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Simple Summary: Patients diagnosed with multiple myeloma today can expect to live for substantially longer than in the past thanks to the range of highly active treatment options now available. Over the course of their disease, patients may receive several different treatment combinations to keep their disease under control. Thus, there is an ongoing need for additional new drugs and regimens to be developed, and, in particular, ones that are convenient, accessible, and active against disease that has returned following multiple different therapies. Among today's standards of care are the immunomodulatory drugs lenalidomide and pomalidomide, which are commonly used in quadruplet and triplet regimens in newly diagnosed patients and those with relapsed disease. However, resistance to these drugs can arise over the course of treatment; therefore, novel, more potent agents are being developed to restore and increase activity against relapsed multiple myeloma, one of which is the investigational agent mezigdomide. Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase–cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation. Among the CELMoDs, mezigdomide has the greatest cereblon-binding potency, plus the greatest potency for the degradation of Ikaros and Aiolos and subsequent downstream antimyeloma effects. Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients who are diagnosed with multiple myeloma are given an initial sequence of treatments that usually, for those who are young and fit enough, includes high-dose melphalan followed by autologous stem cell transplantation. This has contributed to the improvement in survival seen over the past 30 years. However, high-dose melphalan has significant limitations, including short-term side effects and longer-term issues such as an increased risk of developing secondary hematologic malignancies including leukemia. There are now numerous highly efficacious combination regimens for initial treatment that result in increasingly large proportions of patients achieving deep responses with no evidence of minimal residual disease. Moreover, large, randomized studies using these regimens have shown no benefit in overall survival after receiving high-dose melphalan with stem cell transplantation. There is thus a growing rationale for selected eligible patients to defer receiving high-dose melphalan and stem cell transplantation until potentially needed in a subsequent line of treatment. The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT. [ABSTRACT FROM AUTHOR]

High-risk cytogenetics and minimal residual disease (MRD) after chemoimmunotherapy (CIT) predict unfavorable outcome in chronic lymphocytic leukemia (CLL). This phase 2 study investigated risk-adapted CIT in treatment-naïve CLL (NCT01145209). Patients with high-risk cytogenetics received induction with fludarabine, cyclophosphamide, and ofatumumab. Those without high-risk cytogenetics received fludarabine and ofatumumab. After induction, MRD positive (MRD+) patients received 4 doses of ofatumumab consolidation. MRD negative (MRD-) patients had no intervention. Of 28 evaluable for response, all responded to induction and 10 (36%) achieved MRD-. Two-year progression-free survival (PFS) was 71.4% (CI95, 56.5–90.3%). There was no significant difference in median PFS between the high-risk and the standard-risk groups. Ofatumumab consolidation didn't convert MRD + to MRD-. In the MRD + group, we saw selective loss of CD20 antigens during therapy. In conclusion, risk-adapted CIT is feasible in treatment-naïve CLL. Ofatumumab consolidation didn't improve depth of response in MRD + patients. Loss of targetable CD20 likely reduces efficacy of consolidation therapy. [ABSTRACT FROM AUTHOR]

Recent advances in multiple myeloma include numerous approvals of novel therapies with unprecedented efficacy, a rapid and sustained tempo of new drug development, and further refinements to prognostication to include minimal residual disease (MRD) testing and improved risk stratification. The upfront use of immunomodulatory drug and proteasome inhibitor combinations followed by maintenance has resulted in transformative clinical benefit. Four‐drug regimens incorporating monoclonal antibodies are reporting unprecedented rates of complete response and MRD negativity in the absence of intensification. In the context of these advances, the added value of high‐dose melphalan with autologous stem‐cell transplant (HDM‐ASCT) is a key question. From a safety standpoint, HDM‐ASCT is associated with both acute toxicities that reduce quality of life and long‐term toxicities that may limit life expectancy for some patients. The present review discusses the recent advances in induction therapy, the impact of these advances on HDM‐ASCT, the evolving role of MRD testing and the short‐ and long‐term risks of HDM‐ASCT. Recognising that prospective data remains limited, we suggest that HDM‐ASCT not be considered mandatory for eligible newly diagnosed patients who are treated with highly efficacious regimens and achieve deep responses, but rather be held in reserve without early exposure to the clinical and genomic toxicity inherent to this approach. [ABSTRACT FROM AUTHOR]

Although the results of MM-014 Cohort A strongly and encouragingly suggest that they do, the ongoing phase 2 Alliance study of pomalidomide-dexamethasone with or without ixazomib for patients who are refractory to lenalidomide in the first line (NCT02004275), will hopefully provide further confirmatory evidence to this end (Voorhees I et al i , [8]). In the context of the relevant studies of pomalidomide in multiple myeloma to date, the data collectively suggest that consideration of cytogenetic risk is important for, if not critical to, the informed selection of treatment regimens for patients with relapsed/refractory disease. A phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor-based therapy: phase I results. [Extracted from the article]

A letter to the editor is presented that reports the efficiency of intravenous immunoglobulin for treating refractory thymoma-associated pseudo-obstruction.

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells. MM remains incurable, but overall survival of patients has progressively increased over the past two decades largely due to novel agents such as proteasome inhibitors (PI) and the immunomodulatory agents. While these therapies are highly effective, MM patients can be de novo resistant and acquired resistance with prolonged treatment is inevitable. There is growing interest in early, accurate identification of responsive versus non-responsive patients; however, limited sample availability and need for rapid assays are limiting factors. Here, we test dry mass and volume as label-free biomarkers to monitor early response of MM cells to treatment with bortezomib, doxorubicin, and ultraviolet light. For the dry mass measurement, we use two types of phase-sensitive optical microscopy techniques: digital holographic tomography and computationally enhanced quantitative phase microscopy. We show that human MM cell lines (RPMI8226, MM.1S, KMS20, and AMO1) increase dry mass upon bortezomib treatment. This dry mass increase after bortezomib treatment occurs as early as 1 h for sensitive cells and 4 h for all tested cells. We further confirm this observation using primary multiple myeloma cells derived from patients and show that a correlation exists between increase in dry mass and sensitivity to bortezomib, supporting the use of dry mass as a biomarker. The volume measurement using Coulter counter shows a more complex behavior; RPMI8226 cells increase the volume at an early stage of apoptosis, but MM.1S cells show the volume decrease typically observed with apoptotic cells. Altogether, this cell study presents complex kinetics of dry mass and volume at an early stage of apoptosis, which may serve as a basis for the detection and treatment of MM cells. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long‐term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and perceptions of prognosis by line of therapy are lacking. Methods: The authors conducted a cross‐sectional, multisite study of patients undergoing treatment for MM (excluding maintenance) between June 2020 and January 2021. The authors conducted purposeful sampling and recruited patients to 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first‐line therapy; 2) 2 to 3 lines; and 3) 4 or more lines. Patients completed validated questionnaires to assess their QOL, fatigue, psychological distress, and perceptions of prognosis. Results: A total of 180 patients with MM were enrolled (newly diagnosed [n = 60], 2 to 3 lines [n = 60], and ≥4 lines of therapy [n = 60]). QOL, symptom burden, and fatigue scores did not differ by lines of therapy. There were no statistically significant differences in psychological distress by line of therapy. The rates of clinically significant depression, anxiety, and post‐traumatic stress disorder symptoms were 23.9% (43 of 180), 23.9% (43 of 180), and 24.4% (44 of 180), respectively. Most patients (84.7%, 149 of 176) reported that their oncologist told them their cancer was incurable, but only 30.6% (53 of 173) acknowledged that they were terminally ill, and 42.0% (73 of 174) reported that they thought their cancer was incurable. Conclusions: Patients with MM undergoing treatment experience impaired QOL and elevated psychological distress across the disease continuum, regardless of line of therapy. A substantial proportion of patients with MM have significant misperceptions about their prognosis and the curability of their illness despite reporting being informed of the prognosis by their oncologist. Lay Summary: This study discusses 180 patients with MM (newly diagnosed [n = 60], 2‐3 lines [n = 60], and ≥4 lines of therapy [n = 60]). Quality of life, symptom burden, and fatigue scores do not differ by lines of therapy. There are also no statistically significant differences in psychological distress by line of therapy.The rates of clinically significant depression, anxiety, and post‐traumatic stress disorder symptoms are 23.9%, 23.9%, and 24.4%, respectively.Most patients (84.7%) report that their oncologist told them their cancer was incurable, but only 30.6% acknowledge that they are terminally ill, and 42.0% report that they thought their cancer was incurable. Patients with multiple myeloma undergoing treatment experience impaired quality of life and elevated psychological distress across the disease continuum. Although the majority reported that their oncologist had told them that their cancer is incurable, a substantial proportion still reported that they believed their cancer was curable. [ABSTRACT FROM AUTHOR]

Further, factor VIII (FVIII), a potent and key factor in the coagulation process, is greatly increased in ICU patients with COVID-19.16 In this setting, it has been proposed that the systemic hyperinflammation observed in severe COVID-19 is comparable to a cytokine release syndrome (CRS), or cytokine storm. The coronavirus disease 2019 (COVID-19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries,2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies Most reported cases are asymptomatic or present with mild symptoms; however, 7-26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality.3-5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID-19. [Extracted from the article]

Pure red cell aplasia ( PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti-myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy-associated PRCA. [ABSTRACT FROM AUTHOR]