Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades.

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Autologous Stem Cell Transplantation for Patients with Multiple Myeloma with Translocation (4;14): The MD Anderson Cancer Center Experience.

Translocation between chromosomes 4 and 14, t(4;14), has been reported in 15% of patients with multiple myeloma (MM) and is considered a high-risk cytogenetic abnormality associated with inferior outcomes. Autologous hematopoietic stem cell transplantation (auto-HCT) is standard of care for patients with high-risk MM, yet there are scarce data on post-transplantation outcomes of patients with t(4;14) MM. The aim of the present study was to evaluate outcomes of MM patients with t(4;14) who underwent auto-HCT and received contemporary anti-myeloma agents for induction and post-transplantation maintenance. We conducted a retrospective analysis of MM patients with t(4;14), detected by fluorescence in situ hybridization (FISH), who underwent auto-HCT between 2008 and 2018 at MD Anderson Cancer Center. Primary endpoints were progression-free survival (PFS) and overall survival (OS), and secondary endpoints were hematologic response and minimal residual disease (MRD) status after auto-HCT. MRD status in the bone marrow biopsy was evaluated using 8-color next-generation flow cytometry with a sensitivity of 1/10-5 cells. Seventy-nine patients were included (52% male), with a median age of 60 years (range, 32 to 78 years). Forty-four patients (56%) had an additional high-risk cytogenetic abnormality. Fifty patients (63%) achieved at least a very good partial response (≥VGPR) prior to auto-HCT and 20 (25%) had MRD-negative ≥VGPR. At the best post-transplantation evaluation, 90% had ≥VGPR and 63% had MRD-negative ≥VGPR. The median follow-up for survivors was 35.7 months (range, 7.7 to 111.6 months). For the entire cohort, median PFS and OS were 22.9 months and 60.4 months, respectively. Patients with MRD-negative ≥VGPR prior to transplantation had improved PFS and OS on both univariate analysis (UVA) and multivariate analysis (MVA) (hazard ratio [HR], .35 [95% confidence interval (CI), .16 to .76; P = .008] and .12 [95% CI, .03 to .44; P = .002], respectively). The presence of additional high-risk cytogenetic abnormalities was not associated with inferior PFS (P = .57) or OS (P = .70). Post-transplantation lenalidomide-based combinations were associated with improved OS in both UVA and MVA (HR, .14; 95% CI, .04 to .45; P = .001), while their impact on PFS was not statistically significant (P = .37). Our results consolidate t(4;14) as a high-risk abnormality associated with poor outcomes despite novel agent induction, auto-HCT, and post-transplantation maintenance. Despite some inherent study design limitations, including a relatively small cohort and heterogeneity in treatment, we observed that deeper pretransplantation response and post-transplantation maintenance with lenalidomide-based combination were associated with improved outcomes. Novel immune and cellular therapies are needed to improve the outcomes in patients with t(4;14).

Perception of prognosis, quality of life, and distress in patients receiving chimeric antigen receptor T-cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell is potentially curative therapy for patients with hematologic malignancies but can cause life-threatening toxicities. Data on perceptions of prognosis and psychological distress are lacking. METHODS: The authors conducted a cross-sectional study of patients receiving CAR-T. Before hospitalization for CAR-T, patients completed assessments of quality of life (QOL) (Functional Assessment of Cancer Therapy-General), anxiety and depression symptoms (Hospital Anxiety and Depression Scale) and post-traumatic stress disorder symptoms (Post-Traumatic Stress Checklist). Patients also completed the Prognostic Awareness Impact Scale (PAIS), which measures three domains: cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response. RESULTS: A total of 71.8% (102 of 142) of eligible patients were enrolled. A total of 34% of patients reported that their oncologist said their cancer is curable and 64% reported there was >50% chance of cure. Overall, 26%, 30%, and 21% of patients reported clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, respectively. We found no association between patients' cognitive understanding of prognosis and QOL or mood. Higher emotional coping with prognosis was associated with better QOL (Β = 0.72; SE = 0.10; p = <.001) and lower depression (Β = -0.17; SE = 0.02; p = <.001), anxiety (Β = -0.21; SE = 0.02; p = <.001), and PTSD (Β = -0.43; SE = 0.06; p = <.001) symptoms. Higher adaptive response was associated with better QOL (Β = 0.19; SE = 0.09; p = .028) and lower depression (Β = -0.05; SE = 0.02; p = .023), anxiety (Β = -0.09; SE = 0.02; p = <.001), and PTSD (Β = -0.19; SE = 0.05; p = <.001) symptoms. CONCLUSIONS: Patients undergoing CAR-T report overly optimistic perception of their prognosis and have high rates of psychological distress. Higher emotional coping with prognosis and adaptive response were associated with better QOL and less psychological distress, underscoring the need to develop interventions to promote coping with this treatment. PLAIN LANGUAGE SUMMARY: Patients undergoing chimeric antigen receptor T-cell therapy experience report overly optimistic perceptions of their prognosis and have high rates of psychological distress. Notably, higher emotional coping with prognosis and adaptive response were associated with better quality of life and less psychological distress.

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity.

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

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

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

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

Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as "responders" or "nonresponders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Acute Lymphoblastic Leukemia Presenting Initially as Spinal Cord Compression: When Chemotherapy Alone Is Enough.

Spinal cord compression (SCC) is a rare initial presentation and complication of acute lymphoblastic leukemia (ALL) with nearly all reported cases occurring in the pediatric population. We report a 38-year-old previously healthy man who presented with acute on chronic lower back pain, gait instability, urinary retention, and severe thrombocytopenia. Radiologic examination revealed two soft tissue masses of the thoracic spine associated with compression fractures causing spinal canal narrowing and cord compression. Bone marrow biopsy confirmed the diagnosis of ALL. Immediate initiation of high-dose corticosteroids and systemic chemotherapy resolved the patient's symptoms without radiation therapy or surgical intervention. After two courses of chemotherapy, the patient achieved complete remission in the bone marrow. Rapid administration of chemotherapy alone in this case resulted in a complete resolution of SCC. Given the rarity of this complication in adults, no standardized treatment has been established. The success of this case recommends chemotherapy as the initial management of SCC in chemotherapy-naïve ALL.

Cellular Immunotherapy in Lymphoma: Beyond CART Cells.

OPINION STATEMENT: Cellular immunotherapy has been rapidly evolving and increasingly utilized in the management of relapsed and refractory lymphoma. CD19-specific chimeric antigen receptor T cells (CARTs) have achieved impressive results in pivotal clinical trials. Although CART development continues, these products have fundamental limitations that may make them less desirable in particular settings. For example, CARTs can only target cell surface antigens and thus are incapable of targeting intracellular tumor-associated proteins. In contrast to CARTs, conventional T cell receptors (TCR) allow T cells to target any cellular antigen, including intracellular proteins, since they interact with peptides presented by MHC I and II molecules. T cells recognizing EBV antigens through native TCRs have been successfully employed for treatment and prophylaxis of EBV-associated lymphomas, including post-transplant lymphoproliferative disorder. Currently, transgenic TCR-transduced T cells targeting nonviral tumor antigens remain experimental but, if successful, could become an invaluable cellular therapy option. Because the manufacturing process of autologous T cell products, including CARTs and other tumor-specific T cells, takes several weeks, patients often need bridging therapy to maintain disease control, which may be challenging. Novel cellular platforms, such as genetically modified NK and NKT cells, may be amenable to allogeneic use and thus may allow production as a readily available, "off-the-shelf" product. As cellular therapies beyond CART continue to grow, available therapeutic options for relapsed and refractory lymphoma patients are expected to expand further.

Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.

Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

Myelodysplastic syndromes with 5q deletion: pathophysiology and role of lenalidomide.

Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q deletion (del(5q)) as the culprit pathogenetic trigger. Del(5q) affects critical regions 5q31 and 5q33, leading to gene haplodeficiency with subsequent RPS14 haplodeficiency and P53 activation. Subsequent to P53 activation, erythroid cell apoptosis and ineffective erythropoiesis occur. Other pathogenetic elements include protein phosphatase 2a and CDC25C haplodeficiency and decreased miR-145 and miR-146a expression. Lenalidomide is an immunomodulatory agent that selectively suppresses the del(5q) clone. While the mechanism is not fully understood, it is associated with diverse molecular changes including stabilization of MDM2 with subsequent enhanced P53 degradation. Lenalidomide showed success in low- and intermediate-1-risk MDS as reported in the 002, 003, and 004 trials. However, in higher-risk MDS, the results of lenalidomide monotherapy were modest, mandating the use of combination therapy. The role and priority of lenalidomide varies between different guidelines, and accordingly, future efforts are necessary to reach a unified therapeutic algorithm. TP53 mutations are important predictors of AML progression and possible resistance to lenalidomide. It is recommended to identify TP53 mutation early in the disease since it may change the decision regarding choice of therapy. Challenges with lenalidomide therapy remain the long-term effects and timing of its discontinuation.

Management of myeloma-associated renal dysfunction in the era of novel therapies.

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.