Literature Review to Assess Options for RRMM Patients with Triple-Class Exposure Indicates Urgent Need for New Treatments

Patients with relapsed/refractory multiple myeloma (RRMM) who have had 3 prior lines of therapy with immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies typically respond poorly on subsequent therapies and present challenges for future treatment options. A systematic literature review was performed in January 2020 in the Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases, and also included a search of US National Library of Medicine as well as pertinent 2018-2019 conference archives. Studies performed ≤5 years prior were included in the review. The Risk of Bias Instrument was used to assess the quality of randomized controlled trials (RCTs), and the Downs and Black checklist was used to assess study quality of non-RCTs. The goal of the literature review was to identify published data supporting options for patients with RRMM who have had previous triple-class treatment exposure, including an IMiD, a PI, and an anti-CD38 antibody.

The literature search established 24 relevant studies, including 13 clinical trials and 11 real-world studies. Ten real-world studies, including a total of 235 patients, were limited due to bias risk, data restricted to abstract only, and undesirable outcome results with overall response rates (ORRs) seldomly above 30% and overall survival (OS) rates not exceeding 10 months. A large, real-world study, the Monoclonal Antibodies in Multiple Myeloma: Outcomes After Therapy Failure (MAMMOTH) study, was included. It was a retrospective chart review of 275 patients from 14 US academic centers, all of whom were daratumumab or isatuximab refractory and most of whom had undergone prior anti-CD38 treatment. Patients had received a median of 4 lines of therapy and 72% had received autologous stem-cell transplant. The first subsequent regimen following anti-CD38 antibody treatment resulted in a 31% ORR. The ORR was 29% in those who were triple- or quadruple-refractory and 30% in the penta-refractory patients. Among patients who received at least 1 subsequent therapy, they experienced median progression-free survival (PFS) of 3.4 months and OS of 8.6 months after subsequent treatment. The other real-world studies included in the review reported ORRs ranging from 23% to 90%, complete response rates between 3.2% and 21.0%, median PFS between 2.2 months and 7.0 months, and median OS ranging from 5.8 months to 16.0 months.

The literature search found three phase 2 clinical trials that examined treatment regimens that have either been granted FDA approval or are currently being reviewed for approval. The STORM study, parts 1 and 2, evaluated the combination of selinexor and dexamethasone. In STORM 1, 79 patients were included who had received ≥3 prior regimens; the number of regimens ranged from 3 to 17 and the median was 7. In STORM 2, 122 patients were included who had previously undergone treatment with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylator, and glucocorticoids. Patients were disease refractory to at least 1 IMiD, a PI, daratumumab, or glucocorticoids and their most recent regimen (ie, patients who were triple-class refractory to daratumumab, an IMiD, and a PI). STORM 1 reported the ORR as 21% and the median duration of response (DOR), median PFS, and median OS as 5 months, 2.3 months, and 9.3 months, respectively. STORM 2 led to an ORR of 26%. Approximately 2% of patients experienced complete response, and the median DOR was 4.4 months, the median PFS was 3.7 months, and the OS was 8.6 months.

The literature review also included DREAMM-1, a phase 1, dose-finding trial, and DREAMM-2, a phase 2 trial that both assessed belantamab mafodotin. DREAMM-1 included 35 patients who had previously received alkylators, PIs, an IMiD, and a stem-cell transplant if eligible. Approximately 40% of the patients had previously been exposed to daratumumab. Patients received 3.4 mg/kg every 3 weeks. DREAMM-2 included 196 patients who were refractory to previous triple-class treatment including a PI, an IMiD, and an anti-CD38 antibody. Patients received either 2.5 mg/kg or 3.4 mg/kg every 3 weeks. The ORR was 60% in DREAMM-1 and 31% and 34% in the 2.5-mg/kg and 3.4-mg/kg groups, respectively. The complete response rate was 14.3% in DREAMM-1 and 3% in both groups in DREAMM-2. The median DOR was 14.3 months in DREAMM-1 and not reached in DREAMM-2. The median PFS was 12 months, 2.9 months, and 4.9 months in DREAMM-1, DREAMM-2 2.5 mg/kg, and DREAMM-2 3.4 mg/kg, respectively. Grade 3/4 adverse events were most often hematologic or keratopathy, which was the most common reason for treatment discontinuation.

The results of the systematic literature review investigating evidence to support treatment measures in patients with RRMM after >3 lines of prior treatment suggest there are limited efficacy data to guide the treatment of this challenging patient population. Patients who have progressed through available treatment options without significant response are in urgent need of effective and safe new therapy options.

Abstract and Poster EP1033. EHA 2020. June 12, 2020. A systematic literature review to assess efficacy of treatments in triple-class exposed relapsed and refractory multiple myeloma patients.

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