Tafasitamab and lenalidomide for relapsed/refractory diffuse large B-cell lymphoma in a patient on chronic intermittent hemodialysis.

INTRODUCTION: Tafasitamab is an anti-CD19 monoclonal antibody indicated for the treatment of relapsed/refractory diffuse large B-cell lymphoma to be given in combination with lenalidomide. Experiences with tafasitamab in the setting of hemodialysis are limited and the efficacy and safety of this agent in this setting are unknown. CASE REPORT: We describe a patient with relapsed/refractory diffuse large B-cell lymphoma with hemodialysis-dependent end-stage renal disease who successfully received tafasitamab/lenalidomide. MANAGEMENT AND OUTCOME: Tafasitamab and reduced dose lenalidomide were initiated for relapsed diffuse large B-cell lymphoma. Tafasitamab was administered on non-dialysis days. Follow-up imaging for disease response assessment demonstrated a complete response. Therapy was well tolerated; the only major toxicity experienced was grade 4 neutropenia that resolved with dose adjustment to lenalidomide. Over a year from initiating therapy, the patient remains in a complete response. DISCUSSION/CONCLUSION: The combination of tafasitamab and dose-reduced lenalidomide produced a complete response in the treatment of relapsed/refractory diffuse large B-cell lymphoma in the setting of chronic intermittent hemodialysis.

Real-world clinical outcomes with fostamatinib for the treatment of refractory chronic immune thrombocytopenia: a single-center experience.

Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n  = 7; 70%). The median time to response was 9 days. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.

Efficacy of Selinexor in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with del17p and Other High-Risk Abnormalities (A Retrospective Single-Center Study).

Selinexor (Seli) is a first-in-class, oral selective inhibitor of the nuclear export protein, exportin-1 (XPO1). Seli exhibits its antitumor effect through the blockage of XPO1, which increases nuclear retention of tumor suppressor proteins (TSPs), including p53, thereby limiting the translation of oncogenes, triggering cell cycle arrest and the death of malignant cells. Multiple Myeloma (MM) patients with del17p are deficient in TP53 and have a particularly poor prognosis. Given its unique mechanism of action, we investigated whether Seli has increased efficacy in RRMM patients with del17p compared to other high-risk cytogenetics (OHRC). This is an IRB-approved observational study of RRMM patients with high-risk cytogenetics (del17p, t (4;14), t (14;16) or gain 1q) or standard-risk cytogenetics treated at the Levine Cancer Institute (LCI) with a Seli-based regimen between January 2019 and December 2022. Time-to-event endpoints (PFS, OS) were evaluated using Kaplan-Meier (KM) methods. Log-rank tests compared time-to-event endpoints between cohorts [del17p vs. OHRC vs. standard risk]. We identified 40 RRMM patients with high-risk cytogenetics, including 16 patients with del17p and 24 patients with OHRC, as well as 20 with standard-risk cytogenetics. The median age was 62.5 vs. 69 vs. 65.5 years (del17p group vs. OHRC vs. standard risk). The median prior line of therapies was five (range: 3-16) with similar rates of prior autologous stem cell transplant in all arms (68.8% vs. 62.5% vs. 70.0%). The most frequently used regimens were Seli-Pomalidomide-dexamethasone(dex) or Seli-Carfilzomib-dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. The median time to start the Seli-based regimen after initial MM diagnosis was 5.6 years for the del17p group, 4.1 years in OHRC, and 4.8 years in the standard-risk group. The median follow-up time after the start of the Seli-based regimen was 10.5 months (mos) in the del17p group, 8.4 mos in OHRC, and 10.3 mos in the standard-risk group. In the del17p group, 50% had an objective response, 41.7% in the OHRC, and 35% in the standard-risk group (p = 0.71). Depth of response was also similar across the arms (12.5% vs. 12.5% vs. 10.0% VGPR p = 0.99). The median OS was 10.9 mos in the del17p group, 10.3 mos in the OHRC, and 10.3 mos in the standard-risk group (p = 0.92). The median OS was 15.5 mos for patients who received Seli as a bridging therapy versus 9 mos for Seli use for other reasons rather than as a bridge. Overall, Seli-based regimens showed promising responses even in this heavily pretreated population. Our analysis suggests that Seli-based regimens lead to similar outcomes among RRMM patients with del17p, OHRC, and standard-risk cytogenetics. This contrasts with previously reported outcomes using combinations of novel therapies in this population, where the del17p patients often have a poorer prognosis. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response.

High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.

MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.

A Clinical and Correlative Study of Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (Elo-KRd) for Lenalidomide Refractory Multiple Myeloma in First Relapse.

INTRODUCTION: Treatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy. METHODS: Enrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic. RESULTS: Of 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10-5) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group. CONCLUSION: A short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations.

Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities.

Total Therapy 2 examined the clinical benefit of adding thalidomide up-front to a tandem transplant regimen for newly diagnosed patients with multiple myeloma. When initially reported with a median follow-up of 42 months, complete response rate and event-free survival were superior among the 323 patients randomized to thalidomide, whereas overall survival was indistinguishable from that of the 345 patients treated on the control arm. With further follow-up currently at a median of 72 months, survival plots segregated 5 years after initiation of therapy in favor of thalidomide (P = .09), reaching statistical significance for the one third of patients exhibiting cytogenetic abnormalities (CAs; P = .02), a well-recognized adverse prognostic feature. The duration of complete remission was also superior in the cohort presenting with CAs such that, at 7 years from onset of complete remission, 45% remained relapse-free as opposed to 20% on the control arm (P = .05). These observations were confirmed when examined by multivariate analysis demonstrating that thalidomide reduced the hazard of death by 41% among patients with CA-positive disease (P = .008). Because two thirds of patients without CAs have remained alive at 7 years, the presently emerging separation in favor of thalidomide may eventually reach statistical significance as well.

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease.

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. We conducted a phase 2 trial in 76 eligible patients with SMM, combining thalidomide (THAL, 200 mg/d) with monthly pamidronate. In the first 2 years, THAL dose reduction was required in 86% and drug was discontinued in 50%. Within 4 years, 63% improved, including 25% qualifying for partial response (PR); by then, 34 patients had progressed and 17 required salvage therapy. Unexpectedly, attaining PR status was associated with a shorter time to salvage therapy for disease progression (P < .001), perhaps reflecting greater drug sensitivity of more aggressive disease. Low beta-2-microglobulin levels less than 2 mg/L were independently associated with superior overall and event-free survival. Four-year survival and event-free survival estimates of 91% and 60%, respectively, together with a median postsalvage therapy survival of more than 5 years justify the conduct of a prospective randomized clinical trial to determine the clinical value of preemptive therapy in SMM. Trial registered at http://www.clinicaltrials.gov under identifier NCT00083382.

Thalidomide and hematopoietic-cell transplantation for multiple myeloma.

BACKGROUND: High-dose therapy with melphalan can prolong survival among patients with multiple myeloma. We assessed whether the addition of thalidomide, which has activity against advanced and refractory myeloma, would further improve survival. METHODS: Between October 1998 and February 2004, 668 patients with newly diagnosed multiple myeloma received two cycles of intensive melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation. A total of 323 were randomly assigned to receive thalidomide from the outset until disease progression or undue adverse effects, and 345 did not receive thalidomide. The primary end point was the five-year event-free survival rate. Secondary end points were complete response and overall survival. RESULTS: After a median follow-up of 42 months among survivors, the thalidomide and control groups had rates of complete response of 62 percent and 43 percent, respectively (P<0.001), and five-year event-free survival rates of 56 percent and 44 percent (P=0.01). The five-year rate of overall survival was approximately 65 percent in both groups (P=0.90). Median survival after relapse was 1.1 years in the thalidomide group and 2.7 years in the control group (P=0.001). Severe peripheral neuropathy and deep-vein thrombosis occurred more frequently in the thalidomide group than in the control group. CONCLUSIONS: When incorporated into high-dose therapy for myeloma, thalidomide increased the frequency of complete responses and extended event-free survival at the expense of added adverse effects without improving overall survival. (ClinicalTrials.gov number, NCT00083551.).

Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1.

In comparison to total therapy 1 (TT1), the phase 3 trial total therapy 2 (TT2) evaluated the benefit of up-front administration of thalidomide (THAL); TT2 also introduced post-transplant consolidation chemotherapy. With median follow-up times of 5 and 12 years, respectively, outcome comparisons were made of 668 patient's enrolled on TT2 and 231 patients treated on TT1. Complete response (CR) rates were similar at 40% for TT1 and TT2 without THAL versus 60% on the THAL arm of TT2. CR durations were similar with either TT2 arm and both were superior to results of TT1. Event-free and overall survivals were extended from 2.6 to 5.7 years, respectively, with TT1 to 4.8 and 8.0 years with TT2. TT2's major advance vis-à-vis TT1 pertained to the subgroup without cytogenetic abnormalities (CA), supporting the role of post-transplant consolidation therapy, whereas the improved survival of the CA subgroup on the experimental versus control arm of TT2 attests to the role of THAL in this setting. Adjusting for prognostic variables in multivariate and pair-mate analyses, TT2 was superior to TT1 in terms of CR duration, event-free and overall survival. These results provide a basis for the prospective evaluation of the consolidation strategy in a randomized clinical trial design.

Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2.

Total therapy 3 (TT3), incorporating bortezomib up-front into a tandem transplant regimen for newly diagnosed multiple myeloma (MM), effected 2-year complete response (CR) estimates >90%, which appeared superior to results reported for total therapy 2 (TT2). With median follow-up times of 2 years with TT3 and 5 years with TT2, the clinical outcomes of 303 patients in the former and 668 in the latter trial were compared, including the subset of 607 patients with gene expression profiling (GEP) data. With similar baseline prognostic factors, event-free survival (EFS) (P = 0.0002) and CR duration (P = 0.003) were superior with TT3 vs. TT2 with a strong trend noted also for improved overall survival (OS) (P = 0.16). In the GEP-defined FGFR3 subgroup, TT3 imparted significantly superior OS, EFS and CR duration vis-à-vis TT2. Matching 300 patients each by standard prognostic factors, TT3 yielded superior EFS and CR duration and borderline superior OS. The advantage of TT3 still pertained when the comparison was limited to patients who completed TT2 consolidation rapidly within 24 months. Our data strongly suggest that the addition of bortezomib in TT3 was accountable for its superior performance rather than greater compliance with protocol completion as a result of greater dose-density in TT3 vs. TT2.

Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling.

EXPERIMENTAL DESIGN: To determine whether the clinical benefit of complete remission (CR) may depend on prognostic subgroups of patients with multiple myeloma. PATIENTS AND METHODS: Newly diagnosed patients with myeloma received a tandem autotransplant regimen. Using multivariate regression analyses, we examined the prognostic implications of time-dependent onset of CR on overall survival and event-free survival in the context of standard prognostic factors (SPF) and gene expression profiling-derived data available for 326 patients. RESULTS: CR benefited patients regardless of risk status when only SPFs were examined. With knowledge of gene array data, a survival (and event-free survival) benefit of CR only pertained to the small high-risk subgroup of 13% of patients (hazard ratio, 0.23; P = 0.001), whereas the majority of patients with low-risk disease had similar survival expectations whether or not CR was achieved (hazard ratio, 0.68; P = 0.128). CONCLUSIONS: Access to gene expression information permitted the recognition of a small very high-risk subgroup of 13% of patients, in whom prolonged survival critically depended on achieving CR. Absence of such benefit in the remainder should lead to a reassessment of clinical trial designs that rely on this end point as a surrogate for long-term prognosis.

The Arkansas approach to therapy of patients with multiple myeloma.

This chapter gives an account of the experience of the Arkansas myeloma program since 1989 with transplant-supported high-dose melphalan, novel agents, and prognostic factors as they relate to standard laboratory features, gene expression profiling, and magnetic resonance imaging (MRI). Incorporation of novel agents and new concepts, such as post-tandem transplant consolidation therapy, has improved the rate and duration of complete response and prolonged event-free and overall survival rates. With Total Therapy 2, median survival exceeds 8 years, while Total Therapy 3 with added bortezomib has sustained complete remissions in more than 90% of patients at 2 years which, when used as a survival surrogate in Total Therapy 2, assured a high 6-year survival rate of 75%. Gene expression profiling identified 15% of patients with very short survival. MRI-defined focal lesions are associated with poor outcome, while their resolution - although slower than the time course of attaining clinical complete remission - conferred superior survival. Representing a frequent source of recurrence, with genetic profiles (in both plasma and stromal cells) distinct from those in random bone-marrow samples, therapeutic efforts are directed at hastening onset and increasing frequency of focal lesion resolution.

Coccidioides immitis fungemia: clinical features and survival in 33 adult patients.

Coccidioides immitis is a fungus endemic to the southwestern United States. Susceptible hosts, including blacks, Hispanics, Filipinos, Native Americans, and those with compromised immunity, may develop disseminated disease, including fungemia. We retrospectively reviewed the records of all patients (n = 33) with Coccidioides immitis fungemia (CIF) at a 550-bed public hospital in Phoenix, Arizona, from 1990 to 2002. This is the largest reported series of CIF. The purpose of the study was to review the incidence, signs, symptoms, and outcomes of CIF. Twenty-nine patients had human immunodeficiency virus infection. CIF was associated with sepsis, end-stage alcoholic liver disease, and diabetes in four patients. Survival was poor; 24 of the 33 patients died within 28 days. CIF manifested as a systemic inflammatory response syndrome with progressive cardiorespiratory failure. Despite fluid loading, infusion of vasoactive agents, and mechanical ventilation with positive end-expiratory pressure, patients typically experienced a rapidly progressive course and death. CIF portends an ominous prognosis and typically occurs in the setting of advanced human immunodeficiency virus or medical or surgical crises.

Clinical and biological features of multiple myeloma involving the gastrointestinal system.

We report 24 cases of multiple myeloma (MM) with involvement of the gastrointestinal (GI) system. We found a strong association with high A lactate dehydrogenase levels, plasmablastic morphology, and A unfavorable karyotype. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The A median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, and median progression-free survival was 4 months. We conclude that MM involving the GI system is associated with adverse biological features and with short-lasting remissions, even after A high-dose chemotherapy.

Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma.

BACKGROUND: Complete response has been considered a surrogate for favorable long-term outcome in multiple myeloma. Data on the impact of the duration of response on prognosis are lacking. PATIENTS AND METHODS: Of the 899 patients enrolled in Total Therapy trials (Total Therapy 1, N = 231; Total Therapy 2, N = 668), 254 survived for > 5 years. The prognostic impact of continuous (Rc) versus discontinuous (Rd) 4-year remission after 5-year survival was examined along with laboratory features present at baseline and at 5 years. RESULTS: Most baseline prognostic features were evenly distributed among Rc and Rd groups; however, a greater proportion of Rc patients were enrolled in Total Therapy 2 (60%) compared with Rd (19%; P < 0.001). Twelve-year survival (7 years after the 5-year landmark) was 66% with Rc and only 30% with Rd. Hypodiploidy and deletion 13, present in 24 patients at baseline, were associated with a 12-year survival of only 20%. Among the 200 patients lacking these cytogenetic abnormalities, Rc (n = 141) defined a superior 12-year survival rate of 70% versus 35% among those with Rd (n = 59). Initial quality of response (complete response) or having received the scheduled tandem transplantations did not affect post-5-year survival. CONCLUSION: Five-year Rc appears to be an important prerequisite for prolonged subsequent overall survival.

High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients.

BACKGROUND: In this report, the authors describe their collective experience with melphalan-based autotransplants since the inception of their program at the University of Arkansas for Medical Sciences in 1989. METHODS: The authors evaluated the clinical outcomes of 3077 successive patients with multiple myeloma (MM) who underwent at least 1 melphalan-based autotransplantation at the University of Arkansas. Of these, 1078 patients were enrolled on front-line Total Therapy (TT) protocols (TT-P) TT1, TT2, and TT3; 1104 patients were entered on protocols for newly diagnosed or previously treated patients (non-TT-P); and 895 patients were treated off protocol (non-P). RESULTS: The 10-year overall survival (OS) rates after first transplantation were 41%, 19%, and 11% (P< .001) for the TT-P, non-TT-P, and non-P groups, respectively. In the TT-P group, the median OS was 72 months on TT1, was not reached at >or= 7 years on TT2, and was 88% at 2 years on TT3. Among 2683 patients with complete baseline data, absence of hypodiploidy/chromosome 13 deletion, beta-(2)-microglobulin <3.0 mg/L, C-reactive protein <6 mg/L, albumin >or= 3.0 g/dL, and platelet count >or= 100,000/microL all were associated independently with superior OS (P< .001), event-free survival (P< .001), and duration of complete remission (P< .001). CONCLUSIONS: The results from this large, single-institution experience demonstrated that >10-year OS was accomplished in >40% of all patients enrolled on TT-P, whereas such success was observed in only 15% of the remaining patients (including 25% in the presence of all 5 good-risk features). Superior outcomes with protocol-based, primary transplant regimens such as TT-P draw attention to the importance of applying the best available therapies upfront.

Completion of premaintenance phases in total therapies 2 and 3 improves clinical outcomes in multiple myeloma: an important variable to be considered in clinical trial designs.

BACKGROUND: Total Therapy (TT) programs are complex and their execution over the course of several years is fraught with patient attrition due to failure and toxicity of therapy and patient/physician acceptance. METHODS: The impact of completion versus noncompletion of intended treatment steps was examined in protocols TT2 (n=668) and TT3 (n=303) on overall survival (OS) and event-free survival (EFS). RESULTS: By using appropriate landmarks of 36 months with TT2 and 18 months with TT3, representing the maxima to completion of premaintenance phases, postconsolidation OS was superior for 211 patients completing versus 311 patients not completing premaintenance steps on TT2 (P=.001), which also pertained to the 161 patients completing versus 47 not completing intended treatment steps on TT3 (P=.01). On multivariate analysis that included all patients, completion of therapy independently favored longer OS and EFS in the context of both standard prognostic factors and gene expression profiling-defined risk; in addition, TT3 prolonged EFS over results obtained with TT2. CONCLUSIONS: 1) Completion of intended therapy was a significant independent variable conferring superior OS and EFS in TT programs; and 2) after adjusting for completion of therapy, EFS was still superior with TT3 versus TT2, supporting the beneficial role of bortezomib included in TT3. Collectively, these data point to the importance of designing clinical trials that balance the treatment requirements for disease control with host acceptance and tolerance.