Summary
Daratumumab is a CD38‐targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of ...daratumumab (DARA SC) in combination with standard‐of‐care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D‐VRd) for transplant‐eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D‐VMP) for transplant‐ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D‐Rd) for relapsed/refractory MM. In total, 199 patients were treated (D‐VRd, n = 67; D‐VMP, n = 67; D‐Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21‐day induction cycles for D‐VRd was 71·6% 90% confidence interval (CI) 61·2–80·6%, and the overall response rates (ORRs) for D‐VMP and D‐Rd were 88·1% (90% CI 79·5–93·9%) and 90·8% (90% CI 82·6–95·9%). With longer median follow‐up for D‐VMP and D‐Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease–negativity (10‒5) rates were 16·4% and 15·4%. Infusion‐related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard‐of‐care regimens demonstrated comparable clinical activity to DARA IV–containing regimens, with low infusion‐related reaction rates and reduced administration time.
G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T ...cells to mediate killing of GPRC5D-expressing myeloma cells.
In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 μg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study.
At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 μg per kilogram weekly 30 patients and 800 μg per kilogram every other week 44 patients), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-μg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-μg dose level) and 4.2 months (in those who had received it at the 800-μg dose level), the percentages of patients with a response were 70% (95% confidence interval CI, 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively.
Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).
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
This non‐interventional observational study described the current standard‐of‐care for transplant‐eligible newly diagnosed multiple myeloma (TE‐NDMM) patients in France, Germany, Spain, ...and Italy, and recorded the evolution in regimen adoption in distinct elements of frontline treatment during 2017–2020/2021.
Methods
Clinical information on ongoing (I) or previous (II) TE‐NDMM patients was extracted from the Cancerology database. Proportions of patients receiving regimens in each element and the evolution in regimen adoption were determined for the entire population and each country.
Results
Most common induction regimens among I patients were VRd in France (75.3%) and Spain (44.1%), VTd in Italy (65.2%), and regimens other than VRd/VTd/VCd in Germany. Maintenance was ongoing/planned for 78.3%, 62.3%, 65.2%, and 61.4% patients in France, Germany, Spain, and Italy, respectively. Among II patients, VRd induction increased from 27.0% in 2017 to 65.7% in 2019 in France, remained relatively low in Spain and Germany, and not present in Italy. In Italy and Spain, VTd induction declined from 72.4% and 58.3% in 2017 to 52.8% and 17.3% in 2019, respectively. VCd induction in Germany declined from 85.2% in 2017 to 64.1% in 2019.
Conclusion
The use of bortezomib triplets in induction varied markedly over time and between selected countries.
Summary
Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue ...symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health‐related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported‐outcome measures from the pivotal, Phase II HORIZON study (OP‐106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple‐class–refractory disease (n = 50) displayed similar improvements. Patient‐reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple‐class–refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real‐world practice.
T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release ...syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.
Summary
This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) ...patients. Forty‐seven RRMM patients with a median of three prior lines (2–8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1·25 mg/m2 of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1–21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% ≥MR, resulting in a median progression‐free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1‐acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0·04), which also translated into a longer mPFS (9 vs. 2 months; P = 0·014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy.
Trial registration: clinicaltrials.gov identifier: NCT02384083.
Immune escape and impaired immune surveillance have been identified as emerging hallmarks of cancer.
Multiple myeloma represents a genuine example of disrupted immune surveillance characterized by: ...impaired antibody production, deregulation of the T and natural killer cell compartment, disruption of antigen presentation machinery, upregulation of inhibitory surface ligands, and recruitment of immunosuppressive cells. Although the potential value of immunotherapeutic interventions had a clear antecedent in the graft-
-myeloma effect induced by allogeneic stem cell transplant and donor lymphocyte infusions, it is only recently that this field has faced a real revolution. In this review we discuss the current results obtained with immune approaches in patients with multiple myeloma that have placed this disease under the scope of immuno-oncology, bringing new therapeutic opportunities for the treatment of multiple myeloma patients.
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