The addition of daratumumab to lenalidomide and dexamethasone resulted in superior response rate and progression-free survival, as compared with lenalidomide and dexamethasone alone, at a cost of ...more frequent neutropenia and infusion reactions.
The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of care has improved outcomes in patients with multiple myeloma over the past 10 years,
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but most patients still eventually have a relapse.
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Relapse can occur even after standard complete remission in the context of first-line therapy, and studies are therefore evaluating deeper responses in a category termed “minimal residual disease–negative” (i.e., results below the threshold for minimal residual disease) that is prognostic with regard to a rate of disease progression in a time-to-event analysis and overall survival.
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However, this category of minimal residual disease status has . . .
In this phase 1–2 study involving patients with relapsed or refractory myeloma, a bispecific antibody (teclistamab) that mediates T-cell activation and subsequent lysis of myeloma cells expressing ...B-cell maturation antigen induced responses in 63% of the patients, including a complete response in nearly 40%.
In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and ...dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival.
MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0–2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1–2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1–21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172.
Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7–59·9), median progression-free survival was not reached (95% CI 54·8–not reached) in the daratumumab group versus 34·4 months (29·6–39·2) in the control group (hazard ratio HR 0·53 95% CI 0·43–0·66; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached–not reached; control group, 95% CI 55·7–not reached; HR 0·68 95% CI 0·53–0·86; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 54% patients in the daratumumab group vs 135 37% patients in the control group), pneumonia (70 19% vs 39 11%), anaemia (61 17% vs 79 22%), and lymphopenia (60 16% vs 41 11%). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group.
Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.
Janssen Research & Development.
In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone ...D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone Rd, n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone VMP, n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).
•In patients with transplant-ineligible NDMM, durable MRD negativity is associated with improved PFS.•Daratumumab-based therapies are associated with higher rates and durability of MRD negativity.
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CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting ...single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.
This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.
Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 95% of 97 patients), anaemia (66 68%), leukopenia (59 61%), thrombocytopenia (58 60%), and lymphopenia (48 50%). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.
A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.
Janssen Research & Development and Legend Biotech.
CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, ...deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up MFU approximately 28 months), including analyses of high-risk patient subgroups.
Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee.
At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report.
At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.
Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a ...determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors.
•TJP1 expression is a biomarker of proteasome inhibitor sensitivity in myeloma•Signaling through the TJP1/EGFR/JAK/STAT pathway influences proteasome capacity•EGFR/JAK/STAT suppression induces chemosensitization to proteasome inhibitors
Zhang et al. show that TJP1 enhances multiple myeloma sensitivity to proteasome inhibitors by reducing the expression of the immunoproteasome subunits LMP7 and LMP2 via suppression of EGFR/JAK1/STAT3 signaling, and that high TJP1 expression in patient myeloma cells correlates with better response to bortezomib.
The treatment landscape for multiple myeloma (MM) has rapidly evolved over the last 2 decades. The development of triplet and quadruplet regimens including proteasome inhibitors (PI), ...immunomodulatory agents (IMiDs), and anti-CD38 monoclonal antibodies has dramatically extended overall survival. In addition to effective multidrug regimens, autologous stem cell transplant (ASCT) is a cornerstone of management in newly diagnosed multiple myeloma (NDMM). However, despite these combined treatment modalities, curative therapy for MM remains elusive. Recent, novel immunotherapies including chimeric antigen T-cell (CAR-T) therapy have demonstrated deep and durable responses in relapsed and refractory multiple myeloma (RRMM). Currently 2 CAR-T products, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), are approved by the FDA for the treatment of RRMM. The success of CAR-T therapy revolutionized the management of RRMM prompting clinical trials studying CAR-T therapy in the first line setting. The ongoing KarMMa-4, CARTITUDE-5, and CARTITUDE-6 clinical trials may establish CAR-T therapy as a first line option potentially supplanting ASCT in the initial treatment of NDMM. In this review, we discuss the current standard of care management of NDMM, trace the evolution of CAR-T clinical trials in RRMM, and survey ongoing clinical trials studying CAR-T therapy in NDMM.
There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and ...CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma.
This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3−19·2 μg/kg once every 2 weeks or 19·2−720 μg/kg once per week) or subcutaneously (range 80−3000 μg/kg once per week) in different cohorts, with step-up dosing for 38·4 μg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181.
Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 μg/kg, after 60 μg/kg and 300 μg/kg step-up doses (median follow-up 6·1 months, IQR 3·6−8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 40%). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48−79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months’ median follow-up (IQR 5·1−9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported.
Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development.
Janssen Research & Development.
For patients with multiple myeloma (MM), each additional line of therapy (LOT) is associated with lower response rates, shorter treatment duration and treatment-free intervals, and increased rates of ...toxicities and comorbidities. Here, we examine frontline treatment patterns, and attrition rates by LOT among newly diagnosed MM (NDMM) patients in the United States who were eligible or ineligible for autologous stem cell transplant (ASCT).
Data were identified from three US patient-level databases collectively covering the period January 2000 to September 2018. Patients had an index diagnosis of MM on or after January 1, 2007, medical and prescription insurance coverage at diagnosis, a 1-year look-back period prior to the index diagnosis, no prior malignancies in the 1-year period before index diagnosis, and had received ≥1 LOT.
Among patients who did not receive ASCT (non-transplant; n = 22,062), 12,557 (57%) received only 1 LOT and 9505 (43%) received > 1 LOT. Patients receiving only 1 LOT were significantly older, had higher mean Charlson Comorbidity Index (CCI) scores, and higher incidences of comorbidities. Among the 2763 patients receiving ASCT, 2184 received > 1 LOT, and 579 (21%) received only 1 LOT (ie, ASCT was the last treatment). 1682 (61%) patients received induction therapy as frontline treatment, of whom 187 (11%) also received consolidation therapy. The latter group was younger than those who received only induction therapy, had lower mean CCI scores, and comparable or lower incidences of selected comorbidities. The most common frontline therapy for non-transplant and transplant-eligible patients was bortezomib/dexamethasone and bortezomib/lenalidomide/dexamethasone, respectively. Attrition rates across all LOTs were high for non-transplant patients (range, 43-57%) and transplant patients (range, 21-37%). Treatment duration decreased by LOT for non-transplant patients and was consistent across LOTs for transplant patients.
In this analysis, a substantial proportion of patients with NDMM who received frontline therapy did not appear to receive a subsequent LOT. These high attrition rates underscore the need to use the most optimal treatment regimens upfront rather than reserving them for later LOTs in which the clinical benefit may decrease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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