Background
On the basis of the DREAMM‐2 study (ClinicalTrials.gov identifier NCT03525678), single‐agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple ...myeloma (RRMM) who received ≥4 prior therapies, including anti‐CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM‐2 after 13 months of follow‐up among patients who received belamaf 2.5 mg/kg.
Methods
DREAMM‐2 is an ongoing, phase 2, open‐label, 2‐arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti‐CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee.
Results
As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty‐one of 97 patients (32%; 97.5% confidence interval CI, 21.7%‐43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression‐free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6‐3.6 months), respectively. Response and survival outcomes in patients who had high‐risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow‐up.
Conclusions
Extended follow‐up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.
Extended follow‐up of patients enrolled in the ongoing phase 2 DREAMM‐2 study confirms sustained clinical activity without new safety signals in patients with relapsed or refractory multiple myeloma who receive belantamab mafodotin 2.5 mg/kg every 3 weeks. These data show that belantamab mafodotin has the potential to shift the treatment paradigm in this heavily pretreated, anti‐CD38 monoclonal antibody–exposed patient population, which has a poor prognosis and few alternative treatment options.
Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or ...refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.
DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing.
Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 27% of 95 patients in the 2·5 mg/kg cohort and 21 21% of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 20% and 33 33%), and anaemia (19 20% and 25 25%); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort).
Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
GlaxoSmithKline.
Objectives and Methods
We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real‐world practice.
Results
A ...total of 187 patients with RRMM were included in the analysis; 128 patients received DPd, and 59 patients received DKd. A vast majority (80%) of patients had lenalidomide refractory disease and nearly 50% had bortezomib refractory disease. The overall response and complete response rates were 76% and 34% in the DPd group versus 80% and 51% in the DKd group, respectively. With a median follow up of 36 months for the entire patient population, median PFS and OS in the DPd versus DKd groups were 12, 12, 37, and 35 months, respectively. The most common grade 3+ adverse events in the DPd versus DKd groups were neutropenia (32% vs. 7%), anemia (14% vs. 10%), thrombocytopenia (13% vs. 15%), and cardiovascular events (4% vs. 15%), respectively. Both DPd and DKd appeared to be a safe and effective treatment options for RRMM.
Conclusions
While there were more cytopenias associated with DPd and more cardiovascular side effects with DKd, there were no significant differences in the survival outcomes with these two regimens.
Many patients with plasma cell disorder (PCD) on active treatment with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) require hospitalization, with an increased mortality rate over ...healthy adults. The FDA approved two mRNA vaccines against SARS‐CoV‐2: BNT162b2 and mRNA‐1273. To assess the efficacy of vaccination in patients with PCD, retrospectively, we identified all patients on active treatment. A total of 149 patients were included. Neutralizing antibodies (NAbs) levels against SARS‐CoV‐2 adequate, intermediate, and no response were observed in 42%, 32%, and 26%, respectively. Low NAbs were seen in patients on daratumumab combinations or anti‐BCMA therapy, low lymphocytes, and low IgG levels. Twenty‐three (15%) patients have SARS CoV‐2, while 8% required hospitalization, majority of these patients had intermediate or no response based on NAbs levels. Therefore, checking NAbs may be clinically helpful in identifying patients' responses. Further prospective studies should ascertain the value of a third vaccine dose in this population.
Summary
Ide‐cel received approval for relapsed–refractory multiple myeloma based on the results of the KarMMa‐1 trial. However, patients with significant comorbidities, aggressive disease and prior ...B‐cell maturation antigen‐directed therapy (BCMA‐DT) were excluded. This retrospective study evaluated real‐world outcomes of patients who did not meet the KarMMa‐1 eligibility criteria and were treated with standard of care (SOC) ide‐cel. A total of 69 patients from three US centres who did not meet the KarMMa‐1 criteria underwent ide‐cel infusion. The main reasons for trial ineligibility included baseline grade 3–4 cytopenia (39%), prior BCMA‐DT (26%), renal impairment (19%) and Eastern Cooperative Oncology Group performance status ≥2 (14.5%). Cytokine‐release syndrome occurred in 81% vs. 84%, and immune effector cell‐associated neurotoxicity syndrome occurred in 28% vs. 18% of SOC versus KarMMa‐1 patients, respectively. Early infection (≤8 weeks post‐infusion) and severe infection rates were 42% vs. 49% and 30% vs. 22% for the SOC versus KarMMa‐1 cohorts, respectively. Grade 3–4 cytopenias for SOC versus KarMMa‐1 cohorts were: neutropenia (87% vs. 89%), anaemia (51% vs. 60%) and thrombocytopenia (65% vs. 52%). Overall response rate was higher for the SOC cohort (93% vs. 73%), as was the complete response or better rate (48% vs. 33%). However, median progression‐free survival and overall survival were comparable between the two groups. Our findings support broadening the inclusion criteria of future trials evaluating ide‐cel.
Daratumumab demonstrates activity as a single agent and in combination with either immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) in relapsed refractory multiple myeloma (RRMM). ...However, little is known about the benefit of daratumumab retreatment in daratumumab‐refractory MM. This study aimed to analyze the clinical efficacy of daratumumab‐based retreatment (D2) in patients who are daratumumab refractory MM. Retrospectively, we identified 43 RRMM patients from a single‐center database review. The median age was 65 years, 42% patients had high‐risk cytogenetics, and 23% had an extramedullary disease, while the median time between D2 and prior daratumumab was 1 (0.25–39) month. All D2 patients received combination therapy with either pomalidomide, carfilzomib, bortezomib, or lenalidomide. The response rate, median progression‐free, and overall survival were 49%, 7.97 and 32.6 months, respectively. Our study raises the possibility of re‐utilizing daratumumab in combination with different classes of anti‐myeloma drugs to generate responses in RRMM patients who are daratumumab‐refractory.
Summary
Use of surrogate end‐points such as progression‐free survival (PFS) and other time‐to‐event (TTE) end‐points is common in multiple myeloma (MM) clinical trials. This systematic review ...characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end‐points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co‐primary end‐point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval CI 0.38–0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30–0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42–0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.
Background Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. Methods We performed a systematic review to ...evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). Results The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. Conclusions This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population. Keywords: Multiple myeloma, Proteasome inhibitors, Anti-CD38, Cytotoxic therapy, Infection
Objective
Ascertain the benefit of prophylactic antibiotics for patients with newly diagnosed multiple myeloma (MM), given that clinical trials evaluating this have had conflicting results.
Methods
...We performed a systematic review and meta‐analysis evaluating the use of prophylactic antibiotics in patients with MM and its impact on infection risk and mortality.
Results
Across three included studies, a total of 664 patients received antibiotics and 650 patients received no antibiotics. The overall incidence of infection within 3 months was lower for antibiotic group compared to placebo (18.4% vs 23.4%, RR: 0.79, 95% CI 0.62‐1.00, P = .05, I2 = 6.5%). There was no difference in mortality in the first 3 months (1.5% vs 3.5%, RR: 0.47, 95% CI 0.17‐1.27, P = .60, I2 = 28.1%).
Conclusion
Antibiotic prophylaxis for a finite duration can decrease the overall incidence of infection within the first 3 months following diagnosis. This does not lead to a decrease in mortality. Further data on antibiotic resistance patterns, toxicity, healthcare expenditures, and the impact of antibiotics on subsequent therapies can assist providers in helping make decisions on prophylactic antibiotics with their patients.
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