Management and Outcomes of Patients with Refractory Solitary Plasmacytoma after Treatment with Definitive Radiation Therapy.

PURPOSE: Radiation therapy (RT) is the standard treatment for solitary plasmacytoma (SP); however, the optimal management of RT-refractory SPs is unknown. We examined outcomes after early systemic therapy, surgical resection, or observation for patients with RT-refractory disease and assessed the potential impact of treatment selection on disease outcomes. METHODS AND MATERIALS: We retrospectively reviewed patients with SP treated with definitive radiation and evaluated at a single institution with persistent disease on imaging or biopsy. Descriptive statistics were used to characterize patient and disease characteristics and treatment outcomes. RESULTS: Of 102 total SP patients, 17 (17%) were RT-refractory. The median RT dose was 45 Gy, and median follow-up was 71 months from end of RT. Fifteen patients had additional treatment for refractory disease at a median time of 9.5 months after RT, with the following subsequent interventions: surgical resection (n = 4), additional RT (n = 2), systemic therapy without evidence of multiple myeloma (MM; n = 4), systemic therapy for progression to MM (n = 5), and observation (n = 2). Of 4 patients treated with surgical resection, 3 progressed to MM 22 to 43 months after diagnosis. Of 2 patients treated with additional RT, neither responded, and both had pathologic confirmation of residual disease after the second course. Four patients treated with systemic therapy without MM all had complete responses on positron emission tomography and no subsequent MM progression. Eight patients were initially observed after RT for ≥12 months (n = 8) or ≥24 months (n = 6). Of the 2 patients in continued observation, both had stable/unchanged avidity after radiation treatment for 12 and 22 months and ultimately had a slow decrease of disease avidity over multiple years. CONCLUSIONS: Patients with RT-refractory SPs can achieve good local control with alternative therapies, such as surgery or systemic therapy, if needed. Additional RT does not seem to be effective. Given the known high rates of progression from SP to MM, close observation of asymptomatic persistent disease until disease progression is likely sufficient in most cases.

Efficacy of single-dose oral secnidazole for the treatment of trichomoniasis in women co-infected with trichomoniasis and bacterial vaginosis: a post hoc subgroup analysis of phase 3 clinical trial data.

OBJECTIVES: Bacterial vaginosis (BV) and trichomoniasis are the most common causes of vaginitis. Both infections are associated with increased risk of acquisition and transmission of HIV and other sexually transmitted infections as well as adverse reproductive health outcomes. Co-infection is common, with rates ranging from 60% to 80%. We evaluated the efficacy of single-dose oral secnidazole 2 g for the treatment of trichomoniasis in a subgroup of women co-infected with BV and trichomoniasis. DESIGN: Post hoc analysis of data from a phase 3 randomised, double-blind, placebo-controlled, delayed-treatment study. SETTING: 10 centres in the USA. PARTICIPANTS: Subgroup of women (aged ≥12 years) with a confirmed diagnosis of Trichomonas vaginalis and co-infection with BV clinically diagnosed using Amsel's criteria. INTERVENTION: Single dose of secnidazole 2 g or placebo. OUTCOME MEASURES: The primary efficacy outcome was the microbiological cure (negative culture for T. vaginalis) at the test of cure (TOC) visit 6-12 days after dosing in the modified intent-to-treat population (mITT). At TOC, participants received the opposite treatment. RESULTS: Of the 131 T. vaginalis-infected participants in the mITT, 79 (60.3%) met ≥3 Amsel's criteria for BV at enrolment. Microbiological cure rates for trichomoniasis at TOC among this subgroup of women were 97.7% (42/43) for secnidazole and 0% (0/36) for placebo. CONCLUSION: Single-dose oral secnidazole 2 g was highly efficacious in curing trichomoniasis in women co-infected with BV. Appropriate and effective treatment options for co-infection are essential for reducing transmission and reinfection. Secnidazole is the only single-dose medication approved by the Food and Drug Administration for the treatment of BV in women and trichomoniasis in women and men. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03935217; post-results.

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma.

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) have disease that relapses. Allogeneic (allo-) hematopoietic cell transplantation (HCT) is a potentially curative option for a subgroup of patients with high-risk MM. This study assessed the long-term outcome of MM patients who underwent allo-HCT while in first remission as consolidation treatment. Thirty-three patients with newly diagnosed MM who underwent allo-HCT as part of consolidation therapy between 1994 and 2016 were reviewed retrospectively. Of these patients, 70% underwent autologous HCT before allo-HCT. All patients were chemosensitive and achieved at least partial response before proceeding to allo-HCT. Most received nonmyeloablative/reduced-intensity conditioning (88%) and a matched sibling donor graft (85%). Acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. The median duration of follow-up was 64.1 months (range, 1.4 to 199.2 months) for all patients and 164.4 months (range, 56.0 to 199.2 months) for survivors. The median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 to 73.0 months). The median time from treatment to progression was 73.0 months (95% CI, 30.6 months to not reached). The median overall survival (OS) was 131.9 months (95% CI, 38.4 months to not reached). Of all patients, 39% were alive for more than 10 years, with 46% (n = 6) without progression or relapse. The cumulative incidence of relapse was 18% at 1 year, 39% at 5 years, and 46% at 10 years post-allo-HCT. The cumulative incidence of nonrelapse mortality was 3% at 100 days, 18% at 1 year, 21% at 3 years, and 24% at 5 year post-allo-HCT. On multivariable analysis, high-risk cytogenetics were associated with a shorter PFS (hazard ratio [HR], 2.7; 95% CI, 1.01 to 7.21; P = .047) and OS (HR, 4.91; 95% CI, 1.48 to 16.27; P = .009). Achieving complete remission after allo-HCT also was associated with longer PFS (HR, 0.24; 95% CI, 0.09 to 0.64; P = .004) and OS (HR, .23; 95% CI, .07 to .72; P = .012). Allo-HCT may confer a survival advantage in a selected population of MM patients when performed early in the disease course; additional data on identifying the patients who will benefit the most are needed.

KRD vs. VRD as induction before autologous hematopoietic progenitor cell transplantation for high-risk multiple myeloma.

Bortezomib, lenalidomide, and dexamethasone (VRD) induction is standard prior to autologous hematopoietic cell transplantation (auto-HCT) in newly diagnosed, high-risk multiple myeloma (ND-HRMM). Carfilzomib (K) is another proteasome inhibitor approved for MM. In this single-center, retrospective analysis, we compared outcomes in ND-HRMM with pre-transplant KRD or VRD induction. High-risk was defined by t(4:14), t(14:16), 1q21 gain/amplification, or del(17p). Primary endpoints were progression-free (PFS) and overall survival (OS). Of 121 ND-HRMM patients, 63 received KRD, and 58 received VRD. Post-induction, complete (CR), very good partial (VGPR), partial response (PR), and overall response (ORR) rates were 23.8%/49.2%/25.4%/98.4% with KRD, and 19%/46.6%/27.6%/93.1% with VRD. At day 100 post-auto-HCT, these were 38.1%/42.9%/19%/100% with KRD, versus 35.1%/49.1%/12.3%/94.8% with VRD. Pre-auto-HCT, 11 (18.3%) KRD and 7 (12.5%) VRD patients had minimal residual disease (MRD)-negative CR (p = 0.45). Post-auto-HCT, 14 (41.2%) and 13 (43.3%) patients had MRD-negative CR (p = 1.000). Median PFS was 38.2 (95%CI 28.7-NA) and 45.9 months (95%CI 43.2-NA) for KRD and VRD, respectively (p = 0.25). Respective 3-year PFS and OS were 53.5% (95%CI 41.1-69.6) and 95.2% (95%CI 90-100) for KRD and 64% (95%CI 51.6-79.5) and 84.2% (95%CI 73.5-96.3, p = 0.30) for VRD. Overall, KRD induction pre-auto-HCT does not improve outcomes. Prospective, randomized studies are needed to confirm these findings.

Impact of Induction With VCD Versus VRD on the Outcome of Patients With Multiple Myeloma After an Autologous Hematopoietic Stem Cell Transplantation.

Induction therapy with a triplet regimen, followed by high-dose therapy and autologous hematopoietic stem cell transplantation (auto-HCT), is the standard of care for newly diagnosed, transplant-eligible patients with multiple myeloma (MM). Bortezomib-dexamethasone with cyclophosphamide (VCD) or lenalidomide (VRD) are the most used induction regimens. However, previous studies comparing VCD and VRD showed disparate results. The goal of this retrospective study was to compare the "real-world" results of VCD and VRD in transplant-eligible MM patients outside of a clinical trial. We identified 322 patients who received VRD or VCD induction before auto-HCT at our institution. All patients received melphalan conditioning and single-agent lenalidomide maintenance therapy. Overall, 114 patients received VCD, and 208 received VRD. The median age at auto-HCT was 61.9 years (range 33.9-79.6), with 35.4% (114/322) of the cohort being 65 years of age or older. The overall response rate was 99.7% after auto-HCT, with a significantly lower complete remission rate as the final response in the VCD compared to the VRD group (34% versus 53%; P = .001). However, there was no significant difference between the best response rate of very good partial response (VGPR) or better in the VCD compared to the VRD group (92% versus 85%; P = .078). The median duration of ≥VGPR was 50.0 months (95% confidence interval [CI], 42.0-69.1) for both cohorts, and there was no difference between VCD and VRD (P = .769; hazard ratio, 0.95; 95% CI, 0.69-1.31). Median follow-up of survivors was 73 months. There was no difference in the relapse rate between VCD and VRD (P = .749). Median progression-free survival (PFS) was 48.7 months in the VCD and 44.6 months in the VRD group (P = .858). Median overall survival (OS) was 103.8 months with VCD and 101.7 months with VRD (P = .891). At 5 years, the PFS and OS were 38.1% and 76.9% for the VCD group, respectively, and 40.7% and 74.6% for the VRD group, respectively. On multivariate analysis for OS in the entire cohort, Revised International Staging System I and post-auto-HCT best response of stringent complete response (sCR)/CR emerged as significant predictors of superior OS. There was no impact of the type of induction regimen on the OS in the multivariate analysis. Induction therapy with VCD compared to VRD was associated with a lower CR rate, but there was no difference in PFS or OS between the 2 regimens.

Real-world long-term outcomes in multiple myeloma with VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance.

Standard-of-care for newly-diagnosed, autologous hematopoietic stem cell transplantation (auto-HCT)-eligible, multiple myeloma (MM) patients includes bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by melphalan 200 mg/m2 (Mel200)-conditioned auto-HCT and lenalidomide maintenance. We completed a retrospective case series assessing outcomes of 187 MM patients who received this regimen at our institution. The 100-day non-relapse mortality incidence was zero. Before auto-HCT, 9.6 and 52.9% of patients achieved a complete response (CR) or ≥ very good partial response (VGPR), respectively. At day-100 post-transplant, 29.4 and 74.9% had achieved a CR/stringent-CR (sCR) or ≥ VGPR, respectively. At the last evaluation, 57.2% of patients had CR/sCR and 87.1% had ≥ VGPR. Median follow-up, progression-free survival (PFS), and overall survival (OS) were 63.2, 50, and 101.7 months, respectively. The 5-year PFS and OS were 43.1 and 79%. High-risk cytogenetics was associated with worse outcomes. This study illustrates that VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance are associated with good outcomes in MM.

Human herpesvirus 6 myelitis after chimeric antigen receptor T-cell therapy.

This article reports a fatal case of human herpesvirus 6 (HHV-6) myelitis following CD19-targeted chimeric antigen receptor T-cell therapy. Infection from HHV-6 reactivation after haematopoietic stem cell transplant is established, and outside of this population is limited to case reports. The patient developed cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome that responded to corticosteroids both clinically and on imaging. Subsequently, ascending flaccid paralysis developed, leading to neuromuscular respiratory failure and, ultimately, death. Disease progression was refractory to foscarnet and multiple immunomodulating agents. HHV-6 should be considered in patients with encephalitis and myelitis after adoptive T-cell therapy.

Cardiac Magnetic Resonance Predicting Outcomes Among Patients at Risk for Cardiac AL Amyloidosis.

Introduction: Patients with systemic AL amyloidosis (AL) should be evaluated for cardiac amyloidosis (CA), as prognosis is strongly related to cardiac involvement. We assessed the characteristics of patients referred to cardiac magnetic resonance (CMR) with suspected CA from a cancer center and determine predictors of mortality/heart failure hospitalizations (HFH). Methods: Forty-four consecutive patients referred for CMR with suspected CA were retrospectively included. Variables collected included cardiac biomarkers, in addition to echocardiographic and CMR variables. Survival analyses were performed to determine which variables were more predictive of mortality and HFH. Results: Of the 44 patients included, 55% were females. 73% of patients were diagnosed with CA by CMR; 56% of them had an established diagnosis of AL. Patients with CA by CMR had higher native T1, higher extracellular volume (ECV) fraction, higher T2, less negative GLS by Echo, and higher troponin I and B-type natriuretic peptide (BNP). Kaplan-Meier survival analysis revealed that the following were predictive of mortality: an ECV ≥ 0.50 (p = 0.0098), CMR LVEF < 50% (p = 0.0010), T2/ECV ≤ 100 (p = 0.0001), and troponin I > 0.03 (p = 0.0025). In a stepwise conditional Cox logistic regression model, the only variable predictive of a composite of mortality and HFH was ECV (HR: 1.17, 95% CI = 1.02-1.34 p = 0.030). Conclusion: ECV seems to be an important biomarker that could be a predictor of outcomes in cardiac AL amyloidosis. In combination, CMR and serum cardiac biomarkers might help to establish prognosis in patients with CA.

Efficacy and Safety of Single Oral Dosing of Secnidazole for Trichomoniasis in Women: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Delayed-Treatment Study.

BACKGROUND: Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection. We evaluated the efficacy and safety of secnidazole vs placebo in women with trichomoniasis. METHODS: Women with trichomoniasis, confirmed by a positive T. vaginalis culture, were randomized to single-dose oral secnidazole 2 g or placebo. The primary endpoint was microbiological test of cure (TOC) by culture 6-12 days after dosing. At the TOC visit, participants were given the opposite treatment. They were followed for resolution of infection afterward and offered treatment at subsequent visits, if needed. Fifty patients per group (N = 100) provided approximately 95% power to detect a statistically significant difference between treatment groups. RESULTS: Between April 2019 and March 2020, 147 women enrolled at 10 sites in the United States. The modified intention-to-treat (mITT) population included 131 randomized patients (secnidazole, n = 64; placebo, n = 67). Cure rates were significantly higher in the secnidazole vs placebo group for the mITT population (92.2% [95% confidence interval {CI}: 82.7%-97.4%] vs 1.5% [95% CI: .0%-8.0%]) and for the per-protocol population (94.9% [95% CI: 85.9%-98.9%] vs 1.7% [95% CI: .0%-8.9%]). Cure rates were 100% (4/4) in women with human immunodeficiency virus (HIV) and 95.2% (20/21) in women with bacterial vaginosis (BV). Secnidazole was generally well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were vulvovaginal candidiasis and nausea (each 2.7%). No serious TEAEs were observed. CONCLUSIONS: A single oral 2 g dose of secnidazole was associated with significantly higher microbiological cure rates vs placebo, supporting a role for secnidazole in treating women with trichomoniasis, including those with HIV and/or BV. CLINICAL TRIALS REGISTRATION: NCT03935217.

In vitro metabolic profile and drug-drug interaction assessment of secnidazole, a high-dose 5-nitroimidazole antibiotic for the treatment of bacterial vaginosis.

A single-dose oral granule formulation of secnidazole 2 g (SOLOSEC™ ) has been approved in the US as a treatment for bacterial vaginosis. Available data on the likelihood of in vitro drug-drug and alcohol-drug interactions are limited. Secnidazole was incubated with cultured human hepatocytes over a range of concentrations (0-10 000 µmol/L) to assess metabolic profiling. Cytochrome P450 (CYP) and aldehyde dehydrogenase inhibition over a similar concentration range were evaluated in human liver microsomes (HLMs) or recombinant enzymes using competition or time-dependent inactivation assays. Secnidazole exhibited very low metabolism in HLMs at concentrations up to 6400 µmol/L. Secnidazole was found to be metabolized to a limited extent predominantly by CYP3A4 and CYP3A5 among a panel of cDNA-expressed enzymes. Secnidazole inhibited CYP2C19 and CYP3A4, with IC50 values of 3873 and 3722 µmol/L, respectively. Secnidazole did not exhibit time-dependent inhibition. There was no inhibition (IC50 value >5000 µmol/L) observed for any other CYP enzyme or with human recombinant aldehyde dehydrogenase 2 (ALDH2). These results are the first reported observation of the metabolism and drug-drug interaction profile for secnidazole and demonstrate that the agent has minimal to no potential drug interactions of concern.

Organ responses with daratumumab therapy in previously treated AL amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

Beyond Andromeda: Improving Therapy for Light Chain Amyloidosis.

Therapy for light chain amyloidosis (AL) continues to evolve, and a new standard of care for the disease is rapidly forming. The risk of early death however, mainly from cardiac complications, remains an important benchmark yet to be definitively improved upon. This brief review explores recent advances in plasma cell directed therapy for AL, highlighting unique factors specific to these patients and AL biology driving differences in treatment strategies and clinical development compared with multiple myeloma. Improving upon proteasome inhibitor based upfront therapy combinations with the addition of anti-CD38 antibodies has shown promise with improved response rates in the ANDROMEDA (NCT03201965) study. Though depth and kinetics of achieving deep hematologic response as well as rates of biomarker defined organ response were improved with the addition of daratumumab to the combination of bortezomib, cyclophosphamide, and dexamethasone, death rates in each arm remained similar. Evaluation of other targeted and novel therapies in AL is ongoing, and we highlight efforts evaluating B-cell maturation antigen (BCMA) directed therapy, BCL-2 family inhibitors, and other novel agents in the field. We also look ahead to efforts to reimagine the clinical development of anti-fibrillar therapies after late phase study failures. Upcoming anti-amyloid fibril antibody studies explore opportunities to improve outcomes for the sickest AL patients with advanced cardiac disease, focusing on improving overall patient survival and reducing the risk of early death in this uniquely frail population.

Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases.

INTRODUCTION: The advent of immune checkpoint inhibitors in the treatment of certain types of cancers has revolutionized cancer therapy. In general, these novel agents are more tolerable and have better safety profiles than conventional chemotherapy agents. Although a low incidence of myocarditis was noted as a side effect of immune checkpoint inhibitors in clinical trials, it is being increasingly cited in the literature as their use also increases. METHODS: Using a combination of search terms in the PubMed/Medline database and manual searches on Google Scholar and the bibliographies of articles identified, we reviewed all cases reported in the English language citing myocarditis associated with either pembrolizumab, nivolumab, ipilimumab, or any combination of these agents. RESULTS: A total of 42 cases were included in the study. Mean age was 65.5 years; 64% were male, 36% were female. One or two doses preceded the onset of myocarditis in 33% and 29% of cases, respectively. Steroids were used as the first-line therapy in 90% of cases. Complete heart block occurred in 36% of cases. Fourteen (33%) deaths were reported, with 64% and 29% of deaths occurring after one or two doses, respectively. CONCLUSION: Most cases and fatalities of myocarditis occurred shortly after initiation of immune checkpoint inhibitor therapy. Arrhythmias, particularly complete heart block, appear to be related to the occurrence of more severe and fatal cases. The use of serial electrocardiograms or biomarkers of myocardial injury may be crucial in detecting early stages of the disease process. Further research establishing more specific guidelines is necessary in dealing with this potentially fatal side effect.

A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma.

This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous amrubicin 40-80 mg/m2 on day one, lenalidomide 15 mg orally on days 1-14, and dexamethasone 40 mg orally weekly on 21 day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4 months, and the median progression-free survival was 3 months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.Clinicaltrials.gov identifier: NCT01355705.