Collectively, hematological malignancies account for the fourth most common malignancy. Myeloma and lymphoma are the most common types of hematological malignancies. Unfortunately, the management of ...refractory myeloma and lymphoma remains challenging. The discovery of new immunological therapies, namely chimeric antigen receptors T cells (CAR-T), outlined unprecedented B cell malignancies results. In this context, the CAR-T-based approach has led to the proliferation of many clinical studies. In this review, we will deal with the CAR-T structure, and we will summarize the primary clinical studies assessing the risks and benefits of CAR-T cell therapy. We will also deal with the adverse events and management of cytokine release syndromes/immune effector cell-associated neurotoxicity syndrome (ICANS). Subsequently, we will review potential future improvements to overcome refractoriness and improve expansion while decreasing CAR-T's off-target effects. The advances in the CAR-T platform represent a step forward with promising unlimited future possibilities that made it a paradigm-shifting for the management of B cell malignancies.
A clearer understanding of the prognostic implications of t(11;14) in multiple myeloma (MM) is needed to inform current and future therapeutic options. We utilized real-world data from a US database ...to examine treatment patterns and outcomes in patients by t(11;14) status compared with high- and standard-risk subgroups across different lines of therapy (LoT). This retrospective, observational cohort study used de-identified patient-level information from adults with MM and first-line treatment initiation between January 2011 and January 2020, followed until February 2020. The high-risk cohort comprised patients with high-risk genetic abnormalities per mSMART criteria (including those with co-occurring t(11;14)). Among 6138 eligible patients, 6137, 3160, and 1654 received first-, second-, and third-line treatments, respectively. Of 645 patients who had t(11;14), 69.1% had t(11;14) alone, while 30.9% had co-occurring high-risk abnormalities. Altogether, 1624 and 2544 patients were classified as high- and standard-risk, respectively. In the absence of biomarker-driven therapy, treatment patterns remain similar across LoT in high-risk, t(11;14)+, and standard-risk subgroups. Across all LoT, patient outcomes in the high-risk subgroup were less favorable than those in the t(11;14)+ and standard-risk subgroups. Thus, there is an opportunity for novel therapeutics targeted to t(11;14) and other defined subgroups to personalize MM therapy and optimize patient outcomes.
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.
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.
Daratumumab, a CD38 monoclonal antibody, has demonstrated efficacy as monotherapy and combination therapy across several indications, both among newly-diagnosed and refractory patients with multiple ...myeloma (MM). However, there is limited evidence on treatment patterns and effectiveness of daratumumab in the real-world setting, particularly in first line (1 L). This study aimed to describe real-world treatment patterns and clinical outcomes among patients initiating daratumumab across different lines of therapy.
A retrospective chart review of adult patients with MM initiating daratumumab between November 2015 and March 2021 was conducted at two clinical sites in the United States. De-identified patient-level data were abstracted in an electronic case report form. Patient characteristics and treatment patterns were described. Clinical outcomes including overall response rate (ORR), progression-free survival, and time to next line of therapy were reported using descriptive statistics and stratified by line of therapy (1 L, second line 2 L or third line or later 3 L+). A sub-group analysis evaluated treatment patterns and ORR among patients re-treated with daratumumab.
A total of 299 patients were included in the study (mean age: 68 years; 55% male). Among them, 26 were 1 L patients, 66 were 2 L patients, and 207 were 3 L+ patients; 110 patients (36.8%) received a stem cell transplant prior to daratumumab initiation. The mean duration of follow-up was 10 months among 1 L patients and 19 months among 2 L and 3 L+ patients. Patients who initiated daratumumab in 1 L had a 100% ORR, while those initiating in 2 L and 3 L+ had an ORR of 78.8 and 65.2%, respectively. Among re-treated patients, ORR was 66.7% during the first treatment segment, and 52.9% during the second treatment segment. Kaplan-Meier rates of progression-free survival at 12 months were 89.9, 75.2, and 53.1% among patients who initiated daratumumab in 1 L, 2 L, and 3 L+, respectively. Kaplan-Meier rates of time to next line of therapy at 12 months were 94.1, 73.4, and 50.0% among patients who initiated daratumumab in 1 L, 2 L, and 3 L+, respectively.
These findings suggest that daratumumab-based regimens are an effective treatment option across all lines of therapy, with highest response rate in 1 L.
Background
Ki‐67 is an index of proliferative activity and is an established predictive and prognostic marker in multiple malignancies. However, its prognostic relevance in multiple myeloma (MM) is ...unclear. We investigated the relationship between Ki‐67 expression and survival outcomes in MM in the era of novel therapies.
Methods
We interrogated our database to identify patients with MM, newly diagnosed between July 1, 2013 and December 31, 2020, with Ki‐67 expression assessed by immunohistochemistry (IHC) on bone marrow biopsies. Using an established threshold of 5% we defined Ki‐67low (≤5%) and Ki‐67high (>5%) subgroups for association with progression‐free survival (PFS) and overall survival (OS).
Results
Of 167 patients included: 53 (31.7%) had Ki‐67high and 114 had Ki‐67low. More patients with R‐ISS 3 had Ki‐67high (22.2% vs. 9.7%). The gain of 1q21 was overrepresented in the Ki‐67high group (28% vs. 8%). Median PFS in the Ki‐67low group was 3.1 years, and in the Ki‐67high group 1.6 years (log‐rank p < .001, HR: 1.9). Median OS was not reached in the Ki‐67low vs. 4.8 years in the Ki‐67high cohort (HR: 1.9; log‐rank test: p = .018). In the multivariable modeling, after adjusting for other risk factors, HR for Ki‐67high versus Ki‐67low was 2.4 (p < .001) for PFS and 2.1 (p = .026) for OS.
Conclusions
Our results demonstrate that a high Ki‐67 index (>5%) is an independent prognostic marker associated with worse OS and PFS in newly diagnosed MM. IHC staining for Ki‐67 on bone marrow biopsies could be easily adopted as a prognostic biomarker for MM in economically constrained healthcare settings.
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell ...therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen ...(BCMA) targeted chimeric antigen receptor (CAR) T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤3 months after CAR T-cell infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤3 months of infusion (P<0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (P<0.001; median PFS for ≥3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T-cell therapy who may benefit from specific interventions pre and post CAR T-cell therpy to improve outcomes.
Background
Multiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple‐class relapsed/refractory MM (RRMM). Descriptive analyses were performed on ...available data for patient characteristics, disease course, and outcomes of the KCd on triple‐class RRMM patients at our institution.
Patients and Methods
Twenty‐three patients with triple‐class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20‐40) mg orally weekly.
Results
Patients received a median of 6 (3‐10) prior regimens. The median number of cycles administered was 4 (1‐11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression‐free survival (PFS) and Overall‐survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment‐related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%).
Conclusions
KCd showed clinically meaningful efficacy and manageable safety profile in patients with triple‐class RRMM in real‐world.
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