Lenalidomide Maintenance In Patients Research Articles

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p=.01) compared with the lenalidomide group (24% vs. 15%; p<.01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p=.009). Overall survival at 2years was also superior in the lenalidomide group (93% vs. 84%; p=.001). No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

Phase Ib/II Study of Rituximab, Lenalidomide and Methotrexate Followed By Lenalidomide Maintenance in Patients with Newly Diagnosed Primary CNS Lymphoma: The Remla Trial

Purpose: We evaluated the tolerability and efficacy of adding lenalidomide to a rituximab and methotrexate combination (R2-MTX) regimen, followed by lenalidomide maintenance as a first-line treatment of patients with primary central nervous system lymphoma (PCNSL). Patients and methods: This multicenter prospective phase Ib/II study, enrolled immunocompetent patients aged 18-75 years with untreated PCNSL. The phase I study increased lenalidomide dose from 15 to 20 to 25 mg. Patients were treated with rituximab 375 mg/m2 and methotrexate 3.5 g/m2 on day 1 and lenalidomide daily for 14 days every 3-week cycle. After 6 cycles of the R2-MTX regimen, responsive patients received lenalidomide maintenance therapy(lenalidomide 25 mg daily for 21 days every 4-week cycle for 2 years).ASCT was optional in eligible patients before lenalidomide maintenance. The primary phase I endpoint was the maximum tolerated dose of lenalidomide. The primary phase II endpoint was the 2-year progression-free survival (PFS). Results: Eleven patients were enrolled in phase Ib of the study. No Dose-limiting toxicities were observed, and the recommend phase II dose of lenalidomide was 25mg. In phase II, 23 patients were treated. The median follow-up period was 14.2 months (range, 8.0-33.4), the estimated 2-year PFS and OS were 61.5%(95% CI 50.7-91.8 ) and 81.7%(95% CI 57.4-92.9), respectively. In the PR2D group, the objective response rate was 92.%, and estimated 2-year PFS and OS were 78.5%(95% CI 50.7-91.8) and 90.4%(95% CI 66.8-97.5). Compared with historical controls in our center, 2-year PFS were significantly improved (P = 0.0088). Hematological toxicities, GI symptoms and infection were the most frequent adverse events, and grade 3/4 toxicities were seen in 62.5% of patients. Quality of life was stabilized during the lenalidomide maintenance phase. Conclusion: R2-MTX regimen supported the integration of lenalidomide to HD-MTX in induction therapy and maintenance as front-line treatment PCNSL patients with good safety, response rate and 2-year PFS. More importantly, the REMLA trial suggested lenalidomide maintenance could be an option instead of WBRT/ASCT consolidation even in younger patients. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, MEL140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma

Background: Lenalidomide/dexamethasone has been approved as a standard treatment in multiple myeloma and is applied preferentially in older patients with comorbidities. The addition of daratumumab to this therapy is the best treatment option today for patients who are not transplant eligible. Intensity-reduced high-dose melphalan (MEL140) with autologous transplantation also is an effective treatment option for older patients who are transplant eligible but may not tolerate full dose high-dose melphalan (MEL200). A combination of MEL140 with lenalidomide/dexamethasone potentially could produce a better outcome compared with lenalidomide/dexamethasone alone. Methods: In this trial (DSMM XIII; EudraCT-No: 2008-004083-39) patients of age 60-75 years with newly diagnosed multiple myeloma who had symptomatic and measurable disease were randomly assigned to either (A1) 3 cycles of lenalidomide (25 mg po d1-21/28d) with low-dose dexamethasone (40 mg po d1, d8, d15, d22/28d), followed by stem cell mobilization and then further lenalidomide/dexamethasone cycles until progression or (A2) 3 cycles of lenalidomide/dexamethasone as induction, followed by stem cell mobilization, intensity-reduced high-dose melphalan 140 mg/m2 (MEL140) (single or double) with autologous blood stem cell transplantation and lenalidomide maintenance with 10 mg daily until progression. At randomization, patients were stratified according to age (60-70 years vs 71-75 years) and ISS stage (I, II vs III). The primary endpoint was progression-free survival, and secondary endpoints included safety, response rates and overall survival. Here, we report the long-term outcome. Results: 348 patients were included into the study and 339 patients could be analysed per intention-to-treat (ITT). Patient characteristics were well balanced between treatment arms. For all patients, median age was 68 years (range 60 - 75), 29% were older than 70 years, 36.5% had ISS stage I, 35.6% ISS stage II, and 27.9% ISS stage III. After a median follow-up of 68 months, the median progression-free survival (PFS) was 40 months for A1 (169 patients) and 33 months for A2 (170 patients) (HR 1.16; p=0.19) in the ITT analysis. The median overall survival (OS) was 87 months for A1 and 96 months for A2 (HR 1.04; p=0.81). A prespecified per-protocol (PP) analysis was defined to include patients who received at least 6 months of study treatment (also including patients with progressive disease or death during this time period). In this PP analysis the median PFS was 42 months for A1 (139 patients) and 36 months for A2 (131 patients) (HR 1.15; p=0.27); the median OS was 89 months for A1 and 96 months for A2 (HR 1.01; p=0.96). In arm A2, 115 patients (68%) received one or two transplants. For transplanted patients, median PFS was 40 months and median OS was 114 months. Second primary malignancies (SPMs) were observed in 24 patients in arm A1 (skin 12, solid tumor 11, hematologic 1) and in 20 patients in arm A2 (skin 5, solid tumor 11, hematologic 4). Conclusion: In the intention-to-treat population, the combination of MEL140 with lenalidomide/dexamethasone induction and lenalidomide single agent maintenance was not superior to continuous lenalidomide/dexamethasone treatment. Subgroup analyses with a focus on the role of transplant will be presented at the meeting. Sponsor: Gesellschaft für Medizinische Innovation in der Hämatologie/Onkologie - GMIHO

Lenalidomide Maintenance for Patients with Newly Diagnosed Multiple Myeloma Post Autologous Stem Cell Transplant: A Comparison of Real-World Treatment Outcomes and Costs

BACKGROUNDIn 2017, lenalidomide maintenance therapy (R-MT) was approved for patients (pts) who received an up-front autologous hematopoietic stem cell transplantation (ASCT) in the United States (US) and Europe. The total cost of care for pts on R-MT in the US has not been previously studied using a large administrative claims database. This study aimed to compare real-world outcomes and costs among pts with newly diagnosed multiple myeloma (MM) receiving R-MT vs no maintenance (No-MT) post ASCT.METHODSFrom the Truven Marketscan data set, we identified adult pts with ≥ 2 claims for MM (International Classification of Diseases, 9th/10th Revision, Clinical Modification code: 203.0x, C90.0x) 30 days apart and ≥ 1 MM treatment during the identification period (1/1/2011 to 9/30/2016). Pts were required to have continuous enrollment for 6 months pre and ≥ 6 months post initial ASCT date plus 90 days (index date), in addition to ≥ 1 full cycle of therapy with a valid first-line regimen, and evidence of ASCT during follow-up period. Patients were excluded if they had evidence of prior MM diagnosis or treatment. R-MT was defined as lenalidomide monotherapy of < 20 mg per day for ≥ 21 of 28 days. Treatment outcomes and healthcare costs during follow-up were compared among those initiating R-MT vs No-MT. Time to treatment discontinuation (TTTD) was defined as the duration from initiation of R-MT to discontinuation of R-MT. Time to next treatment (TTNT) was defined as the duration from the index date until the initiation of another second-line therapy. Kaplan-Meier (KM) and Cox proportional hazard models were performed to evaluate TTTD and TTNT. Per patient per month (PPPM) total healthcare costs were calculated at 12, 24, and 36 months among pts initiating R-MT or No-MT. Pharmacy costs included oral MM treatments and other oral medications. Outpatient costs were composed of IV medications and physician and ER visits, while hospitalizations were part of inpatient costs. Generalized linear regression models with negative binomial distribution and log link function were used to assess differences in PPPM while adjusting for differences in baseline characteristics.RESULTSA total of 250 and 233 pts initiated R-MT and No-MT, respectively. Mean age (58.5 vs 58.0 y, P= .5236) and Charlson Comorbidity Index score (5.2 vs 5.3, P= .5234) were similar, but there were more males in the No-MT group (52.0% vs 61.4%, P= .0378). Time from start of first-line regimen to ASCT (5.48 vs 5.47 months, P= .9589) and the mean follow-up time post index date (22.1 vs 21 months, P= .1414) were similar in both groups. R-MT pts had a median duration of maintenance of 10 months. The median TTTD using the KM method was 21.02 months (95% CI: 16.78, 25.76). During the study period, a total of 60 (24%) and 99 (42.5%) R-MT and No-MT pts received a second-line treatment. At 12, 24, and 36 months, the proportion of pts who had a second-line treatment was as follows: R-MT-12.4%, 21.2%, 22.8%; No-MT-35.2%, 40.3%, 42.1%. Median TTNT was significantly longer among those treated with R-MT vs No-MT (Figure 1). Adjusted total PPPM costs during the first 12 months of follow-up was higher among pts treated with R-MT vs No-MT ($13,095 vs $8,910, adjusted difference $4,514, P < .0001). Mean pharmacy PPPM costs were higher in R-MT pts ($8,603 vs $2,269, P < .0001) while outpatient costs were higher in the No-MT group ($3,761 vs $5,360, P < .0001), and inpatient costs were similar ($731 vs $1,281, P < .5076). The adjusted difference in total PPPM costs during 12-24 months of follow-up was $6,579, P < .0001. A similar cost trend was observed in months 24-36 of follow-up; however, even fewer patients had sufficient follow-up: Adjusted difference: $6,110, P= .0024.CONCLUSIONPts remain on R-MT for several months to well over a year. R-MT pts incurred higher costs within the study period; however, their TTNT was significantly longer, and they were over half as likely to progress to a second-line treatment compared with No-MT pts. Pharmacy costs in R-MT pts were higher in the initial year of follow-up while No-MT pts had higher outpatient costs, presumably driven by the need for second-line therapy in a higher proportion of patients. Additional follow-up is required to assess total healthcare costs in subsequent years. [Display omitted] DisclosuresHari:Celgene: Consultancy, Honoraria, Research Funding. Ung:Celgene Corporation: Other: Fellowship is funded by Celgene. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Ni:Celgene: Employment. Parikh:Celgene Corporation: Employment. Agarwal:Celgene Corporation: Employment.

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib-Based Induction: An Analysis of Real World Data

IntroductionMultiple myeloma (MM) represents an incurable plasma cell malignancy. Success in the management of this disease requires a focus on prolonging disease control to positively impact survival. This is the rationale behind maintenance chemotherapy after frontline autologous stem cell transplant (ASCT). Recent large-scale phase 3 randomized trials have shown daily low dose lenalidomide, an oral immunomodulator (IMID), has led to markedly improved progression free survival (PFS) and an evolving benefit on overall survival (OS). We sought to evaluate the effect of lenalidomide maintenance in patients with MM undergoing bortezomib-based induction chemotherapy and ASCT in a real world setting.MethodsRetrospective review of patients with MM undergoing initial bortezomib-based induction chemotherapy and ASCT was completed in patients at our institution. Patients who began therapy up until June 30th, 2015 were included to ensure a minimum of 2-yrs follow-up. Patients were analyzed on an intention-to-treat basis. Maintenance chemotherapy included those on lenalidomide alone or lenalidomide plus bortezomib, the latter being a treatment option at our centre for high-risk patients. OS was measured from the time induction therapy was started until death or last follow-up. PFS was measured from the time of induction therapy initiation to relapse, death or last follow-up. Maximal response to treatment was assessed according to the IMWG consensus criteria although an additional endpoint of near CR (nCR) was included to account for patients where the monoclonal protein on electrophoresis disappeared and light chains normalized but where CR was not confirmed with immunofixation and a bone marrow biopsy was not done.Results198 patients were included in the analysis. 121 received lenalidomide based maintenance and 77 received no maintenance between December 2004 to June 30th, 2015. Median ISS score was 2 in both groups without significant difference between them (p=0.98) . In the maintenance and no maintenance groups respectively 32% and 36% had ISS stage 3 disease. The mean number of maintenance cycles received was 25 cycles (0.5 - 84). Sixty percent of patients required dose reductions or discontinuation due to adverse effects excluding relapse. Most commonly this was due to cytopenias (29.8%), rash (10.7%), infection (9.1%) and fatigue (5.8%). 15% discontinued therapy before relapse occurred. Though venous thromboembolism and second primary malignancies (SPMs) are a worry in patients treated long term with IMIDs these were only seen in 3.3% and 1.7% of patients respectively. Median follow-up in the maintenance group was 44 months and 60 months in the no maintenance group. Survival data is shown in figure 1. The median OS was not reached in the maintenance cohort and was 89 months in the no maintenance group (p = 0.01). Estimated 3-year OS was superior in the maintenance group at 88.4% versus 80.5% in the no maintenance cohort. A statistically significant difference in median PFS was also noted favouring the lenalidomide maintenance (55.0 months versus 32.9 months, p=0.002). Of patients treated with lenalidomide-based maintenance 95.0% achieved ≥ VGPR (53.7% ≥ nCR) while 77.9% (29.1% ≥ nCR) of those who did not receive maintenance therapy achieved these endpoints (p=0.03). Further characterization of therapy for relapsed disease as well as PFS after 1st relapse (2nd PFS) and time to second relapse (PFS2) will be presented at the meeting.ConclusionsOur retrospective analysis of lenalidomide maintenance therapy in MM patients treated with bortezomib-based induction chemotherapy and ASCT illustrates the positive impact lenalidomide has had on both PFS and OS. Patients treated with lenalidomide at our centre experienced a more prolonged and profound remission of their disease. The treatment was well tolerated with no unexpected adverse effects. Rates of thromboembolic disease and SPMs were low. Most importantly, the superior OS in the maintenance arm suggests that second line therapy for those not receiving maintenance could not overcome the negative impact of an earlier relapse. This data supports our ongoing approach incorporating lenalidomide-based maintenance continued until progression for all patients who have undergone an ASCT. Importantly, these real world results validate the phase 3 trial experience, helping to further establish this approach as a standard of care. [Display omitted] DisclosuresBelch:Amgen, Celgene, Takeda: Honoraria.

A New Salvage Regimen for Aggressive Lymphomas Based on Gemcitabine, Rituximab, and Oxaliplatin Followed by Lenalidomide (GROC-Rev)

PurposeTo evaluate the impact of lenalidomide in patients with aggressive lymphoma who experienced less than complete response (CR) or as maintenance therapy after CR after gemcitabine, rituximab, and oxaliplatin salvage chemotherapy (GROC-Rev regimen). Patients and MethodsPatients with relapsed/refractory non-Hodgkin lymphoma received up to 6 GROC-Rev courses: rituximab (375 mg/m2 provided intravenously) on day 1, oxaliplatin (100 mg/m2 provided intravenously; 2 hours), gemcitabine (provided 1250 mg/m2 intravenously; 30 minutes) on day 2, and pegfilgrastim (6 mg provided subcutaneously) on day 3. Patients switched to lenalidomide if they did not experience at least partial response (PR) after their second GROC-Rev course, or if they experienced less than a CR after 6 courses. ResultsIn 33 patients, overall response was 61% (CR = 39%). Of 17 patients with PR who continued to 6 courses, 10 (59%) experienced CR and 7 PR as maximum response; of these 7, 1 died before receiving lenalidomide, 1 experienced CR while receiving lenalidomide (17%), and 2 experienced a further PR (33%). Of 16 with disease that failed to respond to GROC-Rev after their second course, 2 died before lenalidomide could be administered, and 2 experienced CR (14%) and 1 PR (7%) after lenalidomide. Overall survival and progression-free survival were 47% and 33% at 2 years. Grade 3/4 adverse events included neutropenia, thrombocytopenia, and/or anemia (n = 5), neutropenic infection (n = 3), urinary tract infection (n = 3), pneumonia (n = 2), cellulitis (n = 2), and seizure (n = 1). Eight went on to receive transplants. ConclusionGROC-Rev is an effective and well-tolerated salvage regimen consisting of chemotherapy followed by lenalidomide maintenance in patients with relapsed/refractory non-Hodgkin lymphoma. Simultaneous administration of these agents is worth exploring in future studies.

Cost-effectiveness of lenalidomide maintenance in patients with multiple myeloma who have undergone autologous transplant of hematopoietic progenitor cells.

The objective of this article is to analyze the ratio of cost-effectiveness and budgetary impact of lenalidomide treatment in patients with multiple myeloma who have undergone autologous transplant in Spain. The analyses were based on clinical trials CALGB 100104 and IFM 2005-02, from the perspective of the National Health System. The alternatives compared were the treatment with lenalidomide against maintenance without treatment (MwT). Efficiency measures used were years of life gained (YGs) and quality-adjusted life years (QALYs). According to the CALGB 100104 trial data, the average health costs of patients who were treated with lenalidomide for 120 months was €836,534.31 and without treatment was €528,963.63. The effectiveness of the lenalidomide group was 7.59YGs (5.72 QALY) against 6.58 of MwT (4.61 QALY). The incremental cost-utility ratio (ICUR) was €277,456.72/QALY and the incremental cost-effectiveness ratio was €303,191.05/YGs. From the analysis, the IFM2005-02 trial obtained 5.13 QALY in the lenalidomide group against the 4.98 QALY in the MwT group, with an ICUR of €1,502,780.55/QALY. In terms of budgetary impact, a range between 799 and 1452 patients susceptible to receive treatment with lenalidomide was assumed in Spain. In conclusion, the results show a high ICUR and budgetary impact, which adds uncertainty about the maximum prudent duration of the treatment.

Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma

BackgroundDespite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept.MethodsGMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life.ResultsSince this is the publication of a study protocol of an ongoing study, no results can be presented.DiscussionThis phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab.Trial registrationNCT02495922 on June 24th, 2015.

Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years

Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months.Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39).Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys.Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 9 courses; grade 3 in 3). LENA dose reduction was indicated in 25 pts (transient in 21), and was due to neutropenia (13), rash (7), diarrhoea (3), or neurotoxicity (2). Three (6%) pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and two pts died due to myelodysplastic syndrome (Table). Grade 4-5 toxicity and SAEs were equally distributed according to maintenance duration (Table).At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received <1 yr of LENA (refusal or SAEs).The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans' algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively.Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. [Display omitted] DisclosuresFerreri:Celgene: Research Funding. Zaja:Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi:Celgene: Research Funding.

Survival Analysis from the CALGB Study of Lenalidomide Maintenance Therapy in Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation Adjusted for Crossover (Alliance 100104)

Survival Analysis from the CALGB Study of Lenalidomide Maintenance Therapy in Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation Adjusted for Crossover (Alliance 100104)

Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial

Patients with relapsed diffuse large B-cell lymphoma (DLBCL) not eligible for autologous stem cell transplantation (ASCT) or having relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy might be an attractive strategy to prolong survival in these patients. Lenalidomide is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL that can be taken for years with an acceptable toxicity profile. We designed a study to investigate safety and efficacy of lenalidomide maintenance in patients with chemosensitive relapse of DLBCL not eligible for ASCT or having relapse after ASCT. In this open-label, single group, multicentre phase 2 trial, we recruited HIV-negative adults with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy from 12 oncology-haematology centres in Italy. All patients were given oral lenalidomide 25 mg per day for 21 of 28 days until lymphoma progression or unacceptable toxicity (severely compromises organ function, quality of life, or both). Primary endpoint was 1-year progression-free survival. The estimated sample size was 47 patients; maintenance was deemed efficacious if at least 19 patients were progression-free survivors at 1 year. All enrolled patients were included in primary analyses, with the exception of patients who post-hoc objectively did not meet the eligibility criteria (modified intention-to-treat). This study is registered with clinicaltrials.gov registry, number NCT00799513. Between March 24, 2009, and Dec 22, 2015, we recruited 48 patients. 46 of 48 enrolled patients were assessable (two patients had unconfirmed diagnoses). 36 (78%) of 46 patients had de novo DLBCL and ten (22%) of 46 patients had transformed DLBCL. At a median follow-up of 25 months (IQR 12-56), 556 lenalidomide courses had been delivered, with an average mean of 12 courses (range 3-41) per patient; 19 patients were still in treatment at a median follow-up of 25 months. Lenalidomide was well tolerated; with the exception of neutropenia, grade 3-4 toxicities were uncommon. We recorded ten severe adverse events in nine patients due to febrile neutropenia (n=4), diarrhoea (n=2), melena, stroke, vomiting, and intestinal infarction; all but one patient recovered, and six of these patients continued with lenalidomide treatment. The exception was the only death due to toxicity (intestinal infarction). At 1 year from trial registration, 28 patients were progression free, which was much higher than the predetermined efficacy threshold. During the whole observation period, 21 events occurred: progressive lymphoma in 19 patients, death due to toxicity in one, death while off therapy in one, 1-year progression-free survival was 70% (95% CI 57-83). With the limitations of a non-randomised design, this trial supports the use of lenalidomide maintenance in patients with chemo-sensitive relapse of DLBCL who are not eligible for ASCT or who had relapse after ASCT. These results warrant further investigation of immunomodulatory drugs as maintenance in high-risk patients with DLBCL. Celgene Corp.

Evaluation of Stem Cell Mobilization in Patients with Multiple Myeloma after Lenalidomide-Based Induction Chemotherapy within the GMMG-HD6 Trial

Introduction: The German-Speaking Myeloma Multicenter Group (GMMG) has initiated a randomized multicenter phase III trial on the effect of elotuzumab in VRD (bortezomib, lenalidomide, dexamethasone) induction/consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD6 trial, NCT02495922). The study compares four cycles induction therapy with VRD vs. VRD + elotuzumab, followed by standard intensification (i.e. mobilization and stem cell transplantation), two cycles consolidation with VRD/VRD + elotuzumab and lenalidomide maintenance +/- elotuzumab. The primary endpoint is determination of the best of four treatment strategies regarding progression-free survival. Here we present a first analysis of stem cell mobilization within this study.Patients and Methods: We performed a retrospective analysis of collection data on all patients who underwent peripheral blood stem cell (PBSC) collection between trial initiation in June 2015 and June 2016. Only patients with completely available datasets in respect of mobilization were considered (n=111). The vast majority of 99 patients (89%) received chemomobilization with CAD (cyclophosphamide, adriamycin, dexamethasone) followed by 5-10 µg G-CSF /kg body weight (bw) /d (starting day +9 until completion of PBSC collection), while in one case (1%) dexamethasone was omitted and in 10 cases (9%) cyclophosphamide mono was administered. One patient underwent steady-state mobilization with G-CSF only (10µg /kg bw /d). 55/111 patients received VRD (50%), whereas the remaining patients received VRD + elotuzumab. According to the recommendations of the study group, PBSCs for three stem cell transplants were to be collected. One transplant ideally consisted of ≥2.5 x10^6 CD34+ cells /kg bw, but in the event of poor mobilization as low as ≥2.0 x10^6 CD34+ cells /kg bw would be considered acceptable.Results: The median number of collected CD34+ cells was 10.4 x10^6 /kg bw (range 2.88 to 23.01 x10^6 /kg bw). Overall, 92 patients (83%) collected ≥7.5 x10^6 CD34+ cells /kg bw and another 12 patients (11%) collected between 6.0 and 7.5 x10^6 CD34+ cells /kg bw, resulting in three transplants, respectively. Only 7 patients (6%) collected below 6.0 x10^6 CD34+ cells /kg bw; 5 of them had been treated in the VRD-arm without elotuzumab. Due to insufficient PBSC mobilization after conventional treatment, 14 patients (13%) received a rescue mobilization with plerixafor, from which 12 patients collected ≥6.0 x10^6 CD34+ cells /kg bw. Overall, 7 serious adverse events (SAEs) occurred during mobilization phase, 4 of them in the study arm with elotuzumab.Conclusions: Cyclophosphamide-based chemomobilization after induction therapy with VRD is feasible. Efficient PBSC collection of ≥6.0 x10^6 CD34+ cells /kg bw could be performed in 104 of 111 patients (94%), with a low incidence of SAEs. The need for rescue mobilization was not higher than that of comparable previous GMMG treatment protocols. The addition of elotuzumab during induction phase did not impede PBSC collection. DisclosuresWuchter:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Munder:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Fenk:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Medac: Other: Travel, accomodations or expenses; Baxalta: Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel, accomodations or expenses; Janssen: Consultancy, Honoraria; Celgene: Other: Travel, accomodations or expenses; BMS: Consultancy, Honoraria. Weisel:Onyx: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

A Prospective Phase 2 Study to Assess Immunophenotypic Remission after Lenalidomide-Based Induction Followed By ASCT and Lenalidomide Maintenance in Patients with Newly Diagnosed Multiple Myeloma

IntroductionASCT is the standard treatment in MM for eligible patients < 70 years of age. The median OS has improved from 3-4 to 5-6 years with combination of novel drugs and ASCT. In spite of initial response MM will relapse or progress in the majority of patients in 2-3 years and several consolidation and maintenance treatments are under evaluation. We designed this FMG-MM02 study (NCT01790737) to explore the response of lenalidomide, bortezomib and dexamethasone (RVD) induction, followed by single ASCT and lenalidomide maintenance in newly diagnosed MM patients. The primary endpoint of the study is immunophenotypic remission (IR), and molecular response will be assessed from patients with sCR/IR. The secondary endpoints include safety, improvement of responses during lenalidomide maintenance and PFS.Patients and methods69 out of 80 included patients proceeded to mobilization after induction with 3 cycles of RVD. Eleven patients (14%) were dropped out due to early toxicity (n=9) or early progression (n=2). The RVD cycle consisted of lenalidomide 25 mg/d po. on days 1-14, bortezomib 1.3 mg/m2 sc. on days 1,4,8 and 11 and dexamethasone 20 mg po. on days 1-2, 4-5, 8-9 and 11-12. Additional nine patients were withdrawn before ASCT due to progression, so actually 60 patients received MEL200+ASCT and lenalidomide maintenance was planned to start three months after ASCT, 10 mg/d on days 1-21 in a 28-day cycle. The multiparameter flow cytometry (MFC) was analyzed from all patients with at least PR response. 53/60 patients have achieved the time-point of three months after ASCT and can be analyzed here. Median follow-up time is 52 (1−115) weeks.ResultsForty-five gr 3-4 SAEs were documented in 39 patients during induction; most common were infections (pneumonia, bronchitis) and gastrointestinal disorders. The nine patients with early drop out due to toxicities had following adverse events: severe liver toxicity, amaurosis fugax, neutropenia, severe sepsis-syndrome with rash, simultaneous diagnosis of adenocarcinoma pulmonum, history of prostate cancer, two patients not eligible to ASCT due to infections and one patient died of hepatorenal syndrome.The overall response rate for RVD induction was 86% in intention-to-treat. The primary endpoint, IR, measured by 6-10 color MFC, was achieved at ASCT in 22/69 (32%) of patients who actually received the planned RVD induction and in 22/80 (28%) by intention-to-treat (ITT). The median sensitivity of MFC-MRD-negativity was <0.01% (range 0.0046%−0.069%). In MFC-MRD-positive patients the median MRD load was 0.14% (range 0.003%−3.0%). At least VGPR was achieved in 36/80 (45%) of patients by ITT and in 36/69 (52%) per protocol treated at ASCT.Three months post-ASCT 24/53 (45%) of evaluable patients had IR with the median sensitivity of MFC-MRD-negativity <0.006% (range 0.003%−0.03%) and in 43% of patients the median MFC-MRD positivity was 0.08% (range 0.003%−0.9%). 12% of patients can not be assessed yet. So far samples of 10 patients in sCR/IR have been analyzed by ASO RQ-PCR and 7/10 were also PCR-MRD negative with the median sensitivity of <0.0006% (<0.0004%−0.02%).The achievement of at least VGPR response or IR at ASCT predicts better outcome with estimated PFS of 23.8 months compared to 15.2 months of patients response worse than VGPR (p=0.001) and the respective figures for IR and non-IR are 24.7 and 17.2 months (p=0.016). Patients with t(4;14), t(14;16), n=9, had shorter median PFS (shorter than patients with del 17p), 12.8 months, compared to estimated 20.8 months of other patients (p=0.053).ConclusionOne third (28%) of patients achieved an IR after RVD induction, which contrasts with only 14% of serological CR/sCR. This discrepancy most probably results from the rather slow kinetics of paraprotein disappearance. Thus, subsequential samples and sufficient follow-up time are mandatory in evaluation of paraprotein responses. The IR was still predicting favorable outcome and only one of these MFC-MRD negative but paraproteinpositive patients has so far relapsed. In spite of quite high initial IR rate the patients with high-risk cytogenetics relapse quite soon. RVD regimen seems not to overcome their poor prognosis, and these patients clearly need more individual treatment choices. DisclosuresSilvennoinen:Amgen: Consultancy, Honoraria; Celgene: Research Funding; Janssen: Research Funding; Genzyme: Honoraria; Sanofi: Honoraria; Research Committee of the Kuopio University Hospital Catchment Area for State Research Funding, project 5101424, Kuopio, Finland: Research Funding. Siitonen:Novartis: Other: charges of EHA congress 2015; Pzizer: Other: charges of EAHAD congress 2015. Putkonen:Celgene: Honoraria; Amgen: Honoraria. Porkka:Celgene: Research Funding. Remes:Roche: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Jantunen:Genzyme: Honoraria; Sanofi: Honoraria; Genzyme: Consultancy.