Assessment of Options for Patients with RRMM with Triple-Class Exposure: Literature Review Indicates Urgent Need for New Treatments

2020 Year in Review - Multiple Myeloma - Multiple Myeloma

Poor response on subsequent therapies is typically seen in 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. In addition, challenges for future treatment options are presented.

In January 2020, a systematic literature review was performed in the Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases. This review also included a search of US National Library of Medicine ClinicalTrials.gov and pertinent 2018-2019 conference archives. Also included in the review were studies performed ≤5 years before. The quality of randomized controlled trials (RCTs) was assessed by the Risk of Bias Instrument, and the study quality of non-RCTs was assessed by the Downs and Black checklist. 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.

There were 24 relevant studies established by the literature search. Included were 13 clinical trials and 11 real-world studies. Ten real-world studies, including a total of 235 patients, were limited because of bias risk, data restricted to abstract only, and undesirable outcome results with overall response rates (ORRs) not typically >30% and overall survival (OS) rates ≤10 months. Included was the Monoclonal Antibodies in Multiple Myeloma: Outcomes After Therapy Failure (MAMMOTH) study, which was a large, real-world study. This retrospective chart review evaluated 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 transplantation. The first subsequent regimen after anti-CD38 antibody treatment resulted in a 31% ORR; ORR rates were 29% and 30% in those who were triple refractory or quadruple refractory and in the patients who were penta refractory, respectively. Patients who received ≥1 subsequent therapies experienced median progression-free survival (PFS) of 3.4 months and OS of 8.6 months after subsequent treatment. Other real-world study data included in the review reported ORRs ranging from 23% to 90%, complete response (CR) 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.

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

Included in the literature review were a phase 1, dose-finding trial, DREAMM-1, and a phase 2 trial, DREAMM-2, that assessed belantamab mafodotin. In the DREAMM-1 study, 35 patients who had previously received alkylators, PIs, an IMiD, and a stem-cell transplant, if eligible, were included. Approximately 40% of the patients had previously been exposed to daratumumab. Patients received 3.4 mg/kg every 3 weeks. In the DREAMM-2 study, 196 patients who were refractory to previous triple-class treatment including a PI, an IMiD, and an anti-CD38 antibody were included. Patients received either 2.5 mg/kg or 3.4 mg/kg every 3 weeks. In DREAMM-1, the ORRs were 60% and both 31% and 34% in the 2.5-mg/kg and 3.4-mg/kg groups, respectively. The CR rates were 14.3% and 3.0% in both groups in DREAMM-1 and DREAMM-2, respectively. Median DOR rates were 14.3 months and not reached in DREAMM-1 and in DREAMM-2, respectively. Median PFS rates were 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.

Results from the systematic literature review that investigated evidence to support treatment measures in patients with RRMM after >3 lines of prior treatment suggest limited efficacy data to guide the treatment of this challenging patient population. Effective and safe, new therapy options are urgently needed by patients who have progressed through available treatment options without significant response.

Reference
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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