Current Novel Targeted Therapeutic Strategies in Multiple Myeloma.

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.

Revisiting Role of Vaccinations in Donors, Transplant Recipients, Immunocompromised Hosts, Travelers, and Household Contacts of Stem Cell Transplant Recipients.

Vaccination is an effective strategy to prevent infections in immunocompromised hematopoietic stem cell transplant recipients. Pretransplant vaccination of influenza, pneumococcus, Haemophilus influenza type b, diphtheria, tetanus, and hepatitis B, both in donors and transplant recipients, produces high antibody titers in patients compared with recipient vaccination only. Because transplant recipients are immunocompromised, live vaccines should be avoided with few exceptions. Transplant recipients should get inactive vaccinations when possible to prevent infection. This includes vaccination against influenza, pneumococcus, H. influenza type b, diphtheria, tetanus, pertussis, meningococcus, measles, mumps, rubella, polio, hepatitis A, human papillomavirus, and hepatitis B. Close contacts of transplant recipients can safely get vaccinations (inactive and few live vaccines) as per their need and schedule. Transplant recipients who wish to travel may need to get vaccinated against endemic diseases that are prevalent in such areas. There is paucity of data on the role of vaccinations for patients receiving novel immunotherapy such as bispecific antibodies and chimeric antigen receptor T cells despite data on prolonged B cell depletion and higher risk of opportunistic infections.

Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation.

Investigators are using checkpoint inhibitors (CPIs) to treat aggressive hematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in some patients with relapsed disease after allo-HSCT. CTLA-4 inhibitors and PD-1 inhibitors are 2 main types of CPIs, which work through activation of the immune system. On one hand, CPIs can achieve graft-versus-tumor effect, and on the other hand, there is a risk of graft-versus-host disease (GVHD). After a comprehensive literature review, we included data (n = 283) from 24 studies (11 original manuscripts and 13 case reports or case series) and evaluated the results to assess the safety and efficacy of CPI use in conjunction with allo-HSCT. Among the 283 patients, 107 received CPI before allo-HSCT, and 176 received CPI after allo-HSCT. The most common indication for CPI use was for Hodgkin lymphoma. The CPIs used in various studies included ipilimumab, nivolumab, and pembrolizumab. Among the patients exposed to CPI before allo-HSCT, 56% developed acute GVHD and 29% developed chronic GVHD. Investigators reported 20 deaths, 60% of which were GVHD-related. The overall mortality risk with GVHD is 11%. In this group, investigators noted an objective response rate (ORR) in 68% of patients, with complete remission (CR) in 47%, partial remission (PR) in 21%, and stable disease in 11%. Among the patients who received a CPI after allo-HSCT for disease relapse, 14% developed acute GVHD and 9% developed chronic GVHD. Investigators reported 40 deaths, 28% of which were GVHD-related. The mortality risk with GVHD is approximately 7%. Investigators reported ORR in 54% of patients, with CR in 33%, PR in 21%, and disease stabilization in 5%. After careful evaluation of collective data, we found that CPI use both before and after allo-HSCT can be highly effective, but exposure can lead to a significantly increased risk of GVHD-related morbidity and mortality in this patient population. Despite limited availability of data, there is need for extreme caution while making decisions regarding the use of CPIs. Detailed discussions and prospective well-designed clinical trials are needed to explore this issue further.

Treating Diffuse Large B Cell Lymphoma in the Very Old or Frail Patients.

OPINION STATEMENT: R-CHOP has been the standard of care for diffuse large B cell lymphoma (DLBCL), curing approximately 60% of patients for more than 2 decades. However, the optimal treatment of patients who are too frail to tolerate this regimen and/or are not candidates for anthracycline therapy continues to be debated. MInT and GELA trials established addition of rituximab to CHOP in DLBCL but excluded patients older than 80 years. Multiple regimens have been tried with varying success in the very elderly, including R-mini-CHOP, R-mini CEOP, R-split CHOP, pre-phase strategies, and R-GCVP. However, there has not been a randomized trial among these strategies. Although addition of novel agents including ibrutinib, brentuximab vedotin, lenalidomide, and many others on the horizon holds promise in this population, none have been tested in a randomized setting or have results awaited. There is also a lack of a validated and easy to use clinical tool in this population to predict patients who will not tolerate R-CHOP. Identifying patients who will not tolerate R-CHOP early with the help of tools like CGA, along with integrating biology-based treatment (ibrutinib, lenalidomide in activated B cell type DLBCL) is being investigated in this population.

Independent predictors of mortality and 5-year trends in mortality and resource utilization in hospitalized patients with diffuse large B cell lymphoma.

Background: This retrospective study analyzed factors influencing all-cause inpatient mortality in 80,930 adult patients (2016-2020) with diffuse large B cell lymphoma using the National Inpatient Sample database. Methods: Utilizing ICD-10 codes, patients were identified, and statistical analysis was conducted using STATA. Fisher's exact and Student's t tests compared proportions and variables, multivariate logistic regression examined mortality predictors, and a 5-year longitudinal analysis identified mortality and resource utilization trends. Results: The inpatient mortality rate was found to be 6.56% with a mean age of 67.99 years. Several hospital- and patient-level factors including specific comorbidities such as congestive heart failure, atrial fibrillation, acute kidney injury, chronic obstructive pulmonary disease, liver failure, pancytopenia, tumor lysis syndrome, and severe protein-calorie malnutrition were independently associated with inpatient mortality. Hospitalization costs showed an increasing trend, impacting the overall population and survivors. Conclusion: These insights may refine risk assessment, treatment selection, and interventions.

Novel Targeted Therapies for Chronic Lymphocytic Leukemia in Elderly Patients: A Systematic Review.

Chronic lymphocytic leukemia (CLL) typically affects older patients; administration of traditional cytotoxic therapies in old patients has very modest benefit with no survival improvement. With better understanding of CLL biology, trends are shifting towards the use of targeted therapies. The objective of this article is to review the safety and efficacy of various novel agents that specifically target the dysregulated pathways, with particular attention to elderly patients. Agents like B-cell receptor (BCR) inhibitors (Bruton's tyrosine kinase inhibitors [ibrutinib]), phosphatidylinositol 3-kinase inhibitors (idelalisib), spleen tyrosine kinase inhibitors (entospletinib), Bcl-2 inhibitors (venetoclax), immunomodulators (lenalidomide), and monoclonal antibodies (obinutuzumab, ofatumumab) have shown activity in CLL with a very favorable toxicity profile. Newer agents have improved clinical outcomes, and have tolerable toxicity profiles in elderly patients, resulting in the treatment with individualized therapy approach for CLL.

Evidence-based supportive care in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clone of plasma cells in the bone marrow. MM and its therapy increase the risk of complications like anemia, osteolytic lesions, pain, infections, and renal abnormalities in MM patients. Supportive care for MM patients improves the quality of life. Treatment with bisphosphonates decreases skeletal-related events. Vertebroplasty and kyphoplasty are done in cases of vertebral compression fractures. Prophylactic antibiotics and antivirals can decrease infections related to morbidity. Plasmapheresis in patients with renal dysfunctions decreases dialysis dependency and improve quality of life.

Concomitant use of blinatumomab and donor lymphocyte infusion for mixed-phenotype acute leukemia: a case report with literature review.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Special considerations for the treatment of multiple myeloma according to advanced age, comorbidities, frailty and organ dysfunction.

Multiple Myeloma (MM) is primarily a disease of old age with a median age of sixty-nine years at diagnosis. The development of novel therapies for induction and use of autologous stem cell transplantation has resulted in improved clinical outcomes and better quality of life for MM patients. Elderly patients, comprising the majority of MM population, have a higher incidence of age-related comorbidities, frailty and organ dysfunction which complicates the coordination of treatment and limits the selection of therapies. Even in the era of multiple chemotherapeutic options, the clinical heterogeneity of the myeloma patients' demands personalized treatments which often require dose-adjustments or dose delays. The use of reduced-dose regimens and various comorbidity indices has improved clinical outcome and regimen tolerability in MM patients with renal, neurological and bone abnormalities. We focus on advancements in the treatment of multiple myeloma with the goal to guide clinicians towards patient-specific management.