Traditional Medicare or Medicare Advantage? The Leukemia and Cancer Perspective.

Today, approximately 50% of patients eligible for Medicare have opted for Medicare Advantage as their primary coverage. Whereas Medicare Advantage is a reasonable option for healthy senior Americans, issues arise once they have serious or chronic medical problems, which are prevalent among older Americans. This review details the pros and cons of standard Medicare vs Medicare Advantage. The authors recommend considering standard Medicare as a better form of insurance coverage. In addition, patients should also enroll in Medicare Part D to get prescription drug coverage; buy a supplemental MediGap policy; and buy additional coverage for hearing, vision, and dental care. Although this is a more complicated process, it is also a better one until Medicare Advantage revises its plans to address the current issues facing Americans on such plans who have serious illnesses.

Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m2 < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0-25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05-4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68-4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50-4.42, P = 0.001), and abnormal free light chain ratio (FLCr) (HR = 3.39, CI:1.98-5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68-0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06-11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57-3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLCr. This association may be stronger among females.

Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-ß (IFN-ß) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNß-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-ß, a biomarker of VSV-IFNß-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-ß of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNß-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.

Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome.

Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

Single center, open label dose escalating trial evaluating once weekly oral ixazomib in ART-suppressed, HIV positive adults and effects on HIV reservoir size in vivo.

BACKGROUND: Achieving a functional or sterilizing cure for HIV will require identification of therapeutic interventions that reduce HIV reservoir size in infected individuals. Proteasome inhibitors, such as ixazomib, impact multiple aspects of HIV biology including latency, transcription initiation, viral replication, and infected cell killing through the HIV protease - Casp8p41 pathway, resulting in latency reversal and reduced measures of HIV reservoir size ex vivo. METHODS: We conducted a phase 1b/2a dose escalating, open label trial of weekly oral ixazomib for 24 weeks in antiretroviral (ART)-suppressed, HIV positive adults (NCT02946047). The study was conducted from March 2017 to August 2019 at two tertiary referral centers in the United States. The primary outcomes were safety and tolerability of oral ixazomib. Secondary outcomes included changes in immunologic markers and estimates of HIV reservoir size after ixazomib treatment. FINDINGS: Sixteen participants completed the study. Ixazomib up to 4mg weekly was safe and well-tolerated, yielding no treatment-emergent events above grade 1. In exploratory analyses, ixazomib treatment was associated with detectable viremia that was below the lower limit of quantification (LLQ) in 9 participants, and viremia that was above LLQ in 4 of 16 participants. While treatment was associated with reduced CD4 counts [baseline 783 cells/ mm3 vs. week-24 724 cells/ mm3 p=0.003], there were no changes in markers of cellular activation, exhaustion or inflammation. Total HIV DNA and proviral sequencing were not altered by ixazomib treatment. Intact proviral DNA assay (IPDA) identified intact proviruses in 14 patients pre-treatment, and in 10/14 of those subjects post treatment values were reduced (P=0.068), allowing a calculated intact proviral half life of 0.6 years (95% CI 0.3, 2.5), compared to 7.1 years (95% CI 3.9, 18, p=0.004) in historical controls. Differentiation Quantitative Viral Outgrowth Assays (dQVOA) identified measurable proviruses in 15 subjects pre-treatment; post-treatment values were numerically reduced in 9, but overall differences were not significantly different. INTERPRETATION: Our study successfully met its primary endpoint of demonstrating the safety of ixazomib for 24 weeks in HIV infected persons. Exploratory analyses suggest that the effects observed ex vivo of latency reversal and reductions in HIV reservoir size, also occur in vivo. Future controlled studies of ixazomib are warranted. FUNDING: This study was funded by Millennium Pharmaceuticals Inc..; the Mayo Clinic Foundation; the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, Division of AIDS, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse. Mayo Clinic also acknowledges generous funding support from Mr. Joseph T. and Mrs. Michele P. Betten.

Prognostic impact of posttransplant FDG PET/CT scan in multiple myeloma.

Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET-) (P < .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET- group (P < .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

Impact of CD138 Magnetic Bead-based Positive Selection on Bone Marrow Plasma Cell Surface Markers.

BACKGROUND: Isolation of malignant plasma cells from bone marrow of patients with monoclonal gammopathies is critical for studies into the disease biology. The plasma cells are typically isolated by positive selection using plasma cell markers such as CD138. Here we have examined the effect of CD138 magnetic bead selection on the expression of other surface phenotypic markers on plasma cells. MATERIALS AND METHODS: Bone marrow aspirates from 16 patients were split and prepared using 2 methods before staining for flow cytometric evaluation. The first method (whole bone marrow) used an ammonium-chloride-potassium lyse of whole bone marrow followed by 2 phosphate buffered saline washes. The second method used CD138-positive magnetic sorting technology (Stem Cell Technology). The cells were run on the FACSCanto flow cytometer after staining for CD38, CD45, CD56, activation markers CD71, CD69, CD154, adhesion markers CD49d, CD49e, CD11a, CD11b, and CD66, B cell markers CD19 and CD20, and for clonality. RESULTS: There was a substantial loss in the expression of CD71, CD11b, CD11a, CD69, and CD49e on plasma cells following CD138-based sorting. Moreover, in 8 of the 16 cases, there was a nearly complete loss of the CD45-positive subset with a loss of discrimination between CD45-negative and CD45-positive plasma cell subsets in the remaining CD138-sorted preparations. CONCLUSIONS: The change in immunophenotype of the plasma cells on magnetic sorting should be kept in mind when isolating plasma cells using CD138-positive selection for analysis of plasma cells. The technique for characterizing plasma cells should be selected based on the study design to prevent loss of crucial and valuable information.

Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first-line therapy in multiple myeloma.

Induction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment-emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first-line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty-five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21-day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22-56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

Implications of detecting serum monoclonal protein by MASS-fix following stem cell transplantation in multiple myeloma.

Measurable residual disease (MRD) assessment by marrow-based next-generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false-negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MASS-FIX). Of all 61 complete responders who were NGF-negative for MRD, around day-100 post ASCT, 59% were MASS-FIX-positive. At median follow-up of 26 months, 69% of MASS-FIX(+)/NGF(-) patients were alive and progression-free versus 96% of MASS-FIX(-)/NGF(-) patients, P = 0·02. MASS-FIX, a simple peripheral blood-based assay complements marrow-based NGF to accurately prognosticate patients with myeloma.

Colon perforation in multiple myeloma patients - A complication of high-dose steroid treatment.

Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high-dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty-five patients required ostomies with all surviving surgery. Twenty-four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8-59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti-myeloma treatment appears to be safe.

The role of bone marrow biopsy in patients with plasma cell disorders: should all patients with a monoclonal protein be biopsied?

We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients "without CRAB/FLC" were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (<1% SMM cohort) were low-risk MGUS without abnormalities in hemoglobin, calcium, and renal function. In patients presenting with low-risk MGUS and normal hemoglobin, calcium, and renal function, the risk of missing a diagnosis of SMM and MM by omitting BM is <1%. BM should be deferred in these patients in preference to clinical and laboratory monitoring.

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes.

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Quality of life is maintained with ixazomib maintenance in post-transplant newly diagnosed multiple myeloma: The TOURMALINE-MM3 trial.

OBJECTIVES: Health-related quality of life (HRQoL) is particularly important during maintenance therapy (MT) in newly diagnosed multiple myeloma post-transplant, when disease symptoms are limited. METHODS: We assessed HRQoL in patients randomised to 26 cycles of MT (ixazomib vs placebo) in TOURMALINE-MM3 (NCT02181413). RESULTS: The characteristics at study entry were well-balanced between ixazomib (n = 386) and placebo (n = 251) arms. At study entry, EORTC QLQ-C30 and MY20 scores were high for functional scales and low for symptom scales and were comparable with those of the general population. Changes in subscale scores across intervals, analysed over 30 four-week intervals using a linear mixed-effects model, were generally small and similar between arms for the EORTC QLQ-C30 Global Health Status/QoL, Physical Functioning, and Pain subscales and EORTC QLQ-MY20 Disease Symptoms subscale and Peripheral Neuropathy item. EORTC QLQ-C30 Nausea/Vomiting and Diarrhoea subscales were consistently worse for ixazomib than for placebo, in line with the ixazomib toxicity profile. Even when least-squares mean differences between arms were statistically significant, none reached the established minimal important clinical difference of 10 in multiple myeloma. CONCLUSIONS: In addition to improvement in progression-free survival with ixazomib, HRQoL was maintained in both arms. Active treatment with ixazomib did not have an adverse impact on HRQoL.

Prognostic value of minimal residual disease and polyclonal plasma cells in myeloma patients achieving a complete response to therapy.

Achievement of a complete response has been associated with improved outcomes in patients with multiple myeloma. Recently, increasing application of minimal residual disease (MRD) assessment has shown that MRD negativity is a powerful prognostic factor for survival outcomes. We wanted to examine the impact of the polyclonal plasma cell (pPC) compartment among patients in complete response (CR) but are MRD positive. This is a retrospective cohort study where 460 myeloma patients were identified who met criteria for CR and had multicolor flow cytometry performed on the bone marrow (BM). Monoclonal and pPCs were estimated during MRD testing. Final outcomes including overall survival (OS) and time to next treatment (TTNT) were compared among the groups. The median OS for the entire cohort was not reached (95% CI; 63 mos, NR) and the median TTNT was 31 months (95% CI; 27,36). Among the MRDneg group, median TTNT was 37.6 months vs 23 months for MRDpos patients (P < .001); the median OS was not reached for either group, but there was a trend toward better survival for MRDneg patients. Among the MRDpos group, median percentage of pPCs was 65% (2.5-98.5), and those with >95% pPCs had a significantly better TTNT (NR vs 23 months; P = .02) and a trend toward better OS. We conclude that achievement of MRD negativity predicts for better response durability and trend toward improved OS and an increased proportion of pPC predicts for better outcomes within those who have residual tumor cells highlighting the importance of marrow normalization.

Molecular signatures of multiple myeloma progression through single cell RNA-Seq.

We used single cell RNA-Seq to examine molecular heterogeneity in multiple myeloma (MM) in 597 CD138 positive cells from bone marrow aspirates of 15 patients at different stages of disease progression. 790 genes were selected by coefficient of variation (CV) method and organized cells into four groups (L1-L4) using unsupervised clustering. Plasma cells from each patient clustered into at least two groups based on gene expression signature. The L1 group contained cells from all MGUS patients having the lowest expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathways (p < 1.2 × 10-14). In contrast, the expression level of these pathway genes increased progressively and were the highest in L4 group containing only cells from MM patients with t(4;14) translocations. A 44 genes signature of consistently overexpressed genes among the four groups was associated with poorer overall survival in MM patients (APEX trial, p < 0.0001; HR, 1.83; 95% CI, 1.33-2.52), particularly those treated with bortezomib (p < 0.0001; HR, 2.00; 95% CI, 1.39-2.89). Our study, using single cell RNA-Seq, identified the most significantly affected molecular pathways during MM progression and provided a novel signature predictive of patient prognosis and treatment stratification.