMM, it does not infer an imminent risk of progression, defined by the IMWG as median TTP of 12 months and 2-year progression rate of at least 80%. On the contrary, select patients with FLC ratio ≥100 can be followed for many years without progressing and some may never progress despite long-term follow-up. These findings suggest that in patients where FLC ratio ≥100 is the only myeloma-defining event, other high-risk features as well as the evolution of FLCs over time should be considered in the decision to start a patient on treatment

African American patients with smoldering multiple myeloma may have a lower risk of progression compared to White patients

8045 Background: The incidence of multiple myeloma (MM) is two to threefold higher in African Americans (AAs) compared to whites when adjusted for socioeconomics, age, and sex. However, there is limited information on whether racial background affects the risk of progression from smoldering MM (SMM) to MM. Methods: Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2019 and who identified as either AA or white were included in the study. Baseline characteristics were collected at the time of diagnosis including laboratory, imaging, and pathology reports. Differences in distributions of continuous and discrete characteristics were assessed by Kruskal-Wallis and chi-square tests. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Univariate and multivariate Cox proportional hazard models were used to estimate effects of risk factors on TTP with hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 576 patients were included (70 were AA, 12%). Median follow-up time was 3 years in AAs and 4 years in whites. Differences in baseline characteristics between AAs and whites included median age (60 years in AAs vs 64 years in whites, p = 0.01), median hemoglobin level (12.3g/dL in AA vs 12.8g/dL in whites, p = 0.02), and immunoparesis including 1 or 2 uninvolved immunoglobulins (31% and 10% in AAs vs 56% and 27% in whites, p = 0.002). There was no difference in bone marrow plasma cells, M-spike, free light chain ratio, or Mayo-2018 SMM risk score. AA race was associated with a significantly decreased risk of progression in the univariate model (HR 0.57, CI 0.34-0.94). In the multivariate model adjusting for age, sex, and variables associated with an increased risk of progression in the univariate model (bone marrow plasma cells, M-spike, free light chain ratio, immunoparesis and low albumin), AA race remained associated with a decreased risk of progression (HR 0.39, CI 0.16-0.95). Overall, AA patients with SMM had a significantly (p = 0.027) longer median TTP (9.7 vs 6.2 years), and a lower 2-year (12.6% vs 20.1%) and 5-year (34% vs 44.6%) progression rate than whites. Because AA patients were younger at diagnosis, we stratified patients by age group, < 65 vs ≥65 years. In patients < 65 years, there was no difference in progression rate. In patients aged ≥65 years, AA patients continued to have a longer TTP than whites (9.8 vs 5.2 years, p = 0.02). Conclusions: In our retrospective single institution experience, AA patients with SMM had a lower risk of progression to MM compared to whites. Both groups had similar Mayo-2018 risk scores, however, AA patients had a lower degree of immunoparesis at baseline. Future studies are needed to better understand if these differences are explained by differences in disease biology including genomic mechanisms, immune microenvironment, and systemic immune response