IMPORTANCE: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone ...lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. OBSERVATIONS: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization—t(4;14), del(17p), and t(14;16)—to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients. CONCLUSIONS AND RELEVANCE: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.
The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin's lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance ...therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for multiple myeloma showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL.
NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan/carmustine, etoposide, cytarabine, melphalan. After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles.
Nineteen patients received BV post-ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue, and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive.
BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.
To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma.
Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not ...otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes.
AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio HR, 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival.
These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.
Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells ...or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.
Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free ...survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.
In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In ...a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT.
We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles.
The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression.
BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.
Background
Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management.
Methods
We present a retrospective ...cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded.
Results
During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2–88.5) months and median PFS was 11.0 (0.2–73.9) months. At diagnosis (r
2
= 0.85, p < 0.001), first relapse (r
2
= 0.69, p < 0.001), multiple relapses (r
2
= 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS.
Conclusions
PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.
External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an ...antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression.
We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (
I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose.
Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later.
CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.
This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) busulfan, therapeutic drug monitoring and clinical ...outcome in hemato-poietic stem cell transplant (HCT) patients. Busulfan is commonly used in HCT as it is toxic to the marrow. Busulfan is available as oral or i.v. formulation. The most common significant toxicity of busulfan is sinusoidal obstruction syndrome. Even with the introduction of i.v. busulfan, variability in the systemic concentrations of busulfan after weight-based dosing and the association between busulfan plasma exposure and outcome in HCT patients have led to the continued use of therapeutic drug monitoring of busulfan. New strategies for personalizing busulfan dosing are being studied to maximize the use of busulfan for optimal disease control with the least toxicity to HCT patients. One such strategy currently being evaluated is if busulfan clearance can be accurately predicted by genetic polymorphism of glutathione S-transferase (GST), with the currently available data suggesting that GST polymorphisms cannot be used to personalize busulfan dosing.
High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of ...intensive induction regimens before transplantation is unknown.
To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.
The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio HR, 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.
An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.
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