Attenuated humoral immune response following anti-SARS-CoV-2 vaccine in heavily pretreated patients with multiple myeloma and AL amyloidosis.
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SUBMITTER: Schiller Salton N
PROVIDER: S-EPMC8646558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AbstractTeclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.
| S-EPMC10787247 | biostudies-literature
Project description:PurposeMelphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.Patients and methodsPatients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.ResultsOf 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.ConclusionMelflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
| S-EPMC8078327 | biostudies-literature
Project description:The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody-drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.
| S-EPMC8170343 | biostudies-literature
Project description:Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)-CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA-CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.
| S-EPMC8655576 | biostudies-literature
Project description:The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.
| S-EPMC7960612 | biostudies-literature
Project description:Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC-non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC-non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC-non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.
| S-EPMC6199662 | biostudies-literature
Project description:Daratumumab is a human CD38-directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ?3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ?1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison. Patient-level data were pooled from two daratumumab monotherapy studies (16 mg/kg; GEN501 and SIRIUS) and two independent US databases (IMS LifeLink and OPTUM), which reflect treatments used in real-world patients with MM who received ?3 prior LOTs or were double refractory to a PI and an IMiD. Using a multivariate proportional hazards regression model, the relative treatment effect of daratumumab versus historical controls was estimated, adjusting for imbalances in characteristics between cohorts. Baseline characteristics that differed between patients treated with daratumumab (N?=?148) and historical control (N?=?658) were prior treatment with pomalidomide (55% vs 15%) or carfilzomib (41% vs 28%) and triple/quadruple refractory status (64% vs 14%). The adjusted overall survival-hazard ratio (OS-HR) for daratumumab versus historical control was 0.33 (95% confidence interval, 0.24-0.46) compared with 0.46 (0.35-0.59) for unadjusted HR. Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib exposure. This adjusted treatment comparison suggests that daratumumab demonstrates improved OS compared with historical control data in heavily pretreated and highly refractory MM patients.
| S-EPMC5518219 | biostudies-literature
Project description:BackgroundPreclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses.Patients and methodsWe conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response.ResultsTwenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) ≥6 months and partial or complete remission (PR/CR) was 50% (five patients with SD ≥6 months; seven PRs (including one unconfirmed); one CR). The rate of SD ≥6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels.ConclusionsThe combination of trastuzumab, lapatinib and bevacizumab was well-tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation.Clintrialsgov idNCT00543504.
| S-EPMC3841018 | biostudies-literature
Project description:BackgroundRadium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown.Patients and methodsWe conducted a retrospective study of 29 patients with mCRPC who received radium-223 at 1 of 3 participating institutions between August 2013 and December 2014. Trend of PSA, radiographic changes, and association of biochemical and clinical variables with PSA trend were measured.ResultsThe median age of patients was 70 years, 79% of patients (N = 23) were European Americans, and 17% of patients (N = 5) were African Americans. Twenty patients (69%) had received at least 3 lines of prior therapies. Some 38% of patients (N = 11) received all 6 cycles of radium-223. Twenty patients (69%) had an increase in PSA during radium therapy, and 4 patients (14%) had a decline in PSA levels. Five patients had visceral metastases on computed tomography imaging performed during the course of radium-223.ConclusionsRadium therapy in mCRPC was associated with an increase in PSA in the majority of these heavily pretreated patients. The development of visceral disease was not uncommon, suggesting a need for follow-up computed tomography monitoring during radium-223 therapy. The significance of early increases in PSA and pain with radium-223 is still uncertain. Although pain and PSA flare have been reported in patients who subsequently have a dramatic response to therapy, we observed that a PSA increase or pain flare correlates to an improvement in bone scans only in a minority of patients.
| S-EPMC6849387 | biostudies-literature
Project description:The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.
| S-EPMC8217489 | biostudies-literature