Lenalidomide-based Maintenance Therapy Research Articles

Clinical analysis of long-term survival and influencing factors of chimeric antigen receptor T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia

Objective: To analyze the survival and influencing factors of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) . Methods: Clinical information of patients who received CAR-T-cell therapy and achieved complete remission of R/R B-ALL between May 2015 and June 2018 at the Shaanxi Provincial People's Hospital was obtained. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and leukemia-free survival (LFS) times of patients, and Cox regression analysis was performed to analyze the prognostic factors that affect patient survival after CAR-T therapy. Results: Among the 38 patients with R/R B-ALL, 21 were men, with a median age of 25 (6-59) years and a median OS time of 18 (95% CI 3-33) months. Multivariate Cox regression analysis showed that positive MLL-AF4 fusion gene expression was an independent risk factor for OS and LFS (OS: HR=4.888, 95% CI 1.375-17.374, P=0.014; LFS: HR=6.683, 95% CI 1.815-24.608, P=0.004). Maintenance therapy was a protective factor for OS and LFS (OS: HR=0.153, 95% CI 0.054-0.432, P<0.001; LFS: HR=0.138, 95% CI 0.050-0.382, P<0.001). In patients with MRD negative conversion, LFS benefit (HR=0.209, 95% CI 0.055-0.797, P=0.022) and OS difference was statistically insignificant (P=0.111). Moreover, patients with high tumor burden were risk factors for OS and LFS at the level of 0.1 (OS: HR=2.662, 95% CI 0.987-7.184, P=0.053; LFS: HR=2.452, 95% CI 0.949-6.339, P=0.064) . Conclusion: High tumor burden and high-risk genetics may affect the long-term survival rate of patients with R/R B-ALL receiving CAR-T, and lenalidomide-based maintenance therapy may improve their prognosis.

IgD Multiple Myeloma, Does It Still Have a Poor Prognosis?

IgD Multiple myeloma is considered unusual myeloma, with just 2% of cases of MM being diagnosed as IgD subtype. The infrequency of its presentation and the poor prognosis make the disease challenging to treat, with many patients being selected for clinical trials. A 63-year-old female presented to the ER after falling on ice. After undergoing a CT Head, multiple lytic lesions in the occipital region were found, confirmed by MRI. 2 months later, a bone marrow biopsy found 90% of marrow replaced by CD138 plasma cells, positive for kappa & negative for lambda, consistent with myeloma. On evaluation, she was found to have pan-hypo-gammglobulinemia. However, the skeletal survey did not find any other lytic lesions. Seeing this, IgD levels were measured and found to be >100 times over the upper normal limit with normal beta2-microglobulin levels, confirming monoclonal gammopathy. A FISH study found the patient positive for t(11;14)/CCND1IGH translocation (85% of cells) and negative for TP53. Palliative radiotherapy for the skull base was performed before the patient started chemotherapy. The patient was deemed a suitable candidate, selected for a clinical trial, and placed on RVd [revlimid + velcade + dexamethasone] with delayed bone marrow transplant. As the patient developed a rash and neuropathy from velcade [bortezomib], it was paused and restarted after three months. The patient was doing well on this chemotherapy regimen for two years and was placed on lenalidomide-based maintenance therapy. Two years later, her disease started progressing with an increased frequency of bone pains and opioid dosing. At this juncture, it was decided to change course and start her on pomalidomide/dexamethasone. This did not help the patient, and the neurological side effects of dexamethasone made us change course and initiate a daratumumab, bortezomib, cyclophosphamide and dexamethasone. This proved unfruitful, too, as the patient developed adverse effects of polyneuropathy, pancytopenia requiring transfusion, and worsening GERD. Seeing the disease relapse and intolerance to the previous regimen, we decided to initiate a once-per-week regimen of selinexor, bortezomib, and dexamethasone. The patient has improved on this regimen and is back to her baseline for physical activity, mental status and pain, and an improved appetite. In this case, we wanted to highlight how incidental findings on a CT lead us to diagnose a rare type of multiple myeloma and how, in the era of novel agents, the survival of patients can be prolonged significantly. Considering the rarity of this subtype, international collaborative studies are suggested to further elucidate the underlying mechanisms for developing potent therapeutic approaches. Most of the data reported on how IgD multiple myeloma progresses was written before the arrival of novel agents. More evaluation of survival times and progression of the disease needs to be done as it's possible that IgD MM is not as poor a prognosis as it once was.

Prospective Comparison Study of Prognostic Value of MRD Detected By 8-Color MFC (EuroFlow-NGF) and NGS in Patients with Multiple Myeloma in ASCT Setting

Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting.Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH.Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF.Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. [Display omitted] DisclosuresTakamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

Outcomes of Patients with Multiple Myeloma Who Received VRD Induction, Autologous Hematopoietic Cell Transplantation and Lenalidomide Maintenance

Background: Recent clinical trials have shown a steady improvement in the outcomes of patients with multiple myeloma (MM), especially in those who have received induction with bortezomib, lenalidomide, and dexamethasone (VRD), followed by autologous hematopoietic cell transplantation (Auto-HCT) and lenalidomide maintenance (Attal et al. 2017, Joseph et al. 2020). Here, we report our center's outcomes of MM patients who received VRD induction, followed by Auto-HCT and maintenance therapy incorporating lenalidomide. Methods: In this single-center retrospective analysis, eligible patients received an auto-HCT between June 2007 and November 2015. We excluded patients who received induction regimens other than VRD or did not receive lenalidomide-based maintenance therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS), which were estimated by using the Kaplan-Meier method. We performed multivariate Cox regression analysis to evaluate the impact of several important variables, including age, sex, race, immunoglobulin subtype, light chain, ISS, cytogenetic risk, conditioning regimen, post-transplant therapy, and best final response, on PFS and OS. Results: We identified 303 patients who fulfilled the eligibility criteria for this study. Table 1 and 2 summarize patient demographics, disease characteristics, therapies and responses. Sixty-two patients (20.5%) had high risk cytogenetics defined as del17p, t(4;14), t(14;16), and 1q21 gain. 132 (43.6%), 72 (23.8%), and 55 (18.2%) patients had ISS stages I, II, and III, respectively. Overall response rate (ORR) at time of Auto-HCT was 93.4% (sCR 7.6%, CR 4%, VGPR 41.3%, and PR 40.6 %). Importantly, ORR after auto-HCT and maintenance therapy was 99.7% (sCR 40.3%, CR 12.5%, VGPR 33.7%, and PR 13.2%). With a median follow up of 45 months (range: 11 - 113 months), the median PFS was 62 months (95% confidence interval (CI) 48- 76 months) and 4-year PFS was 58% (Fig 1). Median OS has not been reached and 4-year OS was 88% (Fig 1). Patients with high-risk cytogenetics had median PFS and OS of 31 months (95% CI 25- 37 months) and 76 months (95% CI 44-108 months), respectively. In contrast, in patients with standard-risk cytogenetics, the median PFS and OS were 73 months (95% CI 62- 84 months) and not reached, respectively (P&amp;lt;0.001; Fig 2). On multivariate analysis, standard-risk cytogenetics (P&amp;lt;0.001- HR 0.349, P=0.001- HR 0.278) and the final best response of &amp;gt;VGPR (P&amp;lt;0.001 - HR 0.439, P=0.001 - HR 0.306) were associated with significantly better PFS and OS, respectively. Conclusions: These results provide further evidence that VRD induction followed by Auto-HCT and lenalidomide-based maintenance is associated with excellent outcomes in MM, especially in patients with standard-risk cytogenetics. Disclosures Bashir: KITE: Other: Advisory Board; Celgene: Research Funding; StemLine: Research Funding; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Lee:Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Amgen: Consultancy, Research Funding. Patel:Celgene: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding. Kebriaei:Amgen: Other: Research Support; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support. Thomas:Pharmacyclics: Other: Advisory Boards; X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Xencor: Research Funding; BMS: Research Funding. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents &amp; Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents &amp; Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy. Qazilbash:Bioline: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Angiocrine: Research Funding.

The Relative Risk of Prognostic Factors of Age Stratified Multiple Myeloma

Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients. Methods: In this study, 778 MM patients were enrolled in the prospective, non-randomized BDH2008/02 clinical trial between January, 2008 and December, 2016. Briefly, the patients accepted bortezomib or thalidomide-based induction therapy. Transplantation eligible patients accepted ASCT, otherwise they accepted the original regimen consolidation therapy. Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years. Conventional FISH panel included del(13q), del(17p), gain(1q), t(11;14), t(4;14), t(14;16), and t(14;20). The positive cut-off value for chromosome deletion or gain was 20%, and for chromosome translocation was 10%. A multivariate Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS. Explained variation of variables was quantified by RD2. Statistical analysis was conducted by Stata/MP 16.0 (Stata Corp., TX, USA) and SPSS 26.0 (IBM Corp., Chicago, Illinois, USA). Results: Among 778 patients with complete data, 59.5% (463/778) were younger than 60 years old, 31.4% (244/778) were 61-70 years old, and only 9.1% (71/778) were over 71 years old. The median PFS of patients≤60, 61-70 and ≥71 years of age was 36.3, 32.6 and 23.1 months, respectively (P&amp;lt;0.001). The median OS in each age group was 86.2, 60.7 and 34.9 months, respectively (P&amp;lt;0.001) (Figure A-D). The median evaluated glomerular filtration rate of the three groups was 89.1, 74.0 and 66.4 ml/min (P&amp;lt;0.001), respectively. The serum β2-microglobulin level gradually increased with age (P&amp;lt;0.001), along with the proportion of patients with ISS 3 stage. Patients ≥71 years old had a higher proportion of ECOG performance status score 3-4, twice than that of patients ≤60 years old. The incidence of high-risk IgH translocation decreased with age, and was 25.4%, 21.3% and 14.3% across age groups. The incidence of gain(1q) increased with age, and was 43.9%, 47.1% and 54.8%, respectively. The incidence of del(17p) and del(13q) seldom changed with age (Figure E). With age, the risk of high-risk cytogenetic abnormalities did not change significantly, accounting for about 50% in each age group. The risk of ISS gradually decreased, accounting for 36%, 27%, and 14% in ≤60, 61-70 and ≥71 year subgroups, respectively. The risk of the ECOG performance status gradually increased with age, accounting for 10%, 17%, and 36% in the three subgroups (Figure F). The overall response rate of induction treatment gradually decreased with age, and were 90.2%, 81.9%, and 69.2%, respectively (P&amp;lt;0.001). Elderly patients with impaired renal function or more than one high-risk cytogenetic abnormalities might benefit more from bortezomib based treatment than younger patients (Figure G). Conclusion: Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group. The risk of poor performance status increases in elderly patients with a reduction risk in ISS. Elderly patients should focus on the status of frailty and molecular events to determine treatment. Figure Disclosures No relevant conflicts of interest to declare.

Current Recommendations for the First-Line Therapy ofSymptomatic Multiple Myeloma

Due to the introduction of novel therapeutic agents, the prognosis of Multiple Myeloma has greatly improved over the last decades. The current standard for fit patients is a bortezomib-based induction therapy, followed by high-dose chemotherapy and autologous stem cell transplantation and lenalidomide-based maintenance therapy. For older, non-transplant-eligible patients, daratumumab in combination with bortezomib or lenalidomide offers a well-tolerated, effective treatment option. Despite large improvements, there is still no cure for most myeloma patients, the aim of therapy is therefore to reach a deep remission to prevent lasting damage followed by a continuous maintenance therapy to uphold the remission and prolong overall survival.

Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

Maintenance Therapy after Second Autologous Stem Cell Transplant in Multiple Myeloma Improves Overall Survival

Introduction: Low dose lenalidomide as a maintenance therapy after the first autologous transplant (autoSCT) has been shown to improve progression free survival (PFS) and possibly overall survival (OS) in standard-risk multiple myeloma (MM). Proteasome inhibitor-based maintenance therapy provides an alternative to lenalidomide and offers PFS and OS advantage in high-risk MM. Most recently oral ixazomib as a maintenance therapy has been shown to reduce the risk of progression by 28%. Despite the advances in maintenance therapy after first autoSCT, no prospective or retrospective studies exist evaluating efficacy of maintenance therapy after second autoSCT. In this retrospective study, we evaluated the impact of maintenance therapy after second autoSCT. Methods: We retrospectively evaluated clinical outcomes of adult MM patients (pts) who received maintenance therapy following second autoSCT. Lenalidomide dose up to 15mg daily and subcutaneous bortezomib 1.3mg/m2 every 2 weeks were considered maintenance therapy. The pts who received higher doses or combinational therapy as maintenance were excluded. We compared outcomes between pts who did and did not receive maintenance therapy following second autoSCT. The objectives were to determine OS, relapse-free survival (RFS), relapse rate and non-relapse mortality (NRM) with maintenance therapy following second autoSCT using Cox regression and competing risk models. Results: Between January 2000 and December 2018, 117 pts underwent second autoSCT and met the inclusion criteria. Of these, 39 received maintenance therapy and 78 did not. Median time between first and second autoSCT was 57 months (range, 4.9-124.2) in the maintenance group and 46 months (range, 3.7-193.5) in the no-maintenance group (p=0.32). Disease status at second autoSCT was complete response (CR) (n=7, 6%), very good partial response (VGPR) (n=22, 19%), partial response (PR) (n=30, 26%), stable (n=21, 18%) and progressive disease (n=32, 27%). Melphalan-based preparative regimen was used in 87% of pts, and BEAM was used in 13% of pts. All pts successfully engrafted and median time to neutrophil and platelet engraftment was 11 and 19 days, respectively. Maintenance therapy after second autoSCT was started at a median day of 105 (range, 62-317). Lenalidomide-based maintenance therapy was commonly used in 23 (59%) pts, and bortezomib as maintenance was used in 16 (41%) pts. Sixteen pts received maintenance therapy after both first and second autoSCT, and 23 received second maintenance only. Median duration of second maintenance therapy was 16 months (range, 8.7-26.5). The best response during maintenance was CR (n=8, 21%), VGPR (n=20, 51%), PR (n=9, 23%), and stable disease (n=2, 5%). Median follow-up for OS was 48 and 60 months in the maintenance and no-maintenance group, respectively. Median OS was not reached in the maintenance group and was 40.8 months in the no-maintenance group (HR 2.32, p=0.02). At 3-year, maintenance group had superior RFS (18% vs 12%; HR 1.65, p=0.03), lower relapse rate (69 vs 81%; SHR 0.58, p=0.02). Median time to progression was 24 months in the maintenance group and 14 months in the no-maintenance group (p=0.04). Although limited by small numbers, we did not observe any impact of cytogenetics at diagnosis on OS and RFS after second autoSCT. RFS was superior with lenalidomide-based maintenance compared to bortezomib-based maintenance (HR 2.17, p=0.05). However, OS was not different. The multivariable analysis revealed that maintenance after second autoSCT was associated with significantly superior OS (HR 0.38, p=0.01), RFS (HR 0.59, p=0.03) and lower relapse rate (SHR 0.63, p=0.04). The common reasons for maintenance therapy discontinuation were disease progression (n=20, 51%), side effects (n=7, 18%), and unknown (n=12, 31%). A total of 10/39 pts who received maintenance therapy and 44/77 pts who did not receive maintenance have died. Conclusion: This is the first study showing efficacy of maintenance therapy after second autoSCT. Maintenance therapy after second autoSCT significantly improved overall and relapsed-free survival and should be considered in all pts after second transplant. Our study also reveals real world practice pattern of using variable dose of maintenance therapy among physicians. Disclosures Deol: Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board.

MCT1 As Molecularly Validated Predictive Marker for Lenalidomide-Maintenance Therapy in Multiple Myeloma

Introduction: Lenalidomide-based maintenance therapy is the currently approved standard of care for multiple myeloma (MM) patients after high-dose melphalan and autologous stem cell transplantation (HD-Mel), which significantly prolongs progression-free (PFS) and overall survival (OS). For patients with del17p bortezomib based maintenance treatment is considered overcoming adverse prognosis of this aberration. Predictive markers of response to lenalidomide maintenance have remained elusive. We have previously shown that IMiDs exert their anti-MM activity via destabilization of MCT1 and CD147 and combined overexpression reduces response to lenalidomide-treatment in vitro and in an in vivo MM xenograft model (Eichner et al. Nature Medicine 2016). Methods: CD138-purified myeloma cell samples of 654 patients receiving high-dose melphalan therapy and autologous stem cell transplantation and either bortezomib (n=101), thalidomide (n=98) or lenalidomide (n=455) maintenance treatment were assessed by gene expression profiling (GEP) using U133 2.0 plus DNA microarrays, 316 by RNA-sequencing (RNA-seq). Expression of CD147 and MCT1 were assessed and correlated with PFS and OS data. Gene expression based risk scores, including UAMS70-gene, Rs-score and gene expression based proliferation index were assessed alongside routine iFISH-analysis. Survival curves and median time to progression were computed with nonparametric survival estimates for censored data using the Kaplan-Meier method. Difference between the curves were tested using the G-rho Log-rank test. Landmark analysis was performed by defining an alternative start point (landmark) at 12 months. In vitro, CD147 and MCT1 were lentivirally overexpressed in MM1S cells, which were subjected to lenalidomide or bortezomib treatment and proliferation analysis. Xenografted MM-tumors were followed by 18FDG-PET and analyzed by immunohistochemistry. Results: Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2months in MCT1high vs. MCT1low,P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance. Likewise, patients with thalidomide maintenance showed reduced PFS (34.8 vs. 43.7 months in MCT1high vs. MCT1low, P=.23) and significantly shorter OS (83.6 months vs. not reached (NR) months in MCT1high vs. MCT1low;P=.03). For bortezomib based maintenance, MCT1 expression had no significant impact on PFS (39.8 months vs. 32.6 months in MCT1high vs. MCT1low) and OS (125.8 months vs. 129.8 months in MCT1high vs. MCT1low). No association with other prognostic factors was found. As still differences between MCT1high vs. MCT1lowexpression myeloma cells might be attributed to undiscerned molecular factors and for functional validation, we lentivirally overexpressed CD147 and MCT1 in human myeloma cell lines. Overexpression of MCT1 significantly reduced cytotoxicity of lenalidomide, while no change was observed in MM cells treated with bortezomib. We subsequently validated our results in vivo. Functional investigations in the mechanism of MCT1 impact on cellular survival are ongoing. Conclusion: Taken together MCT1 expression as potential predictive marker for response to IMiD-based maintenance treatment. Both PFS and OS were significantly reduced in patients with high gene expression levels of MCT1. In vitro and in vivo (xenograft model), MCT1 overexpression reduced sensitivity to lenalidomide unlike bortezomib treatment. Disclosures Salwender: Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations. Bertsch:Sanofi: Other: travel support; Celgene: Other: travel support. Goldschmidt:Chugai: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Takeda: Consultancy, Honoraria; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria. Scheid:Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Bassermann:Celgene: Consultancy, Research Funding.

Peripheral Immunotype Correlates with Minimal Residual Disease Status and Is Modulated by Immunomodulatory Drugs in Multiple Myeloma

Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug–mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRDpos versus MRDneg status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRDpos response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRDneg group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRDpos versus MRDneg patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRDpos patients. Put together, these observations provide a distinctive signature for MRDneg and MRDpos groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.

Treatment Intensification With Autologous Stem Cell Transplantation and Lenalidomide Maintenance Improves Survival Outcomes of Patients With Newly Diagnosed Multiple Myeloma in Complete Response

BackgroundHigh-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. Patients and MethodsWe analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). ResultsOverall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. ConclusionEven in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy.

Impact of post-autologous stem cell transplant (ASCT) maintenance therapy on outcomes in patients (Pts) with newly diagnosed multiple myeloma (NDMM) using the large prospective community-based Connect MM registry.

8040 Background: Maintenance therapy (MT) improved progression-free survival (PFS) and overall survival (OS) in MM clinical trials. The observational Connect MM registry, which is largely community based, was used to assess impact of MT on outcomes in ASCT-eligible NDMM pts. Methods: Adult NDMM pts ≤60 days from diagnosis were eligible for enrollment. Pts receiving induction and ASCT were included and analyzed by 4 MT regimens: No MT, lenalidomide-based (LEN), bortezomib-based (BORT), and LEN+BORT MT. Duration was from 100 days post-ASCT (no MT group) or start of MT until progressive disease, death, discontinuation, or data cutoff. End points were PFS, 2nd PFS, OS, and safety. An exploratory analysis of the impact of baseline characteristics was performed. Results: Of 1493 enrolled pts (Cohort 1; Sep 2009 – Dec 2011), 1450 were treated; 81% (n=1173) were in a community setting. A total of 432 (29%) met analysis criteria. Data cutoff was Jan 7, 2016 (median follow-up of 39.3 mo). Median age was 60 y (range, 24-78 y); 60%, men; and 86%, white. 165 pts did not receive MT. Of 267 pts receiving MT, 213 (80%) received LEN; 30 (11%), BORT; and 16 (6%), LEN+BORT. Only LEN MT is presented, as interpretation of other MT data was limited by small sample sizes. Median treatment duration for LEN MT vs No MT was 35.2 vs 26.1 mo, respectively. PFS and OS significantly increased with LEN MT vs No MT (Table); 2nd PFS was similar for both. Exploratory analyses showed generally similar PFS and OS improvements across subgroups (age, ECOG status, ISS stage, risk group, and induction regimen). No new safety signals were observed. Conclusions: In ASCT-eligible NDMM pts, PFS and OS improved with LEN MT vs No MT and appeared to be independent of induction regimen. Preliminary analysis of 2nd PFS suggests no impact on the efficacy of 2nd line therapy. These data from a largely community-based setting confirm results from randomized phase III trials. Clinical trial information: NCT01081028. [Table: see text]

Maintenance Therapy With Immunomodulatory Drugs in Multiple Myeloma: A Meta-Analysis and Systematic Review

Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial. PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided. Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies. Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection.

The Efficacy and Safety of Immunomodulatory Drugs in Multiple Myeloma Maintenance Therapy: Results of a Meta-Analysis

Objective: To evaluate the efficacy and safety of immunomodulatory drugs (IMiDs) in maintenance therapy of multiple myeloma through meta-analysis of randomized controlled trials (RCTs).Patients and methods: PubMed, Web of Science, ASCO, ESMO and ASH databases were searched for RCTs that investigated the treatment outcomes (overall survival [OS], progression-free survival [PFS] and/or event-free survival [EFS] and/or time to progression [TTP]) of maintenance therapy with IMiDs in patients with multiple myeloma. Study endpoints included OS, PFS/EFS/TTP, and grade 3 or 4 adverse events. Pooled hazard ratios (HRs) for survival outcomes and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2). The random-effect model was utilized in view of clinical heterogeneity in the study population.Results: Eighteen RCTs comprising a total of 6562 patients were included in this meta-analysis. IMiDs used in the RCTs included thalidomide (14 trials) and lenalidomide (4 trials). Overall, IMiD-based maintenance therapy significantly improved OS (HR = 0.91, 95% CI = 0.84 - 0.99, P = 0.027) and PFS (HR = 0.63, 95% CI = 0.60 - 0.68, P < 0.001). Notably, IMiDs maintenance therapy increased OS in the setting of ASCT but showed no OS prolongation without ASCT. On further stratification, thalidomide-based maintenance therapy demonstrated OS benefit only in the setting of ASCT, while lenalidomide-based maintenance therapy did not show OS benefit regardless of transplantation status. For PFS however, both thalidomide- and lenalidomide-based maintenance therapies demonstrated significant survival benefits, regardless of transplantation status (Table 1). IMiD-based maintenance therapy increased the risk of developing grade 3 or 4 neutropenia (RR = 3.04, 95% CI = 2.49 - 3.70, P < 0.001), thrombocytopenia (RR = 2.68, 95% CI = 1.90 - 3.79, P < 0.001), anemia (RR = 1.97, 95% CI = 1.23 - 3.15, P = 0.005), infection (RR = 1.53, 95% CI = 1.22 - 1.92, P < 0.001), fatigue (HR = 1.71, 95% CI = 1.24 - 2.36, P = 0.001), constipation (RR = 2.04, 95% CI = 1.15 - 3.62, P = 0.015), and peripheral neuropathy (RR = 2.02, 95% CI = 1.20 - 3.39, P = 0.008).Conclusions: IMiD-based maintenance therapy results in significant improvement in OS and PFS in multiple myeloma patients but increased the risk of developing some grade 3 or 4 adverse events. While thalidomide-containing maintenance therapy regimens showed OS benefits in the setting of ASCT, lenalidomide-containing maintenance therapy did not prolong OS regardless of transplantation status. Both thalidomide- and lenalidomide-based maintenance therapies increased PFS in multiple myeloma patients independent of transplantation status. When more data on lenalidomide and the newer agent pomalidomide become available, further analysis will be warranted to analyze the efficacy and safety of IMiDs in multiple myeloma maintenance therapy.Table 1Effects of IMiD-based maintenance therapy on OS and PFS in multiple myeloma patientsIMiDASCT statusSurvivalNumber of trialsHR95% CIP valueThalidomide/LenalidomidecombinedOS180.910.84 - 0.990.027with ASCTOS100.880.78 - 0.990.036without ASCTOS90.940.83 - 1.060.299ThalidomidecombinedOS140.920.84 - 1.010.090with ASCTOS80.870.77 - 1.000.049without ASCTOS70.970.85 - 1.100.640LenalidomidecombinedOS40.840.67 - 1.040.102with ASCTOS20.890.66 - 1.200.457without ASCTOS20.780.57 - 1.060.114Thalidomide/LenalidomidecombinedPFS170.630.60 -0.68< 0.001with ASCTPFS90.620.57 - 0.67< 0.001without ASCTPFS90.660.60 - 0.73< 0.001ThalidomidecombinedPFS130.670.63 - 0.72< 0.001with ASCTPFS70.660.60 - 0.72< 0.001without ASCTPFS70.690.62 -0.77< 0.001LenalidomidecombinedPFS40.500.43 - 0.58< 0.001with ASCTPFS20.490.41 - 0.58< 0.001without ASCTPFS20.520.40 - 0.67< 0.001 DisclosuresNo relevant conflicts of interest to declare.