A B S T R A C T PurposeTo assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. Patients and MethodsPatients received bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre-and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. ResultsAmong 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatmentemergent neuropathy, which will require future study. ConclusionSingle-agent bortezomib is effective in previously untreated myeloma. Baseline myelomaassociated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.
Prior studies have shown that myeloma patients exhibiting either genetically defined high-risk disease or plasma cell leukemia have a poor outcome with a median overall survival (OS) of ≤3 years. Results of IFM 2005-01 and 02 suggest that relatively limited bortezomib-containing induction regimens did not produce a major survival benefit among these patients. However, results of recent studies suggest that combination therapy may benefit these patients when given early and again later in the treatment. We evaluated a combination maintenance/consolidation regimen (RVD) following autologous stem cell transplant (ASCT) for high-risk patients to evaluate the impact of this approach on outcome. Following initiation of RVD maintenance, 51% of patients achieved stringent complete response (sCR), with 96% achieving at least VGPR as best response. Median progression free survival (PFS) for all patients is 32 months with a 3-year OS of 93%. The regimen was well tolerated with no grade 3/4 neuropathy. Early ASCT followed by RVD maintenance is a promising strategy for high-risk myeloma patients and delivered excellent response rates, and promising PFS and OS.
B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.
BACKGROUND:The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA-and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomibrefractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARAand POM-naive, and cohort 2 (22 patients) was DARA-and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA-and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA-and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients. Cancer 2019;125:2991-3000.
Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent upon BCL2 for survival. Most myeloma is MCL1 dependent, however a subset of myeloma enriched for translocation t(11;14) is co-dependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We demonstrate that knockdown of CCND1 does not induce resistance to venetoclax, arguing against a direct role for CCND1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response, and further demonstrated that knockout of BIM results in decreased venetoclax sensitivity. RNA-seq analysis identified expression of B cell genes as enriched in venetoclax sensitive myeloma, though no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as biomarker independent of t(11;14). ATAC-seq of myeloma cell lines also identified an epigenetic program in venetoclax sensitive cells that was more similar to B cells than that of venetoclax resistant cells, as well as enrichment for bZIP binding motifs such as the BATF transcription factor. Together these data indicate remnants of B cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax sensitive myeloma independent of t(11;14).
Purpose: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.Experimental Design: Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m 2 ) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.Results: Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.Conclusions: The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation. Clin Cancer Res; 16(20); 5079-86. ©2010 AACR.Multiple myeloma (MM) is a clonal plasma cell disorder characterized by lytic bone disease, renal dysfunction, abnormal hematopoietic function, and the presence of a monoclonal paraprotein in the blood and/or urine. Historical induction regimens rarely achieved major responses [very good partial remission (VGPR) or complete remission (CR)], and before the use of high-dose therapy (HDT) and autologous transplant, few therapeutic options showed significant improvements in overall survival (OS) for newly diagnosed myeloma patients (1, 2). Led first by the Intergroupe Francophone du Myelome (IFM), several groups have now shown improvements in overall response rate, progression-free survival (PFS), and OS for patients randomized to receive HDT when compared with conventional dose chemotherapy (3), rendering HDT a standard treatment approach for younger patients with newly diagnosed MM. In addition, the IFM has shown that achievement of a VGPR is a surrogate for improvement in PFS and OS (4), adding it as a new category in the revised International Myeloma Working Group response criteria (5). Despite these improvements, patients are rarely, if ever, cured of MM through the use of HDT. To improve the efficacy of the HDT maneuver itself, groups have explored the use of multiple cycles of HDT (tandem transplant; refs. 6-8), the use of combination chemotherapy conditioning regimens using agents...
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