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Journal of Clinical Oncology : Official... May 2019Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.
METHODS
A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
RESULTS
A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% 49%), neutropenia (58% 23%), and cutaneous reactions (32% 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% 13%) and leukopenia (7% 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
CONCLUSION
Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lenalidomide; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Male; Middle Aged; Neoplasm Recurrence, Local; Placebos; Rituximab
PubMed: 30897038
DOI: 10.1200/JCO.19.00010 -
Blood Jun 2020Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data... (Review)
Review
Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory follicular lymphoma. Lenalidomide-rituximab has been demonstrated to be an effective chemotherapy-free therapy that improves upon single-agent rituximab and may become an alternative to chemoimmunotherapy.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Follicular; Rituximab
PubMed: 32236519
DOI: 10.1182/blood.2019001751 -
Journal of Clinical Oncology : Official... Apr 2020Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma.
METHODS
We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression.
RESULTS
One hundred eighty-two patients were randomly assigned-92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide.
CONCLUSION
Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Lenalidomide; Male; Middle Aged; Quality of Life; Smoldering Multiple Myeloma
PubMed: 31652094
DOI: 10.1200/JCO.19.01740 -
Nature Communications Aug 2023Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q...
Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.
Topics: Female; Pregnancy; Humans; Lenalidomide; Proteolysis; Immunomodulating Agents; Multiple Myeloma; Myelodysplastic Syndromes; Chromosome Aberrations; Hematologic Neoplasms; Proteolysis Targeting Chimera
PubMed: 37596276
DOI: 10.1038/s41467-023-40385-9 -
Drugs Sep 2020Lenalidomide (Revlimid) is a targeted immunomodulatory drug with multiple mechanisms of action. In the USA and the EU, oral lenalidomide is indicated in combination with... (Review)
Review
Lenalidomide (Revlimid) is a targeted immunomodulatory drug with multiple mechanisms of action. In the USA and the EU, oral lenalidomide is indicated in combination with rituximab or a rituximab product for the treatment of patients with previously treated follicular lymphoma. In the pivotal, phase III AUGMENT trial, lenalidomide + rituximab significantly prolonged progression-free survival (PFS; primary endpoint) relative to placebo + rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma, with the PFS benefit appearing to be specific to patients with follicular lymphoma and extending to elderly patients with this subtype. Lenalidomide + rituximab also demonstrated activity in an interim analysis of the phase III MAGNIFY trial in patients with relapsed or refractory indolent non-Hodgkin lymphoma, including those with rituximab-refractory disease. Lenalidomide had an acceptable tolerability profile. Although grade 3 or 4 neutropenia occurred more frequently with lenalidomide + rituximab than with placebo + rituximab, this was generally well managed with dosage adjustments and growth factor support. In conclusion, lenalidomide in combination with rituximab represents an important new treatment option for previously treated follicular lymphoma, including patients whose disease has become refractory to rituximab.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Lenalidomide; Lymphoma, Follicular; Placebos; Progression-Free Survival; Rituximab
PubMed: 32803669
DOI: 10.1007/s40265-020-01381-1 -
Haematologica Sep 2021Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good...
Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Transplantation, Autologous; Treatment Outcome
PubMed: 34196165
DOI: 10.3324/haematol.2020.275958 -
Blood Dec 2023In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk...
In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.
Topics: Humans; Lenalidomide; Treatment Outcome; Retrospective Studies; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37738563
DOI: 10.1182/blood.2023021274 -
The Lancet. Oncology Jan 2019Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses.
METHODS
The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment.
FINDINGS
Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related.
INTERPRETATION
Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting.
FUNDING
Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Intention to Treat Analysis; Lenalidomide; Maintenance Chemotherapy; Multiple Myeloma; Progression-Free Survival; Transplantation, Autologous; Treatment Outcome
PubMed: 30559051
DOI: 10.1016/S1470-2045(18)30687-9 -
American Journal of Clinical Pathology Nov 2020Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma... (Review)
Review
OBJECTIVES
Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma but also has been associated with an increased risk of secondary B-lymphoblastic leukemia/lymphoma (B-ALL).
METHODS
We report a comprehensive review of the clinicopathologic features of 2 patients with multiple myeloma who developed secondary B-ALL during lenalidomide maintenance.
RESULTS
Our observations showed that the disease may initially present with subtle clinical, morphologic, and flow-cytometric findings. The flow cytometry findings in such cases may initially mimic an expansion of hematogones with minimal immunophenotypic variation. Both patients achieved complete remission of secondary B-ALL after standard chemotherapy; however, one patient continues to have minimal residual disease, and the other experienced relapse. Next-generation sequencing of the relapse specimen showed numerous, complex abnormalities, suggesting clonal evolution.
CONCLUSIONS
Our findings suggest the need for increased awareness and further study of this unique form of secondary B-ALL.
Topics: Adult; Antineoplastic Agents; Bone Marrow; Cytogenetic Analysis; Fatal Outcome; High-Throughput Nucleotide Sequencing; Humans; Immunologic Factors; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Stem Cell Transplantation
PubMed: 32880627
DOI: 10.1093/ajcp/aqaa109 -
Leukemia Mar 2019Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is... (Review)
Review
Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is associated with increase in progression-free survival (PFS) and survival in persons with plasma cell myeloma (PCM). Based on these data, posttransplant lenalidomide is considered by many a standard-of-care in this setting. However, decisions on the use of new therapies should consider not only results of such trials and meta-analyses but also other factors including quality-of-evidence, anticipated desired and undesired effects of the drug, costs and feasibility of the therapy option. In this review, we critically analyzed evidence on posttransplant lenalidomide in PCM, and we identified criteria which should be considered in designating posttransplant lenalidomide the standard-of-care. Using Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach we judged posttransplant lenalidomide improves PFS with high-quality evidence. However, we identified inconsistency and imprecision as limitations in the conclusions regarding a survival benefit rating the quality-of-evidence for a survival benefit moderate. We also highlighted inconsistency in claims of an increased risk of new cancers associated with posttransplant lenalidomide. We emphasize the need for a value-based reasoning which considers PFS and survival as well as health-related quality-of-life and costs. We conclude the decision to use posttransplant lenalidomide should be individualized based on pre- and posttransplant variables such as remission state, risk category and/or posttransplant measurable residual disease (MRD)-test results. Validity of these variables in estimating benefits and risks of posttransplant lenalidomide should be tested in randomized clinical trials.
Topics: Autografts; Disease-Free Survival; Humans; Lenalidomide; Meta-Analysis as Topic; Multiple Myeloma; Quality of Life; Randomized Controlled Trials as Topic; Transplantation, Autologous
PubMed: 30692596
DOI: 10.1038/s41375-019-0383-2