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Simple Summary: Light-chain amyloidosis is a rare disease, and treatment for relapsed light-chain amyloidosis patients is an unmet need. Venetoclax is an oral medication that has proven great efficacy in many hematological cancers, including multiple myeloma. Venetoclax is considered a promising agent for the treatment of relapsed light-chain amyloidosis. We aimed to report the outcomes of therapy in 26 relapsed light-chain amyloidosis patients treated with venetoclax. We found a very high response rate (88%), and most responses were deep and prolonged. Treatment was effective even when doses were reduced. Venetoclax treatment was safe, and one patient died due to infection. These promising results require confirmation in a randomized trial. Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1–7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9–39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28–94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3–4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

Neutropenia postchemotherapy is associated with favorable outcomes, which was attributed to optimal dosing. However, little is known about the neutrophil decline rate as a predictor of cancer outcomes, which may reflect a dynamic marker of chemosensitivity. We assessed the association between the neutrophil decline rate and disease outcomes in a known cohort of 212 lymphoma patients, treated with thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan (TECAM) conditioning followed by autologous transplant in our center between 2000 and 2013. Slower neutrophil decline rate was correlated with worse overall survival, mediated not by shorter time to progression (TTP), but rather by worse survival post-progression, possibly pointing to chemosensitivity at each line of therapy as the responsible mechanism. The effect was seen across histologies and was independent of stronger predictors of outcome like performance status (PS) and response before transplant. Prospective research is needed to confirm our results and expand their validity to other clinical scenarios. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) progression is dependent on its interaction with the bone marrow microenvironment and the immune system and is mediated by key surface antigens. Some antigens promote adhesion to the bone marrow matrix and stromal cells, while others are involved in intercellular interactions that result in differentiation of B-cells to plasma cells (PC). These interactions are also involved in malignant transformation of the normal PC to MM PC as well as disease progression. Here, we review selected surface antigens that are commonly used in the flow cytometry analysis of MM for identification of plasma cells (PC) and the discrimination between normal and malignant PC as well as prognostication. These include the markers: CD38, CD138, CD45, CD19, CD117, CD56, CD81, CD27, and CD28. Furthermore, we will discuss the novel marker CD24 and its involvement in MM. The bioactivity of each antigen is reviewed, as well as its expression on normal vs. malignant PC, prognostic implications, and therapeutic utility. Understanding the role of these specific surface antigens, as well as complex co-expressions of combinations of antigens, may allow for a more personalized prognostic monitoring and treatment of MM patients. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first‐ and second‐line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M‐spike and light chain (LC) responses for each patient. Methods: We reviewed all patients who received first‐line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019. Results: Analyzing 360 patients, we observed no correlation between response kinetics to first‐ versus second‐line therapy at the individual patient level. Time to best response to first‐line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second‐line setting, independent of other factors. Patients with IgA‐MM cleared their M‐spike faster than IgG‐MM, probably reflecting different half‐lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar. Conclusions: Analyzing both M‐spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. Objectives: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. Patients: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005–2017 were included. Results: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0–1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. Conclusions: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL. [ABSTRACT FROM AUTHOR]

High dose chemotherapy followed by autologous stem cell transplant (ASCT) is a cornerstone of frontline therapy for multiple myeloma (MM) [[1]]. Four of the ten transplants were performed as second-line therapy, including two for relapsed disease 42 and 48 months after frontline ASCT (Patients #4 and #5 on Table 1) and one relapsing 47 months after frontline syngeneic transplant (Patient #3). GVHD was questioned in 2 patients (Patients #3 and #5), both receiving allogeneic-like conditioning and cyclosporine prophylaxis. Two of nine patients developed a secondary cancer during follow up (Patient #5 myelodysplastic syndrome 7 years post-syngeneic transplant; Patient #4 transitional cell carcinoma 11 years post-syngeneic transplant). [Extracted from the article]

Summary: Cytomegalovirus (CMV) is a ubiquitous virus that infects people worldwide. CMV is known to trigger thrombocytopenia, but this association is probably underdiagnosed since CMV infection in healthy adults is usually either asymptomatic or causes only mild symptoms. A systematic literature review was carried out and yielded 23 publications that reported 25 patients. All haematology centres in Israel were searched for adult immunocompetent patients with CMV‐associated thrombocytopenia, and five new cases were identified. The median age of the combined 30 patients was 33 years (range 18–80), 73% were men, 77% presented with CMV‐related symptoms, 48% had enlarged spleens, 95% had atypical lymphocytes in peripheral blood and 68% had elevated transaminase levels. The response rate to first‐line steroid‐containing regimens was only 31%, whereas 11 patients who were treated with an anti‐CMV agent had a response rate of 82%. Moreover, four patients received thrombopoietin receptor agonists (TPO‐RA) to which three (75%) responded. Taken together, these distinctive features of a case with thrombocytopenia should alert to CMV infection as the source. While steroids were effective in less than one‐third of the cases, both anti‐CMV therapy and TPO‐RA exhibited excellent efficacy, suggesting that those agents should be introduced earlier in the therapeutic course. [ABSTRACT FROM AUTHOR]

Background: Aberrant thyroid function is highly prevalent in Down syndrome (DS). We aimed to find whether subclinical hypothyroidism (SCH) or low-normal free T4 (FT4) are associated with a detrimental clinical outcome in untreated DS patients. Methods: 157 patients assessed at Hadassah Down Syndrome Center between 2004 and 2010 by comprehensive clinical evaluation and tests for hemoglobin, FT4 and thyroid-stimulating hormone (TSH) were subdivided into subgroups including: clinical hypothyroidism, SCH, euthyroid submedian or supramedian FT4, and alternatively for euthyroidism and TSH levels (submedian or supramedian TSH). Results: Hypothyroidism was found in 21.7% and SCH in another 14.9% of the patients. Moderate/severe hypotonia were more frequent among SCH patients compared to euthyroid patients (52.6 vs. 16.4%, p = 0.002). Patient's hemoglobin levels were lower in the euthyroid submedian FT4 group compared to the euthyroid supramedian FT4 group (10.9 vs. 0% below the normal range, p = 0.001). Interestingly, FT4 levels correlated negatively with increasing age among euthyroid DS patients (Pearson's correlation coefficient = -0.324, p = 0.009). Conclusion: SCH and euthyroid submedian FT4 may have significant clinical sequelae, such as hypotonia and anemia. Interventional studies with L-thyroxine replacement may be indicated in these subpopulations. Our finding that FT4 levels decrease with age in DS (contrasting the general population trend) may indicate redefining the normal FT4 levels range in DS. [ABSTRACT FROM AUTHOR]

Simple Summary: Light-chain (AL) amyloidosis is a rare disease similar to the more common disease, multiple myeloma (MM). Both are caused by proliferation of malignant plasma cells. In AL amyloidosis, disease is a result of the deposition of aggregates of proteins, namely immunoglobulin light chains, secreted by the malignant plasma cells, in target organs such as the heart or kidneys. Historically, treatment of AL amyloidosis has followed that of MM. A wide range of novel immunotherapies, i.e., therapies which utilize or activate immune mechanisms to eliminate the disease, are already established in MM and are gradually being adopted in AL amyloidosis as well. Although promising, the increased frailty of typical AL amyloidosis compared to MM patients is a concern in the administration of these therapies, which may be associated with severe side effects. We review both the promise and the challenges with the expansion of MM immunotherapies to AL amyloidosis. Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients. [ABSTRACT FROM AUTHOR]

Background: Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression‐free survival (PFS) of 6–16 months. Ibrutinib penetrates the blood–brain barrier and has shown activity in PCNSL. Methods: This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2‐year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60–85 years old who responded to first‐line high‐dose methotrexate (HDMTX)‐based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. Results: Twenty patients were enrolled, with a median age of 72 years (range, 61–80). Median time on ibrutinib maintenance was 12.5 (range, 2–46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1‐ and 2‐year PFS are 90% and 72.6%, respectively, and the 2‐year OS is 89%. Conclusions: The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly. Ibrutinib maintenance following first‐line high dose methotrexate‐based chemotherapy in elderly patients with primary central nervous system lymphoma is feasible and probably also effective. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from multiple myeloma receive many lines of treatment including chimeric antigen receptor T cell (CART) therapy. Myeloma patients may develop devastating secondary malignancies such as myelodysplastic syndrome (MDS). The causative relationship between various anti-myeloma treatments and MDS is not fully understood. We report a study of five CART-treated patients myeloma patients who had MDS (four only after CART and one already prior to CART). We found that all these patients had all their MDS-related molecular changes (mutations) already prior to CART even if they did not have overt MDS in bone marrow evaluation before CART. No new mutations developed after CART, but the frequency of pre-existing mutations did increase. Our study presents evidence that anti-myeloma CART therapy may promote the expansion of pre-existing MDS clones rather than causing the development of new ones. Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide‐treated MM patients who developed delayed hypersensitivity‐induced rash and were treated with desensitization. Methods: A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel. Results: Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3‐week‐long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first‐generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune‐mediated or non‐dermatological adverse reactions. Conclusions: Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed. [ABSTRACT FROM AUTHOR]

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% – recurrent SP, 36.8% – active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy. [ABSTRACT FROM AUTHOR]

Surface antigens are commonly used in flow cytometry assays for the diagnosis of multiple myeloma (MM). Some of these are directly involved in MM pathogenesis or interactions with the microenvironment, but most are used for either diagnostic or prognostic purposes. In a previous study, we showed that in-vitro, CD24-positive plasma cells exhibit a less tumorigenic phenotype. Here, we assessed the prognostic importance of CD24 expression in patients newly diagnosed with MM as it correlates to their clinical course. Immunophenotyping by flow cytometry of 124 patients uniformly treated by a bortezomib-based protocol was performed. The expression of CD24, CD117, CD19, CD45, and CD56 in bone marrow PCs was tested for correlations to clinical parameters. None of the CD markers correlated with the response rates to first-line therapy. However, patients with elevated CD24+ expression on their PCs at diagnosis had a significantly longer PFS (p = 0.002) and OS (p = 0.044). In contrast, the expression of CD117, CD56, or CD45 was found to have no prognostic value; CD19 expression was inversely correlated with PFS alone (p < 0.001) and not with OS. Thus, elevated CD24 expression on PCs appears to be strongly correlated with survival and can be used as a single-surface antigenic prognostic factor in MM. [ABSTRACT FROM AUTHOR]

Background: The treatment of relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) is limited to a few agents. Romidepsin, a histone deacetylase inhibitor, was approved for PTCL treatment as a single agent in the R/R setting, yet with partial efficacy. Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity. Objectives: To study the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity. Methods: We report on a series of 7 heavily pretreated PTCL patients (2–5 previous lines of therapy) treated with a romidepsin-bendamustine combination. Results: Four patients were not previously exposed to either drug. Of these, 2 achieved complete remission. Interestingly, 1 patient continued treatment with a prolonged progression-free survival of more than 4 years. Toxicity was minimal and no treatment-related deaths or discontinuation were noted. Significant nausea and vomiting were reported in over 50% of patients. Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma. Conclusions: Although reporting a small number of patients, our data suggest that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study. [ABSTRACT FROM AUTHOR]