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Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity. [ABSTRACT FROM AUTHOR]

Salvage autologous stem cell transplant (sASCT) may be associated with improved survival in multiple myeloma (MM) and is an option for patients with long time to relapse (TTR) after initial Autologous transplant (ASCT1). Due to potential mobilization failure after maintenance therapy (MT), adequate peripheral blood progenitor cells (PBPC) are frequently collected for later sASCT. Evaluate utilization of stored PBPC in MM. Provide a cost analysis of collecting and storing PBPC for sASCT. Determine utilization of sASCT in those eligible who had a prolonged TTR. We included MM patients who received ASCT1 at our institution between 2009 and 2016. Extra day of collection (EDC) was defined as additional collection of ≥2 × 106 cells/kg PBPC for a second transplant. TTR was calculated as months from ASCT1 to relapse. Eligibility for sASCT was defined as TTR ≥18 months without MT or ≥36 months on MT. Patients who underwent tandem transplant (tASCT) (defined as two transplants within 6 months) were excluded from relapse analysis. Patients with inadequate relapse data defined as death or lost to follow up (LTFU) at ≤36 months prior to relapse, or ≤6 months follow up after relapse were excluded. Costs were obtained from the institution charge master. Descriptive statistics were calculated for the final cost benefit analysis. 154 MM patients received ASCT1 from 2009-2016. Median age was 59 years. Median follow up was 151 months. Median TTR was 20 months. 58% were male. Ethnicity was 76% Caucasian and 24% Black. 62% had IgG MM subtype, 23% IgA MM and 15% other. Majority (95%) were European Cooperative Oncology Group (ECOG) 0 or 1. 13% had high risk cytogenetics. 53% received MT. 137(89%) had PBSC stored for sASCT. 3 were used for sASCT and 10 for tASCT. 124 (90.5%) did not use stored cells. 54 (39%) met collection targets for two transplants in single collection while 83 (%) required ≥1 EDC with cumulative 108 EDC. (Figure 1) Cumulative cost savings for plerixafor use, cell collection, processing, analysis and storage was estimated at $2,252,244. (Figure 2). Total 60 doses of plerixafor were used for EDC. (31 patients with 1EDC, 10 with 2EDC and 3 with 3 EDC). 97 patients were studied for relapses. 54 (77.5%) relapsed. 5 deaths and 8 LTFU occurred within ≤6 months of relapse. 42 patients were further analyzed. 25 of them met criteria for sASCT based on TTR and only 2 received sASCT.1 patient with sASCT did not have MT data and was excluded. (Figure 3) Only 25% (24/98) patients who underwent ASCT1 were eligible for sASCT. Only 2% (2/98) received sASCT. Collecting and storing PBPC for sASCT is associated with high cost, but overall utilization at our institution is low. Our findings should be compared against practices at other institutions to help develop guidelines for selection of subset of MM where this practice may be of higher value. [ABSTRACT FROM AUTHOR]

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p <.01), absolute neutrophil count recovery days (median 23 vs 25 days, p =.03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p =.01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF. [ABSTRACT FROM AUTHOR]

Background: Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults. Methods: The authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori. Results: An increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2. On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1‐1.7 [P =.06]), REL (HR, 1.03; 99% CI, 0.9‐1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1‐1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1‐1.4 [P =.02]) compared with the reference group (those aged 60‐69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2, including day 100 NRM (1% [95% CI, 1%‐2%] vs 0% [95% CI, 0%‐1%]; P =.003]), 2‐year PFS (64% [95% CI, 60%‐67%] vs 69% [95% CI, 66%‐73%]; P =.003), and 2‐year OS (85% [95% CI, 82%‐87%] vs 89% [95% CI, 86%‐91%]; P =.01]), likely representing frailty. Conclusions: The results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups. Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy for the management of patients with multiple myeloma, which is a disease of older adults. The results of the current large database study confirm that AHCT remains an effective consolidation therapy in fit older adults aged ≥70 years. [ABSTRACT FROM AUTHOR]

Aim: High‐dose melphalan followed by autologous haematopoietic cell transplantation remains the standard‐of‐care therapy for multiple myeloma (MM). Gastrointestinal toxicity concomitant with electrolyte derangement is a primary cause of morbidity from transplant. Here, we assessed the dynamics of electrolyte imbalances and its role in hematologic counts and engraftment. Ω Patients and Methods One hundred and eighteen MM patients that received transplant were studied. Results: Engraftment speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) and full engraftment defined as the first of three consecutive days with ANC > 500 × 106/L. The defined median ES was 2 days (range 0‐5 days) and 40 patients had ES ≤2 days. Engraftment occurred at a median of 10 days. The median time‐to‐nadir for phosphorus and potassium was 10 and 4.28 days, respectively. The drop in phosphorus and potassium serum level was statistically greater in patients with an ES ≤2 days compared to patients with ES ≥2 days. Magnesium level were not significantly affected and there was no significant difference between the drop in serum phosphorus and potassium based on severity of nausea or oral mucositis. Conclusion: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous levels and a steep rise in neutrophil counts around the engraftment period following stem cell transplant. These events indicate a "genesis syndrome" characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described after HCT for certain high‐grade lymphomas and leukemias. SUMMARY AT A GLANCE: There is a significant correlation between the magnitude of drop in serum potassium and phosphorous levels and a steep rise in neutrophil counts around the engraftment period following autologous haematopoietic cell transplantation after high‐dose melphalan in the treatment of multiple myeloma. The report raises awareness on the monitoring of these electrolytes in this relatively homogeneous group of patients. [ABSTRACT FROM AUTHOR]

Summary: Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477. [ABSTRACT FROM AUTHOR]

• Microbiome composition present at pretransplantation baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and neutropenic fever, and with the rate of neutrophil engraftment. • The microbial communities present at count nadir are associated with regimen-related gastrointestinal toxicities observed with high-dose melphalan. • Although bacteriome diversity largely recovers within 1 month after transplantation, recovery of oral and gastrointestinal mycobiome diversity takes longer to recover. Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome. [ABSTRACT FROM AUTHOR]

Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). The curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. Currently, there is no standard post-transplant therapy for patients with ALL. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Eligibility included patients aged 16-75 who have undergone alloHCT for CD22+ALL, have a high risk for relapse, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of veno-occlusive disease (VOD). The primary objective of this phase I clinical trial is to define a post alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of VOD, disease free survival (DFS) and overall survival (OS) at 1 year post alloHCT. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). As of October 1st, 2019, 9 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice), two went off treatment after 3 cycles of INO (patient choice and physician choice) and one experienced a DLT due to prolonged thrombocytopenia. We have completed 1 year post-transplant follow up on 5 patients. All patients are alive and in CR. No patients experienced VOD. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising. [ABSTRACT FROM AUTHOR]

Patients (pts) with rapidly progressive lymphoma and urgent need for therapy have worse prognosis and may not be able to receive CAR-T cells. Decreasing apheresis to infusion time can make CAR-T cells available to this patient population. We present the results of a phase I trial using rapid on-site CAR-T manufacture for relapsed/refractory B cell non Hodgkin lymphoma (NHL). Adult pts with CD19+ B NHL who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc) encoding antiCD19 binding motif, CD8 linker and TNFRS19 transmembrane region, and 4-lBB/CD3z costimulatory domains. GMP compliant manufacture was done using CliniMACS Prodigy, in a 12 day culture. Dose escalation was done using 3+3 design, with 3 dose levels (0.5, 1 and 2 × 106 CAR-T cells/kg). Lymphodepletion was done with cyclophosphamide (60mg/kg × 1) and fludarabine (25mg/m2/d × 3). As of September 30, 2019, 14 pts were enrolled and treated. Table 1 lists baseline characteristics. 12 pts had refractory NHL, 6 had bulky disease and 9 had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 48% [range 29-62] with median culture expansion of 41-fold [range 30-79]. All pts received their infusion of antiCD19 CAR-T cells. CAR-T cell doses were 0.5 × 106/kg (n = 4) and 1 × 106/kg (n = 10). Median apheresis to infusion time was 13 days [range 13–20]. CAR-T persistence, based on vector sequence, peaked in peripheral blood MNCs between days 14-21. All evaluable subjects had persistent CAR-Ts on PCR measurements done on days 30, 60 and 90. CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence (fig 1). Six pts experienced CRS. Five pts had grade 1 – 2 CRS and 1 pt died on day 8 due to CRS. Two pts presented grade 4 CRES, resolved after corticosteroids. No other grade ≥3 non-hematologic toxicity was observed. The most common non – hematologic toxicity was fatigue (n=7). Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all pts. Among 12 evaluable pts, 8 have achieved complete response (CR) and two had partial response (PR). Two pts did not respond. The CR rate was 67% and overall response rate was 83%. Three pts have died, causes of death include progressive disease (n=2) and CRS (n=1). After a median follow up 4.5 months (range 1 – 14) all responding pts are alive; 1 pt relapsed 6 months after treatment with CD19+ disease and entered CR after antiCD19 antibody drug immunoconjugate. AntiCD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. The short manufacture times achieved by local CAR-T cell manufacture enables treatment of a very high risk NHL population that would otherwise not be able to receive CAR-T products due to rapidly progressive disease. [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT)-specific comorbidity index (Sorror et al. Blood 2005) is highly recommended by National Marrow Donor Program as a risk assessment tool before HCT. Prior malignancies has one of the highest weighted score of 3 in this risk model. The isolated prognostic value of prior malignancies has not been evaluated in Multiple Myeloma (MM) patients (pts) who underwent autologous HCT (AHCT) in large databases. We hereby used national cancer database (NCDB) to evaluate this. NCDB covers more than 70% of newly diagnosed cancer pts in the U.S. We reviewed NCDB, using ICD-O code of 9732, to identify pts who were diagnosed with MM between 2010 and 2014, underwent systemic treatment within 90 days of the diagnosis, and subsequently AHCT. Prior malignancy was not incorporated into Charlson comorbidity index at NCDB and reported separately. Average annual transplant volume of a cancer center for MM is calculated among pts who met the inclusion criteria. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Cox hazard analysis was performed to identify independent predictors of OS. We reviewed 12,427 pts and included 4358 pts who met inclusion criteria. Of which, 2481 (57%) were male, 693 (16%) were black, and 412 (10%) had at least one malignancies prior to MM. Median age at the diagnosis and time to initiation of systemic treatment after the diagnosis were 60 years (range: 25 – 80) and 17 days (range: 1 – 90), respectively. The Charlson comorbidity index was 0, 1, and ≥2 for 3646 (84%), 558 (13%), 154 (3%) pts, respectively. Durie-Salmon stage (DSS) at diagnosis was 1, 2, and 3 for 562 (13%), 1040 (24%), 2756 (63%) pts, respectively. Patient and treatment characteristics are compared between prior and no prior malignancy cohorts in table 1. Median follow-up time of pts was 36 months. Five-year OS of MM pts with and without prior malignancies was 75.6% (95% CI: 69.6 – 82.2) and 73.9% (95% CI: 71.6 – 76.2), respectively (p = 0.7) (Figure 1A). On multivariable analysis, each 10-year increase in age (HR 1.14, 95% CI: 1.02 – 1.26, p = 0.017), each 1 increase in comorbidity index (HR 1.24, 95% CI: 1.08 – 1.42, p = 0.002) and year of MM diagnosis (HR 1.15, 95% CI: 1.06 – 1.24, p = 0.0008), DSS 3 vs 1 or 2 (HR 1.38, 95% CI: 1.16 – 1.64, p = 0.0002), immunotherapy prior to AHCT (HR 0.72, 95% CI: 0.61 – 0.86, p = 0.0001), and each 10 increase in annual AHCT volume of a cancer center for MM (HR 0.98, 95% CI: 0.97 – 0.99, p = 0.016) were independent predictors of OS (Table 2). In this large cohort analysis, prior malignancy was not a predictor of OS for MM pts who underwent AHCT. The role of prior malignancies in defining "transplant eligibility" requires future evaluation and the weighted value of this item in the comorbidity index should be considered for downward revision. [ABSTRACT FROM AUTHOR]

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed and refractory aggressive lymphomas. Cytokine release syndrome (CRS) is a well-known complication of CAR-T cell therapy. Tocilizumab, a humanized monoclonal antibody targeting the interleukin 6 receptor, is approved for treatment of CRS. Our institutional standard has been recently modified to prescribe tocilizumab prophylaxis prior to CAR-T cell infusion. We present a retrospective review of the outcomes of subjects treated with and without prophylactic tocilizumab (PT). Relapsed / refractory (r/r) lymphoma treated with anti-CD19 CAR-T cells at our institution were included. Baseline demographic and clinical characteristics, as well as laboratory results were obtained from our Hematologic Malignancies and Stem Cell Therapy Database. Prior to institution of prophylactic tocilizumab, patients received this agent only if they presented evidence of CRS grade 2 or higher. In May 2019, our institutional practice changed to provide PT 8mg/kg, 1 hour prior to infusion of CAR-T cell product. CRS was measured according to the ASTCT Consensus Grading. Positron Emission Tests (PET) scans were done to assess response on Day 30. CART cell vector Persistence was measured using PCR and was done at different time points including Day 30. Fourteen relapsed / refractory lymphoma pts were treated with antiCD19 CAR-T cells; 6 pts received prophylactic tocilizumab. Median follow up was 149 days. CAR-T cells dose was 0.5 × 106 CAR-T cells/Kg dose in 4 pts, while 10 pts received 1 × 106/kg CAR-T. Baseline characteristics are listed in table 1.Both groups were similar. There were no differences in the rate of bulky disease, prior ASCT or number or prior lines of therapy. Baseline lymphocyte counts, C – reactive protein (CRP) and ferritin were also comparable between groups (Table 2). CRS of any grade was observed in 6/8 (75%) of patients without PT vs. 1/6 (17%) in patients treated with PT (p = 0.05). There was a statistically significant difference in the peak CRP, with patients receiving PT having a CRP peak of 0.74mg/dl vs. 15.3mg/dl in patients without PT. Complete response was observed in 5/8 (63%) pts without PT vs. 4/5 patients with PT. All patients had detectable Anti-CD19 CAR-T cells on day 30. Our findings suggest prophylactic tocilizumab is associated with reduced incidence of CRS. This decreased rate of CRS is not associated with impaired disease control and response rates are comparable with those previously reported. Use of PT did not appear to affect CAR-T cell persistence. Subsequent studies should evaluate the optimal CRS prophylaxis schedule in patients treated with CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Clostridium difficile is the leading cause of infectious diarrhea among hospitalized patients and is a major concern for patients undergoing hematopoietic cell transplantation (HCT). Risk factors and the natural history of C. difficile infection (CDI) are poorly understood in this population. The objective of this study is to determine the incidence of CDI during and after auto-HCT and to identify risk factors for the development of CDI including diagnosis. Methods: We performed a retrospective study to describe the epidemiology, timing, and risk factors for CDI among adult patients who received autologous HCTs at our center from January 2007 through December 2018. CDI was defined any stool C. difficile toxin positive test after the day of stem cell infusion. Results: Overall, 516 patients received auto-HCT for Multiple Myeloma (MM) and lymphoma during the study period, 271 and 245, respectively. Overall, the 1-year incidence of CDI was 6.2% (n=30). Seventy two percent of the patients who developed CDI had lymphoma and 18% had MM (p=0.001). The median time from day of stem cell infusion to CDI positive test was 5 days (range 1:228) for lymphoma pts and 10.5 days (rage 4-42) for MM pts (p-value: 0.269). Median age for MM pts was 54 years and 58 for lymphoma pts (p-value: 0.328). Given the different patient population and therapy history between MM and lymphoma patients, we limit our analysis to MM subset to assess the potential risk factors impacting CDI occurrence after transplant. Previous antibiotic use (i.e., other than acyclovir), co-morbidities and other variables were assessed (Figure-1). Among MM patients, prophylactic antibiotics or corticosteroid use before transplant were not statistically significant associated with CDI. Twenty seven percent of patients with CDI had history of previous CDI vs. only 5% in no-CDI cohort (p-value: 0.001). Lymphopenia was present in 54% of CDI cohort at diagnosis whereas 29% of no-CDI cohort had lymphopenia (p-value: 0.031). Furthermore, chronic kidney disease (CKD) was associated significantly with CDI occurrence (p-value: 0.001). Conclusion: These results suggest lymphoma patients undergoing auto-HCT are at higher risk of developing CDI than MM patients which is different from older reports (Alonso, et al. Clinical infectious diseases. 2012). Our data illustrates pre-transplant prophylactic antibiotics or corticosteroid use is not associated with higher CDI incidence after transplant for MM patients undergoing transplant, while history of previous CDI in the year before transplant, lymphopenia and CKD may be significant predictors. This findings merits further confirmations in larger series. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy in induction and maintenance therapy after transplant for patients (pts) with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% (Nardone, et al, Clinical Lymphoma Myeloma and Leukemia. 2013) and importantly heralds a favorable prognosis (Kojima, et al. Blood. 2016) suggesting more robust immune stimulation by this class of drugs; however, lack of optimal management strategy of this toxicity can deprive large subset of pts from maintenance therapy after transplant and lead to potential detrimental impact on survivals. The concurrent weekly dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. Archives of dermatology. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD which may not be achieved by standard weekly Dex. Here, we present our experience with this regimen. In this retrospective study, pts with MM treated with lenalidomide and pomalidomide were reviewed for any IMiD-associated dermatologic toxicity. We followed the same corticosteroid regimen for all IMiD-related rash in our clinic without changing Dex dosing. A total of 160 pts were evaluated. The incidence of rash was found to be 13% (n=21). IMiDs were instituted as part of induction regimen in 71% (n=15) and as maintenance therapy after transplant in 29% (n=6) of pts. Median time to development of rash after IMiD initiation was 28 days (range, 2-232). The rashes were characterized as morbilliform in 86% (n=18), urticaria in 9.5% (n=2) and blisters in 5% (n=1) of pts. Pruritis or pain was associated with 86% of rashes (n=15). According to NCI-CTCAE, rashes were graded as low (I-II) in 89% (n=17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all pts were able to restart the same IMiD either at same (n=5, 24%) or reduced (n=16, 76%) dose with none re-experiencing any dermatologic adverse effect afterward. There was no association between rash development and changes in creatinine clearance (p=0.42). Median eosinophil count at rash development was observed to be significantly higher as compared to eosinophil count at IMiD initiation (380 × 106 vs 130 × 106 respectively, p=0.01). The proposed 3-week corticosteroid regimen showed 100% success rate in terms of reinstituting IMiDs, therefore it may provide a highly effective and practical short term immunosuppression required to enable pts to restart IMiDs. [ABSTRACT FROM AUTHOR]

Achieving and maintaining Complete Response (CR) after autologous hematopoietic cell transplant is the key to improved clinical outcomes in patients (pts) with multiple myeloma (MM). Daratumumab (DARA), an IgG1 Kappa anti-CD38 monoclonal antibody, have shown significant anti-myeloma activity leading to increasing usage in the peri-transplant settings. Frequently, use of DARA may be associated with appearance of low concentration band on serum protein electrophoresis (SPE) impacting CR assessment after transplant. The incidence and factors influencing appearance of this band are largely unknown. This band potentially can be an indirect measurement of the plasma DARA concentration influenced by amount of administered agent and but also with volume of CD38 positive myeloma cells binding to DARA. The objective of this study is to analyze the factors influencing appearance of this band on SPE. Methods: 77 pts who received DARA were retrospectively studied. Pts who did not have available SPE after starting DARA (n: 9) and those who had AL Amyloidosis without Myeloma (n: 3) were excluded. The host and disease characteristics extracted. Pts assigned to two cohorts based on presence (PB) or absence (NB) of the accessory band. The disease response assessment was assessed based on IMWG criteria. Result: Median age for pts in PB and NB was 62 and 64.4 years respectively. All pts received weight-based dosing (16mg/Kg). 31 pts had detectable band assigned to PB cohort and 34 pts without any detectable band assigned to NB. The accessory band appeared over a median of 46 days after starting therapy (range: 7-390 days) and predominantly (74%) during the weekly DARA schedule. No significant difference noted in median weight and serum creatinine between PB and NB cohorts. Median M-spike on SPE at the start of DARA was 1.1 gr/dL (range: 0 - 5.5 gr/dL) in NB cohort vs. 0.3 gr/dL (range: 0 3.8 gr/dL) in PB patients (p-value <0.012). 45% of pts had IgG MM in PB while 55% in NB (p-value: 0.349), 29% of patients had IgA in PB and 20% in NB cohort (p-value: 0.231) and light-chain disease was present in 25% of pts in PB cohort whereas only 4% in NB (p-value: 0.041). 17 pts (55%) had Partial Response (PR) or better in PB while only 5 pts (14%) had PR or better in NB cohort. (p-value: 0.001). In multi-variate analysis the pre-DARA M-spike remained the significant predictor of the band appearance (OR: 2.03, CI: 1.21-4.31, p-value: 0.003). Conclusion: Based on our data, the frequency of detecting this band is not impacted by type of myeloma (i.e., IgG vs. IgA) but by the magnitude of the M-spike. This may be reflective of larger disease volume in bone marrow with less M protein detected in the peripheral blood. The appearance of accessory band associated with DARA treatment during weekly dosing may be a surrogate early marker for predicting disease response. Further large scale studies are required to confirm this findings. [ABSTRACT FROM AUTHOR]

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between 2005 and 2014 were analyzed. Results: Median age at diagnosis was 67 (19-90); 55% were males. 57% of pts lived in areas where the median income was < $46k/year (individual income data was not available); Primary insurance was Medicare (52%), private insurance (35%) or Medicaid (5%), and 3% were uninsured. 40% were treated in academic institutions. Median follow up was 30.2 (range, 0-145.2) months. By univariate analysis, better OS was observed in pts with primary MM, lower Charlson Comorbidity Index (CCI), treatment in academic institutions, higher median regional income, or private insurance (p <0.001 for all) (Table-1). 96% of pts were treated in facilities located ≤ 120 miles from area of residence. Amongst pts younger than 65 years, 33% of pts with private insurance received transplant compared to 20% of those on Medicare (p<0.001). For those 65 years and older, 11% of privately insured pts were transplanted compared to only 6 % for those on Medicare (p<0.001). Median age of pts on Medicare and private insurance, was 74 and 57 years old, respectively. When restricting the analysis to pts ≥ 65 years old, pts with private insurance had longer OS compared to Medicare pts (p<0.001). Table-2 shows the results of multivariate analysis. There was a statistically significant difference in survival between patients with private insurance and those with Medicare in favor of the private insurance among pts older than 65 years old (41.9 vs. 30.8 months, p <0.001 (Fig-1)). Similarly insurance type was a significant predictor of survival among pts who received therapies other than transplant among pts younger or older than 65 (Fig-2), however when considering pts who received transplant, there was no difference in survival between privately insured pts and Medicare in both age group (Fig-3). Conclusions: Although insurance type and regional income are associated with MM survival among pts who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of pts that received an autologous transplant in this large database. This finding merits further investigation. [ABSTRACT FROM AUTHOR]

Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes (CTLs). Immunoproteasomes are highly-specialized proteasome variants that are expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify Compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma (MM) cells. Compound A increased the presentation of individual MHC-I-bound peptides >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that Compound A binds the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of Compound A on antigen presentation. Treatment of MM cell lines and patient bone marrow-derived CD138+ cells with Compound A increased the antimyeloma activity of allogenic and autologous T-cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T-cells reduced the growth of myeloma xenotransplants in NSG mice. Taken together, our results demonstrate the paradigm-shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy.

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8 + T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8 + T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents., (© 2024. The Author(s).)

Obesity is a common health problem in patients with multiple myeloma (MM) that has been linked to poor clinical outcomes and quality of life (QoL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of 3 treatment interventions after a single hematopoietic cell transplantation (HCT) (n = 758), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QoL in MM patients. A total of 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high-risk disease according to cytogenetic assessment. The median duration of follow-up was 6 years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QoL measures. This study suggests that visceral obesity, as measured by WHR, might not have a significant impact on clinical outcomes in MM patients undergoing HCT. These findings add to the existing literature on the topic and provide valuable information for healthcare professionals and MM patients. Further studies are needed to confirm these results and to investigate other potential factors that may affect clinical outcomes and QoL in this patient population using modern imaging technologies to assess visceral obesity., (Copyright © 2024. Published by Elsevier Inc.)

Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells. High-throughput screens revealed that histone deacetylase 6 (HDAC6) inhibitors activated proteasomes to unmask neoantigens and amplify the tumor-specific antigenic landscape. Treatment of patient CD138+ cells with HDAC6 inhibitors significantly promoted the antimyeloma activity of autologous CD8+ T cells. Pharmacologic blockade and genetic ablation of the HDAC6 ubiquitin-binding domain released HR23B, which shuttles ubiquitinylated cargo to proteasomes, while silencing HDAC6 or HR23B in multiple myeloma cells abolished the effect of HDAC6 inhibitors on proteasomes, antigen presentation, and T-cell cytotoxicity. Taken together, our results demonstrate the paradigm-shifting translational impact of proteasome activators to expand the myeloma immunopeptidome and have revealed novel, actionable antigenic targets for T cell-directed immunotherapy., Significance: The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Abstract: The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post-allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a "3+3" model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post-allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT)., Patients and Methods: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma-specific immunity at 1-year posttransplant., Results: The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control; P = 0.37, 80% CI 44.5%, 61.3%, and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control; P = 0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control; P = 0.4). Vaccination induced a statistically significant expansion of multiple myeloma-reactive T cells at 1 year compared with before vaccination (P = 0.024) and in contrast to the nonvaccine arm (P = 0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year posttransplant., Conclusions: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study. See related commentary by Qazilbash and Kwak, p. 4703., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: The gold standard for monitoring response status in patients with multiple myeloma (MM) is serum and urine protein electrophoresis which quantify M-spike proteins; however, the turnaround time for results is 3-7 days which delays treatment decisions. We hypothesized that machine learning (ML) could integrate readily available clinical and laboratory data to rapidly and accurately predict patient M-spike values., Methods: A retrospective chart review was performed using the deidentified, electronic medical records of 171 patients with MM., Results: Random forest (RF) analysis identified the weighted value of each independent variable (N = 43) integrated into the ML algorithm. Pearson and Spearman coefficients indicated that the ML-predicted M-spike values correlated highly with laboratory-measured serum protein electrophoresis values. Feature selected RF modeling revealed that only two variables-the first lagged M-spike and serum total protein-accurately predicted the M-spike., Conclusion: Taken together, our results demonstrate the feasibility and prognostic potential of ML tools that integrate electronic data to longitudinally monitor disease burden. ML tools support the seamless, secure exchange of patient information to expedite and personalize clinical decision making and overcome geographic, financial, and social barriers that currently limit the access of underserved populations to cancer care specialists so that the benefits of medical progress are not limited to selected groups.

Background: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed)., Patients and Methods: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients., Results: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods., Conclusion: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Age is an adverse prognostic factor in diffuse large B cell lymphoma (DLBCL), but there are limited data on the outcomes of patients' ≥80 years, including those treated with dose reduced chemoimmunotherapy., Patients and Methods: We conducted a retrospective analysis of 542 patients, 85 (16%) were ≥80 years of age., Results: Although the very elderly group had more frequent comorbidities and decreased performance status, 89% received therapy. Four-year PFS was 42% vs. 61% (P < .001) in patients ≥80 years vs. younger patients, while 4-year OS was 42% vs. 72% (P < .0001), respectively. In patients treated with anthracycline-containing regimens (n = 416) 4-year cumulative incidence of relapse with death as competing risk was not different between age groups. Median survival for DLBCL patients ≥80 years treated with R-CHOP or R-miniCHOP was 4.5 years. Survival after first relapse was significantly different between age groups: 5 vs. 19 months (P = .002), respectively., Conclusion: Very elderly DLBCL patients have worse OS and PFS compared with younger patients but can achieve long term disease control and potentially be cured with chemoimmunotherapy. Older DLBCL patients treated with effective regimens do not have increased rates of relapse, but outcomes after relapse remain poor., (Copyright © 2021. Published by Elsevier Inc.)

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score. A group of 790 patients were diagnosed from 2002 to 2014 (DLBCL = 542, FL = 248). Median follow- up was 49 months. We observed 106 VTE, with higher incidence in DLBCL (5-year cumulative incidence = 16.3% vs 3.8% in FL patients). Five-year OS for patients with VTE was 51.4% vs 73.1% in patients without VTE (P < .001). Baseline VTE risk factors identified in the training cohort included lymphoma subtype, previous VTE, ECOG performance status ≥2, decreased albumin, increased calcium, elevated WBC, absolute lymphocyte count or monocyte count, and presence of bulky disease. Addition of new variables to the Khorana score improved its performance measured by Akaike information criterion and Concordance index. A new risk model including lymphoma subtype, albumin, WBC count, and bulky disease was validated in time-based ROC analyses. These findings were confirmed in the validation cohort. Lymphoma subtypes have different VTE risk. The effect of lymphoma subtype was independent from disease burden and the use of systemic therapy. The Khorana risk-score was validated in time to event analyses, and a more robust lymphoma-specific VTE risk score is proposed. These findings suggest lymphoma patients with highest VTE risk can be identified with baseline parameters., (© 2020 Wiley Periodicals, Inc.)

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, which typically evolves over time from its precursor, monoclonal gammopathy of undetermined significance. While the underlying mechanisms of this evolution remain elusive, immunomodulatory factors affecting the bone marrow (BM) microenvironment are suspected to play a role. There is an increasing evidence that the gut microbiome exerts an influence on its host's adaptive and innate immune systems, inflammatory pathways and the BM microenvironment. Dysbiosis, therefore, may impact tumorigenesis in MM. This article gives an overview of potential mechanisms by which the microbiome may influence the pathogenesis of MM, MM patients' responses to treatment and toxicities experienced by MM patients undergoing autologous transplant. It also discusses the potential role of the mycobiome in MM, a less studied component of the microbiome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High-dose chemotherapy and autologous stem cell transplantation (ASCT) are integral components of the overall treatment for patients with multiple myeloma (MM) aged ≤ 65 years. The emergence of oligoclonal immunoglobulin bands (ie, immunoglobulins differing from those originally identified at diagnosis [termed clonal isotype switch (CIS)]) has been reported in patients with MM after high-dose chemotherapy followed by autologous stem cell transplantation. However, the clinical relevance and the correlation with immune reconstitution remains unclear., Patients and Methods: Patients with MM who had undergone ASCT from 2007 to 2016 were included in the present study. The percentage of natural killer cells, B-cells, and T-cells was measured using flow cytometry in pre- and post-ASCT bone marrow samples. CIS was defined as the appearance of a new serum monoclonal spike on serum protein electrophoresis and immunofixation that differed from original heavy or light chain detected at diagnosis., Results: A retrospective analysis of 177 patients with MM who had undergone ASCT detected CIS in 39 (22%). CIS after ASCT correlated with improved progression-free survival (52.2 vs. 36.6 months; P = .21) and overall survival (75.1 vs. 65.4 months; P = .021). Patients with a relapse had an isotype that differed from a CIS, confirming the benign nature of this phenomenon. CIS was also associated with lower CD8 T-cell percentages and a greater CD4/CD8 ratio (2.8 vs. 0.2; P = .001) compared with patients who did not demonstrate a CIS, suggestive of more profound T-cell immune reconstitution in this group., Conclusion: Taken together, our data have demonstrated that a CIS is a benign phenomenon and correlates with a reduced disease burden and enriched immune repertoire beyond the B-cell compartment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Induction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML)., Patients and Methods: We retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS)., Results: In multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]., Conclusion: Rapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia., (Copyright © 2018 Elsevier Inc. All rights reserved.)