Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

[CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-T CELLS) THERAPY FOR B-CELL HEMATOLOGICAL MALIGNANCIES - FROM THE ISRAELI SOCIETY OF HEMATOLOGY AND TRANSFUSION MEDICINE].

INTRODUCTION: Using immunotherapy to fight cancer, and specifically, the use of engineered T-cells expressing a chimeric receptor against an antigen found on malignant cells (chimeric antigen receptor, CAR-T cells) constitutes a significant breakthrough in the treatment of the disease. In recent years, several CAR-T therapies have been approved in Europe and the USA, and some are already approved and funded through the national health basket in Israel, for the indications of diffuse large B-cell lymphoma, mantle cell lymphoma and B-cell acute lymphoblastic leukemia, after the failure of at least two lines of treatment. The treatment with CAR-T cells achieves prolonged remissions and even long-term cure of patients who had a very poor prognosis. However, the treatment involves significant side effects, and requires specific expertise in the management of patients both during the period of preparation for cell transplantation, and following the treatment. During the immediate post-infusion period, the most common adverse reactions are cytokine release syndrome (CRS) which stems from the activation of the immune system, and neurological toxicity that can accompany CRS. These effects require close monitoring, grading their severity, and providing anti-cytokine therapy or steroid therapy until control of symptoms is achieved. Later effects can be persistent cytopenias, immune over-activation, and prolonged immune deficiency. Treatments for additional indications and new CAR-T constructs are being developed and will allow more effective and safer treatment. This article summarizes the principles for CAR-T administration that, as currently provided in Israel, include the short- and long-term follow-up of the patients.

Response rates of extra-nodal diffuse large B cell lymphoma to anti-CD19-CAR T cells: A real word retrospective multicenter study.

Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)-only and 12 of 126 (10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8-13.6] vs. 14.1 [95% CI: 10-18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5-18.2] vs. 18.4 [95% CI 14.8-22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9-15.5] vs. 4.28 months [95% CI 0.6-7.9], p = .010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4-19.6] vs. 8.7 months [95% CI 4.6-12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.

[18F]FDG PET-CT in patients with DLBCL treated with CAR-T cell therapy: a practical approach of reporting pre- and post-treatment studies.

PURPOSE: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. METHODS: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion. RESULTS: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). CONCLUSION: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.

Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience.

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.

Characteristics and recognition of early infections in patients treated with commercial anti-CD19 CAR-T cells.

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Advances in chimeric antigen receptor T cells.

PURPOSE OF REVIEW: To discuss the important advances in CAR T cell therapy over the past year, focusing on clinical results where available. RECENT FINDINGS: Approximately 30 years after they were first conceived of and 15 years after the first small-scale single-center clinical trials, the past 3 years represent a major milestone in the development of CAR T cells. In the United States, the Food and Drug Administration (FDA) approved Tisagenlecleucel for the treatment of relapsed/refractory B-ALL and Axicabtagene Ciloleucel, for adults with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) in 2017. Tisagenlecleucel received a second indication in adults with R/R DLBCL in 2018. Regulatory approval for CAR T cells was then granted in Europe, Canada, Australia, and Japan. Most recently, in July 2020 the FDA granted regulatory approval to a third CAR T cell product, Brexucabtagene Autoleucel for mantle cell lymphoma. All products target the CD19 antigen but differ in the costimulatory molecule within the CAR construct. Currently, it is unknown whether there are any differences in clinical activity or toxicity between these products. SUMMARY: The CAR T cell the platform is evolving at a rapid pace and is expected to further improve the therapeutic outcomes of hematological malignancies.

Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy.

Multiple myeloma (MM) is a chronic progressive malignancy of plasma cells. Although treatment with the novel proteasome inhibitor, bortezomib, significantly improves patient survival, some patients fail to respond due to the development of de novo resistance. We have previously shown that cytotoxic drugs can induce pro-tumorigenic host-mediated effects which contribute to tumour re-growth and metastasis, and thus limit anti-tumour efficacy. However, such effects and their impact on tumour cell aggressiveness have not been investigated using cytostatic agents such as bortezomib. Here we show that plasma from bortezomib-treated mice significantly increases migration, viability and proliferation of MM cells in vitro, compared to plasma from vehicle treated mice. In vivo, bortezomib induces the mobilization of pro-angiogenic bone marrow cells. Furthermore, mice treated with bortezomib and subsequently were used as recipients for an injection of MM cells succumb to MM earlier than mice treated with the vehicle. We show that bortezomib promotes pro-inflammatory macrophages which account for MM cell aggressiveness, an effect which is partially mediated by interleukin-16. Accordingly, co-inoculation of MM cells with pro-inflammatory macrophages from bortezomib-treated mice accelerates MM disease progression. Taken together, our results suggest that, in addition to the known effective anti-tumour activity of bortezomib, host-driven pro-tumorigenic effects generated in response to treatment can promote MM aggressiveness, and thus may contribute to the overall limited efficacy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

BACKGROUND: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. MAIN RESULTS: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram-positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram-positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.

Should autotransplantation in acute myeloid leukemia in first complete remission be revisited?

PURPOSE OF REVIEW: Despite numerous studies, the best postremission therapy in acute myeloid leukemia (AML) is a subject of intense controversy. Major prognostic factors for disease outcome are the genetic alterations of AML, patient's age, and performance status. AML is more common in older adults, with a median age of 72 years. However, in this age group the unfavorable cytogenetics dominates at a time when biologically it may be most difficult to administer optimal intensive therapy. RECENT FINDINGS: Autologous stem cell transplantation (ASCT) enables the administration of high-dose therapy supported by stem cell infusion with a treatment-related toxicity not significantly higher than that associated with chemotherapy and significantly lower than in allogeneic stem cell transplantation. The dilemma of best postremission therapy has not been resolved because of the paucity of randomized controlled studies, especially in various cytogenetic risk and age groups. Instead, the use of genetic randomization by donor availability, analysis of outcome based on intention-to-treat, and mixed populations in the registry data produce variable results. SUMMARY: ASCT has been associated with prolonged disease-free survival as compared to chemotherapy, especially in the favorable and intermediate risk groups. Advances in immunotherapy in AML may propel ASCT as a platform for various immunologic maneuvers.

Adult Nephrotic Syndrome after Hematopoietic Stem Cell Transplantation: Renal Pathology is the Best Predictor of Response to Therapy.

Nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HSCT) is a rare phenomenon usually associated with graft-versus-host disease (GVHD). This systematic review of post-HSCT NS cases reported in the literature aimed to identify risk factors and unique features of the disease in this clinical setting. One hundred sixteen cases of post-HSCT NS published in the English literature between 1988 and 2015 were revealed and analyzed. The median onset of NS was 20.5 months (range, 3 to 174) post-HSCT. NS development was associated with acute or chronic GVHD in 87.2% of cases. Membranous nephropathy (MGN) was the most frequent pathology (65.5%), followed by minimal change disease (MCD) (19%). Complete remission of the NS was achieved in 63.5% of patients (59.1% of MGN cases and 81.3% of MCD cases; P = .15). Patients presenting with MCD recovered at a median of 1.75 months (range, 1 to 12) and with MGN a median of 7 months (range, 1 to 53) (P = .001). NS was treated with corticosteroids alone in 16.8% of patients and with a combination of corticosteroids and other immunosuppressive agents in 73.5% of patients. Univariate analysis failed to identify a single predictive factor of response to therapy. In conclusion, post-HSCT NS usually develops concomitant to GVHD and is associated with high rates of response to therapy. Although most patients were treated with a combination of immunosuppressive drugs, single-agent therapy with steroids may be sufficient in some cases.

Early Antibiotic Deescalation and Discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single-Center Prospective Unblinded Randomized Trial.

The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n = 51) or EDD arm (n = 59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P = .016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.

Immunogenicity of a Third Dose of the BNT162b2 mRNA Covid-19 Vaccine in Patients with Impaired B Cell Reconstitution After Cellular Therapy-A Single Center Prospective Cohort Study.

Patients with delayed B-cell reconstitution/B-cell aplasia after cellular therapy show decreased immunogenicity to the BNT162b2 mRNA COVID-19 vaccine. We prospectively evaluated both humoral and cellular immune response to a third vaccine dose in patients after allogeneic HCT (n = 10) or CD19-based chimeric antigen receptor T cells (CAR-T) therapy (n = 6) with low absolute B cell numbers and who failed to mount a humeral response after 2 vaccine doses. Humoral response was documented in 40% and 17% after allogeneic HCT and CAR-T therapy, respectively. None of the patients with complete B-cell aplasia developed anti-vaccine antibodies. Cellular response was documented in all patients after allogeneic HCT and in 83% of the patients after CAR-T. T-cell subclasses levels were not predictive for response, while a longer duration from infusion of cells was associated with a better cellular response. We conclude that cellular response develops with repeated vaccine doses even in patients with B-cell aplasia or delayed B-cell reconstitution, and these patients should therefore be vaccinated. These results should be considered in future studies analyzing immunogenicity in this population. Larger and longer follow-up studies are required to confirm whether cellular immunogenicity translates into vaccine efficacy.

Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy.

Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both in vitro and in vivo. These effects are regulated in part by IL1ß, as blocking the IL1ß axis by a pharmacologic or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high proinflammatory macrophages in the bone marrow negatively correlate with survival rates (HR, 1.722; 95% CI, 1.138-2.608). Furthermore, a positive correlation between proinflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a protumorigenic cross-talk involving proinflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population. IMPLICATIONS: Our findings suggest that proinflammatory macrophages in bone marrow biopsies represent a potential prognostic biomarker for acquired MM resistance to bortezomib therapy.