ALBERT

Description: Introduction In the last 3 years, 4 new drugs indicated for MM have been approved, positively affecting the prognosis of patients with this disease. While these novel therapies offer therapeutic options to patients who have failed other treatments, adoption of new agents has historically lagged in African Americans, potentially limiting improvement in outcomes for this population. One of the newer drugs is daratumumab, a fully human anti-CD38 monoclonal antibody, first approved in November 2015 to treat relapsed or refractory disease in 3rd and 4th lines of therapy (LoTs). We sought to examine differences in daratumumab uptake stratified by race and identify factors associated with use of this drug in the real world. Methods This retrospective cohort study used information from the Flatiron Health (FlH) database, which is derived from pooled electronic health record (EHR) data; Institutional Review Board approval with a waiver of informed consent was obtained. The cohort included 3240 patients followed for MM from 11/16/2015 to 05/31/2018 across the United States and was limited to patients with a confirmed diagnosis of MM, who received at least one LoT starting on 11/16/2015 or later, and who were white or African American. Patients whose start of MM treatment (captured through chart review) was 〉 30 days before the start of structured activity in the FlH database were excluded as this may indicate missing therapy data. The proportion of LoTs including daratumumab stratified by year of LoT start was plotted for African-American and white patients. P values were calculated using chi-squared and Kruskal-Wallis tests. Results African-American patients were less likely to receive daratumumab for any LoT than white patients (12.1% vs. 15.4%, P = 0.041). Daratumumab uptake increased year by year, but net adoption lagged in African-American patients compared to white patients (Figure). For LoTs with a start date in 2015 (after 11/16/2015), 2.0% of those received by African-American patients included daratumumab, compared to 2.5% of those received by white patients. For the first 5 months of 2018 (before 05/31/2018), these percentages increased to 15.8% for African-American patients and 16.8% for white patients. Patients receiving daratumumab for any LoT were more likely to be younger at diagnosis (median age 66 years, IQR: 59-73 years vs. 70 years, IQR: 62-77 years; P 〈 0.001) and to be followed at academic centers than at community clinics (13.8% vs. 10.4%, P = 0.031). Consistent with previous literature, African-American patients in this cohort were younger at diagnosis than white patients (median age at diagnosis 67 years, IQR: 59-74 years vs. 70 years, IQR: 62-77 years; P 〈 0.001), and fewer were followed at academic centers (7.3% vs. 11.8%, P = 0.001). Conclusions While the absolute difference in daratumumab utilization is modest, this disparity has persisted over the last 3 years, with African-American patients lagging behind white patients. This trend may indicate inequities in access to and utilization of expensive newer treatments, which is particularly notable because of the higher incidence of MM in African Americans. Our study was limited as it did not control for gender, regional differences, cytogenetics, or insurance type. Further research is also required to determine if the observed treatment differences are associated with differences in clinical outcomes. To our knowledge, this is the first study to examine racial disparities in daratumumab uptake using recent, EHR-derived data from the real world. Disclosures Maignan: Flatiron Health: Employment. Backenroth:Flatiron Health: Employment. McQuarrie:Flatiron Health: Employment. Lipitz:Flatiron Health: Employment. Williams:Flatiron Health: Employment. Carson:Flatiron Health: Employment.

Description: Background: Melphalan in combination with dexamethasone is an active and the standard regimen in AL amyloidosis. Unfortunately very often patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent approved for the treatment of CLL, NHL, and MM in Europe and the US. But its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an updated unplanned interim analysis. First data were reported at ASH 2014 (Abstr.3480). Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ³ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR). Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59-15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 - 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. The duration of each cycle was 28 days. Results: As of 7/15/15, 26 patients have received treatment and 28 patients have been enrolled. Median age of enrolled patients was 66 (range 44-77). Enrolled patients received a median of 1.5 prior regimens (range 1-4). Twelve of the enrolled patients received prior autologous stem cell transplant. Median number of cycles for treated patients is 3.5 (range is 1-12), with 4 patients still receiving treatment. Of note, only 2 patients discontinued treatment due to disease progression. Only 9 patients discontinued treatment due to AE. Most common drug-related AEs (all grades, 〉25%) included fatigue (39%), nausea (35%) and Anemia (27%),. No grade ≥3 drug-related AE occured in 〉20% of patients. Of note, no cardiac events were observed, including any increase in NT-proBNP.Of 24 patients eligible for response evaluation, 11 (46%) have responded hematologically, including (≥PR 42%, CR 4%). The median time to best response of treatment (partial response or better) was 1.57 months (range 0.97 to 15.1 months). The CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. Better responses were especially observed in less heavily treated patients. With a median follow-up of 13.4 months (range 1.5 to 30.3 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.5 months (95% CI,1.5-29.1months) (Figure 2). Conclusions: In our updated unplanned interim analysis we found that Bendamustine in combination with dexamethasone is feasible and effective in pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events related to Bendamustine were not observed. Preliminary hematologic response rates are promising in this pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Axiom: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Will discuss the use of Bendamustine and Dexamethasone under clinical trial NCT01222260. Comenzo:Takeda Millennium: Research Funding; Prothena: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Osman:Millennium / Takeda: Research Funding.

Description: Background: Melphalan is an alkylator and in combination with dexamethasone an active and standard regimen in AL amyloidosis. However these patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent with established efficacy in CLL, NHL, and MM but its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an interim analysis. Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ≥ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR) of patients who received at least 2 cycles of therapy. Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59 – 15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 – 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. Results: As of 7/15/14, 15 patients have received treatment. Median age was 66.5 (range 43-76). Patients received a median of 2 prior regimens (range 1-4). Six patients received prior autologous stem cell transplant. Median number of cycles is 3.5 (range is 1-9), with 5 patients still receiving treatment. Of note, only 1 patient discontinued treatment due to disease progression. Only 3 patients discontinued treatment due to AE. Most common drug-related AEs (all grades) included fatigue (67%), nausea (53%), anemia, constipation and dyspnea (47% each), limb edema and increased creatinine (40% each). Grade ≥3 AE occurring in 〉25% of patients were only fatigue and chronic kidney disease (27% each). Of note, no cardiac events were observed, including any increase in NT-proBNP. No deaths have occurred in association with the treatment. Of 11 patients eligible for response evaluation, 5 (45%) have responded hematologically, including (≥PR 36%, CR 9%). Median time to PR was 2 cycles and the CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. With a median follow-up of 8.7 months (range 1.4 to 18.6 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.2 months with a range of 0.4-15.7 months (Figure 2) Conclusions: Bendamustine in combination with dexamethasone is feasible and effective in heavily pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events were not observed. Preliminary hematologic response rates are promising in this heavily pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Lentzsch: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding. Off Label Use: Bendamustine treatment in amyloidosis .