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Blood Jul 2021Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The... (Randomized Controlled Trial)
Randomized Controlled Trial
Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Dexamethasone; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Glycine; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Survival Rate
PubMed: 33763699
DOI: 10.1182/blood.2020008787 -
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 -
The Lancet. Oncology Oct 2020Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in... (Randomized Controlled Trial)
Randomized Controlled Trial
Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial.
BACKGROUND
Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT).
METHODS
In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1-8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1-14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1-21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing.
FINDINGS
Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5-23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8-37·8) in the KRd group and 34·4 months (30·1-not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83-1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3-4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death).
INTERPRETATION
The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs.
FUNDING
US National Institutes of Health, National Cancer Institute, and Amgen.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Intention to Treat Analysis; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Oligopeptides; Proteasome Inhibitors; Treatment Outcome
PubMed: 32866432
DOI: 10.1016/S1470-2045(20)30452-6 -
Journal of Clinical Oncology : Official... Feb 2023Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data...
PURPOSE
Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset.
METHODS
We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed.
RESULTS
The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively.
CONCLUSION
Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.
Topics: Humans; Middle Aged; Aged; Rituximab; Lenalidomide; Piperidines; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide
PubMed: 35952327
DOI: 10.1200/JCO.22.00597 -
Journal of Clinical Oncology : Official... Mar 2023With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).
METHODS
POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression.
RESULTS
Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ≥ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% 41.6%), anemia (19.8% 22.4%), pneumonia (17.3% 11.0%), thrombocytopenia (15.5% 15.7%), and diarrhea (10.2% 3.9%).
CONCLUSION
D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).
Topics: Humans; Aged; Lenalidomide; Multiple Myeloma; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Disease Progression
PubMed: 36599114
DOI: 10.1200/JCO.22.00940 -
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 -
Deutsches Arzteblatt International Mar 2023Myelodysplastic syndromes (MDS) are malignant diseases arising from hematopoietic stem cells. Their overall incidence is 4 cases per 100 000 persons per year, and they... (Review)
Review
BACKGROUND
Myelodysplastic syndromes (MDS) are malignant diseases arising from hematopoietic stem cells. Their overall incidence is 4 cases per 100 000 persons per year, and they are usually diagnosed when evaluating cytopenia. The median survival time is three years. Myelodysplastic syndromes take a variable course; one-quarter of patients go on to develop acute leukemia.
METHODS
This review is based on publications retrieved by a selective search of the literature from 2013 to 2022, including relevant guidelines, in the PubMed database. The time period was chosen to reflect developments since the publication of the latest EHA guidelines in 2013.
RESULTS
The gold standard of diagnosis is cytomorphology of the blood and bone marrow, supplemented by banding cytogenetics, histomorphology, and somatic mutation analyses. The new classification proposed by the WHO incorporates the molecular and cytogenetic findings. The Molecular International Prognostic Scoring System (IPSS-M), which takes somatic mutations into account, is now available as an aid to prognostication. Quality of life evaluation with standardized instruments is helpful in many ways. Low-risk patients are treated supportively with erythrocyte transfusions and iron chelation therapy. Erythropoietin-a can be given to patients whose erythropoietin level is less than 200ng/mL, lenalidomide to those with a 5q deletion, and luspatercept to those with an SF3B1 mutation. High-risk patients should be evaluated as early as possible for allogeneic hematopoietic stem cell transplantation with curative intent. 5-azacytidine improves outcomes in patients for whom stem cell transplantation is not suitable.
CONCLUSION
Once a precise diagnosis has been established, new prognostic instruments such as the IPSS-M enable risk-adapted treatment based on the biological aspects of the patient's disease as well as his or her age and comorbidities.
Topics: Humans; Male; Female; Quality of Life; Myelodysplastic Syndromes; Lenalidomide; Hematopoietic Stem Cell Transplantation; Prognosis; Erythropoietin
PubMed: 36718105
DOI: 10.3238/arztebl.m2023.0005 -
Blood Oct 2019Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in... (Randomized Controlled Trial)
Randomized Controlled Trial
Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10-6 sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chemotherapy, Adjuvant; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Transplantation Conditioning; Transplantation, Autologous
PubMed: 31484647
DOI: 10.1182/blood.2019000241 -
Leukemia Mar 2022
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Oligopeptides; Progression-Free Survival
PubMed: 34732857
DOI: 10.1038/s41375-021-01431-x -
Nature Communications Jul 2022The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we...
The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to define the myeloma surfaceome at baseline, in drug resistance, and in response to acute drug treatment. We provide a scoring system for surface antigens and identify CCR10 as a promising target in this disease expressed widely on malignant plasma cells. We engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting CCR10 using its natural ligand CCL27. In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. We find that acute lenalidomide treatment increases activity of MUC1-targeting CAR-T cells through antigen upregulation. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.
Topics: Drug Resistance; Humans; Immunotherapy; Lenalidomide; Multiple Myeloma; Proteomics; Tumor Microenvironment
PubMed: 35840578
DOI: 10.1038/s41467-022-31810-6