•Cilta-cel, a BCMA-targeting chimeric antigen receptor−T-cell therapy, induced clinical responses in patients previously exposed to noncellular anti-BCMA therapies.•Results of this study may inform ...sequencing strategies for anti-BCMA therapies in patients with relapsed/refractory MM.
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B-cell maturation antigen (BCMA)–targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 70.0% in the MRD-evaluable subset). Overall response rate (95% confidence interval CI) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9—not estimable) and 9.1 (1.5—not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events 1 treatment related, 3 unrelated). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.
B-cell maturation antigen (BCMA) is the target for multiple, new therapeutics in relapsed multiple myeloma (MM). Cohen and colleagues begin to address the question of sequencing by reporting a small series of patients treated with anti-BCMA chimeric antigen receptor (CAR) T cells after failure of anti-BCMA antibody-based biologicals. The authors report responses in 60% of patients and highlight the need for larger studies in this setting and a better understanding of the mechanisms of resistance to individual agents.
Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the ...GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.
Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been ...limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.
The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization.
Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4
9.4 months; hazard ratio HR, 0.659; 95% CI, 0.542 to 0.801;
< .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6
12.9 months; HR, 0.586;
< .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8%
8.0%), vomiting (24.2%
4.3%), and diarrhea (23.2%
12.3%). There was no increase in new primary malignancies (5.2%
6.2%); rates of on-study deaths were 2.6% versus 2.2%.
Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 ...monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.
Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary ...analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow-up is presented. After 19.4 (range: 0 to 27.7) months of median follow-up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P <0.0001) and improved the overall response rate (83.8% versus 63.2%; P <0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% confidence interval, 0.12-0.29; P <0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow-up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse.
clinicaltrials.gov identifier: NCT02136134.
Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In ...CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM.
Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an ...increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice.
Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be ...enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM.
DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles.
Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed.
The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www.
gov as NCT03848845.
Almost all patients with multiple myeloma (MM) will eventually develop disease that has relapsed with or become refractory to available treatments and will require additional therapy. However, data ...are still lacking on how best to sequence regimens in the relapsed/refractory (RR) setting after the failure of early-line lenalidomide, bortezomib, and/or daratumumab, the most commonly used agents in clinical practice today. With the treatment landscape rapidly changing in response to emerging clinical trial data and approvals of several new drugs and additional combinations, it is critically important to focus on patients with RRMM. Variability in patient baseline characteristics, such as the number of prior lines of treatment, refractoriness to prior treatments, prior stem cell transplant, and timing and dosing of prior lenalidomide, makes it difficult to select the best options for patients with RRMM for whom first-line treatments have failed. The aim of this review is to provide both an overview of current therapies and future directions within the RRMM treatment landscape, and a framework for clinicians to choose the most promising next treatment option.
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