Background Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. Methods We performed a systematic review to evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). Results The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. Conclusions This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population.
ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701
Despite dramatic improvements in survival, multiple myeloma (MM) remains largely incurable, and most patients develop disease that is refractory to available treatment options. 1 Use of chimeric antigen receptor T-cell therapy (CART) is a novel approach that is associated with impressive outcomes in heavily pretreated patients. Given the rapid evolution of this treatment paradigm, we assessed the efficacy and toxicity of CART for MM utilizing the most up-to-date results.Four databases were searched (Web of Science/MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials). An example search strategy is shown in supplemental Table 1. Two independent reviewers (G.R.M., A.R.) screened all studies, and conflict was resolved through mutual discussion. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. 2 Our search strategy was restricted to include all prospective trials exclusively enrolling $2 patients with MM that were published in manuscript or presented in abstract form from 1 January 2013 through 15 November 2020. Furthermore, all abstracts that were presented live at the 62nd American Society of Hematology Annual Meeting were included with most updated information. All other studies, including editorials, case reports, case series, and review articles, were excluded. The primary outcomes were the pooled response rate for all MM CART, pooled rate of grade 3/4 cytokine release syndrome (CRS), and pooled immune effector cell-associated neurotoxicity syndrome (ICANS). Proportional outcomes were pooled using a random effects model, and the DerSimonian and Laird Method with a correction factor of 0.5 was used. Statistical software Open Meta-Analyst (Brown School of Public Health) was used for calculations. The I2 statistic was used to test for heterogeneity between the studies. The I2 of values of ,30%, 30% to 60%, 61% to 75%, and .75% were suggestive of low, moderate, substantial, and considerable heterogeneity, respectively. 3,4 Data were collected by 3 independent reviewers (G.R.M., A.R., and N.B.) and stored using Microsoft Excel. Variables collected include demographic information of participants, information on safety (ICANS, CRS), and efficacy outcomes (response rate, minimal residual disease data, duration of response, progression-free survival [PFS]).A total of 30 clinical trials that met inclusion criteria was included (supplemental Figure 1). A total of 921 patients was evaluable for efficacy analysis, and 950 patients were available for safety analysis, as pertains to CRS. A total of 781 patients was available for safety analysis of ICANS. Table 1 lists the characteristics/outcomes of these studies. The median prior lines of therapy was 6, based on the 21 studies that reported that data, and 74.4% of patients were triple refractory, among the 5 studies that clearly reported that data.The pooled response rate was 78.3% (95% confidence interval [CI], 72.3-84.3; I2, 88.9) (Figure 1). The pooled grade 3/4 or higher CRS rate w...
Therapeutic strategies based on a specific oncogenic target are better justified when elimination of that particular oncogene reduces tumorigenesis in a model organism. One such oncogene, Musashi-1 (Msi-1), regulates translation of target mRNAs and is implicated in promoting tumorigenesis in the colon and other tissues. Msi-1 targets include the tumor suppressor adenomatous polyposis coli (Apc), a Wnt pathway antagonist lost in ∼80% of all colorectal cancers. Cell culture experiments have established that Msi-1 is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a mutually repressive feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc and Msi-1 mutually repressive feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, mice with germline Apc mutations (Apc Min ) or with the Apc 1322T truncation mutation have a dramatic reduction in intestinal polyp number when Msi-1 is deleted. Taken together, these results provide genetic evidence that Msi-1 contributes to intestinal tumorigenesis driven by Apc loss, and validate the pursuit of Msi-1 inhibitors as chemo-prevention agents to reduce tumor burden.
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