Outcomes of Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma Receiving Salvage Cytotoxic Therapy with Supportive Stem Cell Boost.

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the neoplastic proliferation of plasma cells, which produce monoclonal immunoglobulin that can cause vital organ damage, subsequently leading to significant morbidity and mortality. Autologous hematopoietic stem cell transplant (ASCT) is the standard-of-care management of eligible patients with newly diagnosed MM. Experts recommend collecting enough stem cells upfront to support a possible tandem transplant, salvage ASCT, or a stem cell "boost" to allow for the administration of multiagent cytotoxic chemotherapy in patients with relapsed/refractory disease. OBJECTIVE: There is currently a paucity of data on the response rates and outcomes of patients with relapsed MM who undergo cytotoxic chemotherapy followed by a stem cell boost; this study examines the outcomes of patients treated with this approach. METHODS: We conducted a retrospective chart review from two oncologic treatment centers in the United States of adult patients who underwent a first ASCT between 1999 and 2021 and subsequently received cytotoxic chemotherapy followed by stem cell boost further on in their disease course. Survival analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. RESULTS: We found that the majority (56.6%) of these patients responded to therapy and that 60.6% of these patients were able to receive at least one subsequent line of therapy post-boost. Furthermore, patients who responded to therapy had significantly longer median overall survival compared to those who did not respond (323 days vs 93 days, p=0.0045), and age did not affect response to therapy. CONCLUSION: This data allow clinicians to appropriately implement and inform patients of the therapeutic uses and clinical outcomes of stem cell boost in patients with multiply relapsed/refractory MM.

Interaction between age and gender on survival outcomes in extramedullary multiple myeloma over the past two decades.

BACKGROUND: Extramedullary multiple myeloma (MM) (EMM) is a rare and aggressive subentity of MM that can be present at diagnosis or develop anytime during the disease course. There is a paucity of data on the clinical characteristics and overall epidemiology of EMM. Furthermore, there is a scarcity of data on how the interaction of age and gender influences the survival of EMM. AIM: To evaluate the clinical characteristics of patients with EMM over the past 2 decades and to identify epidemiologic characteristics that may impact overall prognosis. METHODS: A total of 858 patients diagnosed with EMM, between 2000 and 2017, were ultimately enrolled in our study by retrieving the Surveillance, Epidemiology, and End Results database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of EMM. Variables with a P value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. RESULTS: From a sample of 858 EMM, the male gender (63.25%), age range 60-79 years (51.05%), and non-Hispanic whites (66.78%) were the most represented. Central Nervous System and the vertebral column was the most affected site (33.10%). Crude analysis revealed higher OM in the age group 80+ [HR = 6.951, 95% confidence interval (95%CI): 3.299-14.647, P = 0], Non-Hispanic Black population (HR = 1.339, 95%CI: 1.02-1.759, P = 0.036), Bones not otherwise specified (NOS) (HR = 1.74, 95%CI: 1.043-2.902, P = 0.034), and widowed individuals (HR = 2.107, 95%CI: 1.511-2.938, P = 0). Skin involvement (HR = 0.241, 95%CI: 0.06-0.974, P = 0.046) and a yearly income of $75000+ (HR = 0.259, 95%CI: 0.125-0.538, P = 0) had the lowest OM in the crude analysis. Crude analysis revealed higher CSM in the age group 80+, Non-Hispanic Black, Bones NOS, and widowed. Multivariate cox proportional hazard regression analyses only revealed higher OM in the age group 80+ (HR = 9.792, 95%CI: 4.403-21.774, P = 0) and widowed individuals (HR = 1.609, 95%CI: 1.101-2.35, P = 0.014). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups. Eyes, mouth, and ENT involvement had the lowest CSM in the multivariate analysis. There was no interaction between age and gender in the adjusted analysis for OM and CSM. CONCLUSION: EMM is a rare entity. To our knowledge, there is a scarcity of data on the clinical characteristics and prognosis factors of patients with extramedullary multiple myeloma. In this retrospective cohort, using a United States-based population, we found that age, marital status, and tumor site were independent prognostic factors. Furthermore, we found that age and gender did not interact to influence the mortality of patients with EMM.

Impact of the COVID-19 Pandemic on Treatment Patterns for Patients With Metastatic Solid Cancer in the United States.

BACKGROUND: The COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is unknown. We assessed the COVID-19 pandemic's impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer. METHODS: We used an electronic health record-derived longitudinal database curated via technology-enabled abstraction to identify 14 136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at approximately 280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy. RESULTS: The adjusted probability of treatment within 30 days of diagnosis was similar across periods (January-March 2019 = 41.7%, 95% confidence interval [CI] = 32.2% to 51.1%; April-July 2019 = 42.6%, 95% CI = 32.4% to 52.7%; January-March 2020 = 44.5%, 95% CI = 30.4% to 58.6%; April-July 2020 = 46.8%, 95% CI= 34.6% to 59.0%; adjusted percentage-point difference-in-differences = 1.4%, 95% CI = -2.7% to 5.5%). Among 5962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences = 1.6%, 95% CI = -2.6% to 5.8%). There was no meaningful effect modification by cancer type, race, or age. CONCLUSIONS: Despite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not affect TTI or treatment selection for patients with metastatic solid cancers.

Optimal Management of Patients with Advanced or Metastatic Cholangiocarcinoma: An Evidence-Based Review.

Cholangiocarcinomas are rare tumors originating at any point along the biliary tree. These tumors often pose significant challenges for diagnosis and treatment, and often carry a poor prognosis. However, in recent years, studies have identified significant molecular heterogeneity with up to 50% of tumors having detectable mutations, leading to the guideline recommendations for molecular testing as part of the diagnostic workup for these tumors. In addition, better classification of these tumors and understanding of their biology has led to new drugs being approved for treatment of this resistant tumor. This manuscript will provide a comprehensive review of the epidemiology, risk factors, diagnostic approach, molecular classification, and treatment options for patients with advanced cholangiocarcinomas.

Impact of the COVID-19 pandemic on treatment patterns for US patients with metastatic solid cancer.

BACKGROUND: The COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is unknown. We assessed the COVID-19 pandemic's impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer. METHODS: We used an electronic health record-derived longitudinal database curated via technology-enabled abstraction to identify 14,136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at ∼280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy. RESULTS: The adjusted probability of treatment within 30 days of diagnosis [95% confidence interval] was similar across periods: January-March 2019 41.7% [32.2%, 51.1%]; April-July 2019 42.6% [32.4%, 52.7%]; January-March 2020 44.5% [30.4%, 58.6%]; April-July 2020 46.8% [34.6%, 59.0%]; adjusted percentage-point difference-in-differences 1.4% [-2.7%, 5.5%]. Among 5,962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences 1.6% [-2.6%, 5.8%]). There was no meaningful effect modification by cancer type, race, or age. CONCLUSIONS: Despite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not impact time to treatment initiation or treatment selection for patients with metastatic solid cancers.

High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators.

Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy.

Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR).

OBJECTIVE: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis. PATIENTS AND METHODS: We performed a retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016. RESULTS: There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis. CONCLUSION: These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct.

Fgfr1 inactivation in the mouse telencephalon results in impaired maturation of interneurons expressing parvalbumin.

Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1(f/f);hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1(f/f);NesCre+). Similar to findings in Fgfr1(f/f);hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1(f/f);NesCre+ mice when compared to control littermates (Fgfr1(f/f)). Fgfr1(f/f);NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1(f/f);hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1(f/f) control or Fgfr1(f/f);hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1(f/f);NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence.