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Lenalidomide is an 'immunomodulating agent', which means it affects immune system functions, though the exact way it does this is still being researched. It is also an 'angiogenesis inhibitor', which means it slows the growth of new blood vessels, which tumours need to develop in order to grow.

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Web Resources: Lenalidomide
Latest Research Publications

Web Resources: Lenalidomide (7 links)

Latest Research Publications

Chari A, Vogl DT, Gavriatopoulou M, et al.
Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.
N Engl J Med. 2019; 381(8):727-738 [PubMed] Related Publications
BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.
METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.
RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.
CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Wang X, Xie H, Zhang L
Multiple myeloma with onset of pancreas involvement: A case report.
Medicine (Baltimore). 2019; 98(30):e16567 [PubMed] Related Publications
RATIONALE: Multiple myeloma is the second most common hematological malignancy. Extramedullary involvement is one of the indicators of poor prognosis. There is no consensus in treatment options and the efficacy. This article reports a case of multiple myeloma with onset of pancreas involvement. Amyloidosis secondary to multiple myeloma and a partial response to the chemotherapy treatment further emphasized its rarity.
PATIENT CONCERNS: In this article, we report a 59-year-old male patient with a chief complaint of fatigue for 8 months and upper abdominal pain for 2 months.
DIAGNOSIS: The patients were diagnosed as amyloidosis secondary to multiple myeloma with pancreatic occupying (head-neck junction area) lesion based on laboratory examination and pathology from lymph node puncture and skin biopsy.
INTERVENTIONS: An intensive chemotherapy treatment as bortezomib, lenalidomide, dexamethasone, cisplatin, epirubicin, cyclophosphamide, and etoposide was given. Due to intolerance, treatment regimen was further adjusted to bortezomib, lenalidomide, and dexamethasone.
OUTCOMES: The patient was 12 months alive. After 4 cycles of chemotherapy, a partial response was achieved and abdominal magnetic resonance imaging suggested a reduced pancreatic occupying lesion.
LESSONS: This case demonstrates that pancreatic involvement, digestive system neoplasm, and amyloidosis-related clinical features may be the earliest manifestations of multiple myeloma. For these patients, an intensive chemotherapy regimen may be a possible treatment approach.

Spicka I, Ocio EM, Oakervee HE, et al.
Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma.
Ann Hematol. 2019; 98(9):2139-2150 [PubMed] Free Access to Full Article Related Publications
The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m

Facon T, Kumar S, Plesner T, et al.
Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.
N Engl J Med. 2019; 380(22):2104-2115 [PubMed] Related Publications
BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10
CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

Barwick BG, Neri P, Bahlis NJ, et al.
Multiple myeloma immunoglobulin lambda translocations portend poor prognosis.
Nat Commun. 2019; 10(1):1911 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.

João C, Bergantim R, Neves M, et al.
Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.
Ann Hematol. 2019; 98(7):1689-1701 [PubMed] Related Publications
Patients older than 75 years old with multiple myeloma (MM) have shorter survival and are usually treated differently from what features in clinical trials. In this study, the authors characterized the Portuguese population of MM patients above 75 years old, treated between 2009 and 2016. We compared the outcomes obtained with bortezomib-based protocols (BBP), thalidomide-based protocols (TBP), and chemotherapy (CT) using univariate and multivariate controlling for age, performance status, International Staging System score, renal impairment, and number of comorbidities. We retrieved data from 386 patients, treated in 12 hospitals. Three hundred thirty-one cases were analyzed: 119 patients treated with BBP, 65 with TBP, 147 with CT. Median age was 79 years; CT-treated patients were older, had a worse performance status, and have more comorbidities. The median follow-up was 25 months. The 2-year OS was 58% and the median OS was 29.5 months. Patients treated with BBP had more frequently very good partial response (VGPR) or better response, and the subgroup of more fit patients had a significantly longer progression-free survival (PFS) and OS. The most frequently grade 3-4 toxicities were hematologic, infectious, and neurologic and were significantly lower in TBP and CT groups vs BBP. The most common second line was CT, followed by lenalidomide. Patients treated with lenalidomide had a higher probability of VGPR or better and a superior 1-year PFS. Despite the limitations of a retrospective study, our cohort represents the reality of older patients with MM in a western country. The hazard of death or progression was higher for old, fit patients treated, in first line, with CT and with TBP compared with that of BBP.

Sorigue M, Sancho JM
Recent landmark studies in follicular lymphoma.
Blood Rev. 2019; 35:68-80 [PubMed] Related Publications
Follicular lymphoma (FL) is the most common indolent lymphoma. Therapeutic advances in the past decade have improved its prognosis, but some questions remain open, particularly over adapting therapy to each individual patient's disease risk. Several trials and large studies dealing with biological and therapeutic aspects of FL have been published in the past few months and may have immediate or near-future practice-changing implications. These studies include risk-assessment by gene expression profiling, the therapeutic strategy in localized FL, use of obinutuzumab or lenalidomide in the front-line setting, stem cell transplant in early treatment failure and phosphatidylinositol 3-kinase (PI3K) inhibition and chimeric antigen receptor (CAR) T-cells in multiply relapsed disease. This review aims to contextualize these studies, summarize their design and results, assess their impact, highlight related questions that remain unanswered and, finally, provide a personal view as to how they change our approach to non-transformed FL.

Hollmann S, Moldaver D, Goyert N, et al.
A U.S. Cost Analysis of Triplet Regimens for Patients with Previously Treated Multiple Myeloma.
J Manag Care Spec Pharm. 2019; 25(4):449-459 [PubMed] Related Publications
BACKGROUND: In recent years, the FDA has approved several 3-agent (i.e., triplet) combinations for previously treated multiple myeloma (MM), and the National Comprehensive Cancer Network (NCCN) now recommends triplet regimens over doublets. Little is known about the real-world cost of triplet combinations because of the limited time that they have been on the market since FDA approval. Furthermore, traditional cost analyses developed to support market entrance rely on utilization assumptions that are difficult to validate when numerous comparators simultaneously enter the market.
OBJECTIVE: To perform a 1-year cost analysis of novel triplets used for the treatment of patients with previously treated MM controlling for differences in utilization.
METHODS: FDA-approved, NCCN-recommended (preferred and category 1 for previously treated MM) treatments included in the analysis were daratumumab plus lenalidomide plus dexamethasone (DARA/LEN/DEX), daratumumab plus bortezomib plus dexamethasone (DARA/BOR/DEX), elotuzumab plus lenalidomide plus dexamethasone (ELO/LEN/DEX), carfilzomib plus lenalidomide plus dexamethasone (CAR/LEN/DEX), and ixazomib plus lenalidomide plus dexamethasone (IXA/LEN/DEX). To control for market uptake, the model was designed to estimate the cost of treating an average patient over a 1-year time horizon. Drug administration and dosing, required comedications, postprogression therapy, monitoring requirements, and adverse event (AE) rates were based on FDA prescribing information or clinical trials. AEs ≥ grade 3 that occurred in ≥ 5% of patients were included. RED BOOK wholesale acquisition costs were used for drug acquisition costs. Costs of drug administration, AE management, and patient monitoring were based on the 2018 Center for Medicare & Medicaid Services payment rates or from published literature (inflated to 2018 U.S. dollars). The treatment duration for each regimen was estimated from modeled progression-free survival data; the 12-month progression-free survival rate was assumed to be equivalent to the probability that an average patient remained on therapy for at least 1 year after treatment initiation, which was used to estimate time-depended treatment-related costs. The probability of progression within 1 year of treatment initiation was used to inform the average postprogression therapy costs for each regimen.
RESULTS: The estimated cost per patient for each triplet regimen was $13,890 (DARA/BOR/DEX), $22,231 (IXA/LEN/DEX), $24,322 (ELO/LEN/DEX), $26,410 (DARA/LEN/DEX), and $27,432 (CAR/LEN/DEX). Drug acquisition costs and treatment duration were the largest drivers of cost. Scenario analyses with plausible alternative input parameters found the maximum per month cost of therapy to be $30,657 (CAR/LEN/DEX) and the minimum per month cost of therapy to be $13,784 (DARA/BOR/DEX).
CONCLUSIONS: This analysis controlled for differential utilization rates for 5 FDA-approved, NCCN-recommended triplet therapies for the treatment of previously treated MM. Of the examined regimens, treatment with DARA/BOR/DEX was estimated to have the lowest average monthly cost per patient, while CAR/LEN/DEX was the most expensive. As is common with modeling, some assumptions were necessary, and results may not be generalizable.
DISCLOSURES: This study was funded by Janssen Scientific Affairs, which employs Maiese and funded Cornerstone Research Group, a health economic consulting group, to complete the cost analysis, interpret data, and develop the manuscript. Janssen was involved in the design of the analysis, interpretation of results, and manuscript development and approval. Grima is a founding partner of Cornerstone Research Group, which employs Hollmann, Goyert, and Moldaver. Hollmann, Goyert, and Moldaver were responsible for creation of the economic model. This work was peer-reviewed and presented as an abstract at the Lymphoma and Myeloma 2017 International Congress; October 26-28, 2017; New York, NY.

Hadjiaggelidou C, Mandala E, Terpos E, et al.
Evaluation of regulatory T cells (Tregs) alterations in patients with multiple myeloma treated with bortezomib or lenalidomide plus dexamethasone: correlations with treatment outcome.
Ann Hematol. 2019; 98(6):1457-1466 [PubMed] Related Publications
The exact role of regulatory T cells (Tregs) in multiple myeloma (MM) has not been yet determined. Data regarding alterations of Tregs during therapy with novel agents (NA), i.e., bortezomib and lenalidomide are conflicted and limited. We evaluated prospectively alterations of Tregs and searched for correlations with disease characteristics, response, and outcome in 29 patients with active MM treated with either bortezomib-dexamethasone (BD; 11 patients) or lenalidomide-dexamethasone (LenDex, 18 patients). Additionally, we recorded changes of lymphocytes subsets and cytokines related to Tregs function and MM biology, i.e., interleukin (IL) 6, 2, 17, and TGF-β. Compared with controls, patients had significantly higher median levels of Tregs%, IL-6, and IL-17 (p < 0.001). Median CD4 T and B cells frequencies were significantly lower, whereas CD8 T and natural killers were increased compared to controls. In BD group, no significant alterations of Tregs% were observed. Patients treated with LenDex, displayed a significant reduction of Tregs% (p < 0.001) especially those who achieved at least very good partial response (≥vgPR) (p = 0.04). Lymphocyte subsets or cytokines did not significantly change during therapy. In summary, Tregs% are higher in patients with active MM compared with controls, and they significantly decrease after treatment with LenDex but not with BD; After therapy with LenDex, Tregs reduction between baseline and major response correlated with achievement of ≥vgPR suggesting a possible predictive role, that may contribute to therapeutic strategy.

Trudel S, Tessoulin B, Jullien M, et al.
Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study.
Ann Hematol. 2019; 98(6):1441-1447 [PubMed] Related Publications
Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.

Pandey A, Singh K, Patel S, et al.
Hyaluronic acid tethered pH-responsive alloy-drug nanoconjugates for multimodal therapy of glioblastoma: An intranasal route approach.
Mater Sci Eng C Mater Biol Appl. 2019; 98:419-436 [PubMed] Related Publications
In the present investigation, FePt alloy nanoparticles were synthesized with controlled size and elemental composition followed by surface modification using (3-Aminopropyl) triethoxysilane (APTES). Lenalidomide was covalently bound to FePt-NH

Gabeeva NG, Zvonkov EE, Koroleva DA, et al.
Successful experience of treatment of a patient with generalized non-GCB- DLBCL using the R-mNHL-BFM-90 protocol with lenalidomide: case report and review of literature.
Ter Arkh. 2018; 90(7):96-101 [PubMed] Related Publications
Diffuse large B-cell lymphoma is categorized by gene expression profiling into germinal center (GCB) and activated B-cell (ABC) subtype, also referred to as non-germinal center B-cell (non-GCB) by immunohistochemistry. ABC DLBCL is characterized by NF-κB pathway activation and high expression of IRF4/MUM1, a key transcription factor in B cell differentiation. Patients with ABC DLBCL have a significantly worse outcome when treated with standard chemotherapy (R-CHOP). Lenalidomide have shown activity in the ABC-DLBCL in combination with R-CHOP. But about 40% of patients remain resistant. We present the experience of treatment of a patient with generalized non-GCB-DLBCL using the intensive protocol R-mNHL-BFM-90 with lenalidomide.

Barosi G, Gale RP
Is lenalidomide the standard-of-care after an autotransplant for plasma cell myeloma?
Leukemia. 2019; 33(3):588-596 [PubMed] Related Publications
Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is associated with increase in progression-free survival (PFS) and survival in persons with plasma cell myeloma (PCM). Based on these data, posttransplant lenalidomide is considered by many a standard-of-care in this setting. However, decisions on the use of new therapies should consider not only results of such trials and meta-analyses but also other factors including quality-of-evidence, anticipated desired and undesired effects of the drug, costs and feasibility of the therapy option. In this review, we critically analyzed evidence on posttransplant lenalidomide in PCM, and we identified criteria which should be considered in designating posttransplant lenalidomide the standard-of-care. Using Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach we judged posttransplant lenalidomide improves PFS with high-quality evidence. However, we identified inconsistency and imprecision as limitations in the conclusions regarding a survival benefit rating the quality-of-evidence for a survival benefit moderate. We also highlighted inconsistency in claims of an increased risk of new cancers associated with posttransplant lenalidomide. We emphasize the need for a value-based reasoning which considers PFS and survival as well as health-related quality-of-life and costs. We conclude the decision to use posttransplant lenalidomide should be individualized based on pre- and posttransplant variables such as remission state, risk category and/or posttransplant measurable residual disease (MRD)-test results. Validity of these variables in estimating benefits and risks of posttransplant lenalidomide should be tested in randomized clinical trials.

Kastritis E, Gavriatopoulou M, Roussou M, et al.
Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis.
Amyloid. 2018; 25(4):234-241 [PubMed] Related Publications
We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2-100) and median number of prior therapies was 1 (range 1-4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.

Ito Y, Makita S, Tobinai K
Development of new agents for peripheral T-cell lymphoma.
Expert Opin Biol Ther. 2019; 19(3):197-209 [PubMed] Related Publications
INTRODUCTION: Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation.
AREAS COVERED: Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries. In addition, mogamulizumab (anti-CC chemokine receptor 4 antibody), chidamide (histone deacetylase inhibitor), and forodesine (purine nucleoside phosphorylase inhibitor) have been approved in Asian countries, including China, and Japan. In this review, we have summarized the available data regarding these approved agents and new agents currently under development for PTCL.
EXPERT OPINION: Novel agents will be a promising therapeutic option in selected patients with relapsed/refractory PTCL and will change the daily clinical practice in the treatment of PTCL. However, these are not a curative option when used as a single agent. Further clinical developments are expected, comprising 1) combination therapies of new agents with cytotoxic chemotherapies; 2) 'novel-novel' combinations; 3) immune therapies, including chimeric antigen receptor T-cell therapy; and 4) predictive marker analysis.

Li S, Meng XY, Maman STD, et al.
Lenalidomide and Low Dose Dexamethasone Plus Elotuzumab or Carfilzomib for Relapsed or Refractory Multiple Myeloma: A Comparison of Progression-Free Survival with Reconstructed Individual Participant Data.
Biomed Res Int. 2018; 2018:9057823 [PubMed] Free Access to Full Article Related Publications
Background: Refractory and relapsed multiple myeloma (RRMM) remains a clinical challenge. We compared the progression-free survival (PFS) of RRMM patients treated with lenalidomide and low dose dexamethasone plus elotuzumab or carfilzomib (ELD vs. CLD), using reconstructed individual patient data (IPD) based on two published trials reports.
Methods: We extracted data of study-level characteristics from original trial reports. We evaluated the comparability between the two treatment groups in terms of baseline status. Digitization of PFS Kaplan-Meier curves, reconstruction of IPD data, and subsequent survival analysis were performed. Distribution of progression and death events over time was visualized as histograms and corresponding kernel density lines, and Kaplan-Meier survival curves were plotted. Hazard ratio (HR) and corresponding 95% confidence interval (95% CI) were calculated.
Results: Significant difference in race and disease stage distribution was found (P < 0.0001). Higher proportion of white patients and patients with advanced disease in the carfilzomib group was identified. Survival analysis revealed better PFS in the carfilzomib group (elotuzumab group vs. carfilzomib group: HR = 1.36, 95% CI = [1.11-1.67]).
Conclusion: The CLD regimen may result in better PFS as compared with the ELD regimen in RRMM patients.

Morabito F, Skafi M, Recchia AG, et al.
Lenalidomide for the treatment of mantle cell lymphoma.
Expert Opin Pharmacother. 2019; 20(5):487-494 [PubMed] Related Publications
INTRODUCTION: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens. Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated. Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.

Burgos S, Montalban-Bravo G, Fuente L, et al.
Novel EZH2 mutation in a patient with secondary B-cell acute lymphocytic leukemia after deletion 5q myelodysplastic syndrome treated with lenalidomide: A case report.
Medicine (Baltimore). 2019; 98(1):e14011 [PubMed] Free Access to Full Article Related Publications
RATIONALE: The gene deletion (5)(q22q35) is reported in 10-20% of myelodysplastic syndrome (MDS) cases and is associated with response to lenalidomide and favorable prognosis. The authors report here a clinical case of MDS transformation to B-cell acute lymphocytic leukemia (B-ALL) with an associated accrual of an additional mutation following treatment with lenalidomide.
PATIENT CONCERNS: A 69-year-old man presented with progressive anemia, normal white blood cell count, and thrombocytopenia consistent with MDS. He was administered lenalidomide for 27 months, then developed acute B-cell lymphocytic leukemia and acquired a previously unreported mutation in the gene enhancer of zeste homolog 2 (EZH2).
DIAGNOSES: After 27 months of therapy with lenalidomide, a surveillance bone marrow aspiration (BMA) revealed 90% cellularity with persistent multilineage dysplasia and a population of blasts comprising 54% of all bone marrow elements by morphology, consistent with B-ALL, even though the patient was asymptomatic. Conventional karyotype showed no signs of del(5)(q22q35) MDS, however bone marrow next-generation sequencing (NGS) demonstrated the accrual of a nonsense mutation (c.211del pL71*) in exon 3 of EZH2. A confirmatory BMA yielded 70% blasts and clinical features indicative of B-ALL.
INTERVENTIONS: Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) was administered for 21 days.
OUTCOMES: A follow-up BMA was performed 2 months after mini-hyper-CVD therapy, showing dysplastic features with 25% ring sideroblasts, but no evidence of B-ALL. The patient is currently receiving monthly-low dose decitabine, ofatumumab, and dexamethasone, and is transfusion independent and asymptomatic after 7 cycles.
LESSONS: The present study shows an extremely rare progression of del(5)(q22q35) MDS to B-ALL with accompanying NGS data and a newly described acquisition of an EZH2 frameshift mutation. This case highlights the importance of NGS as a diagnostic and surveillance tool for MDS.

Kishimoto W, Takiuchi Y, Nakae Y, et al.
A case of AITL complicated by EBV-positive B cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide.
Int J Hematol. 2019; 109(4):499-504 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein-Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.

Park DE, Cheng J, Berrios C, et al.
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Proc Natl Acad Sci U S A. 2019; 116(3):1027-1032 [PubMed] Free Access to Full Article Related Publications
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.

Munakata W, Tobinai K
Adult T-Cell Leukemia-Lymphoma.
Cancer Treat Res. 2019; 176:145-161 [PubMed] Related Publications
Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-lymphocyte malignancy caused by an RNA retrovirus, human T-cell leukemia virus type 1. ATL is clinically classified into four disease subtypes. The acute, lymphoma type, and cases of the chronic type involving unfavorable prognostic factors are regarded as aggressive ATL subtypes that require immediate treatment. Dose-intensified chemotherapy, such as the VCAP-AMP-VECP regimen, is considered to be the most recommended treatment for aggressive ATL. However, ATL remains difficult to cure and has an extremely poor prognosis, even when such chemotherapy is employed. Allogeneic stem cell transplantation is the only known curative therapy and is recommended for younger patients with aggressive ATL. However, because of the increasing age at the onset of ATL, only a small fraction of patients with ATL can benefit from such transplants; therefore, there is an unmet medical need for novel drugs. Mogamulizumab, a defucosylated, humanized anti-C-C motif chemokine receptor 4 (CCR4) monoclonal antibody, was developed using a novel glycoengineering technique. Mogamulizumab monotherapy achieved clinically meaningful effects in patients with relapsed aggressive ATL and has exhibited acceptable toxicity profiles both inside and outside of Japan. In addition, lenalidomide has shown promising antitumor activity in patients with ATL. Furthermore, based on the results of translational research, several promising novel agents are currently being investigated and might contribute to improving the prognosis of ATL.

Boudhabhay I, Titah C, Talbot A, et al.
Multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy, revealed by retinal abnormalities: A case report.
Medicine (Baltimore). 2018; 97(52):e13638 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Crystal sorting histiocytosis (CSH) is a rare disorder that is morphologically characterized by the accumulation of monoclonal immunoglobulin crystals, predominantly of a kappa light chain type, within lysosomes of macrophages. CSH may result in a variety of clinical manifestations depending on the involved organs. In this case report, we aim to describe a patient with ophthalmic manifestations which lead to the diagnosis of multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy.
PATIENT CONCERNS: A 60-year-old male patient presented with progressive bilateral decreased vision for 2 years.
DIAGNOSIS: Ophthalmic explorations showed bilateral macular and papillary edema, and multiple crystalline deposits in the anterior stromal cornea and in the retina. Laboratory tests showed nephrotic syndrome and renal dysfunction. Further work-up revealed IgG kappa multiple myeloma, with biopsy-proven combined crystalline podocytopathy and tubulopathy.
INTERVENTIONS: The patient received chemotherapy (bortezomib, cyclophosphamide, and dexamethasone for 3 cycles, then bortezomib, lenalidomide, and dexamethasone).
OUTCOMES: Despite partial hematologic response and improvement of the papilledema and macular edema, the patient developed dialysis-dependent end-stage renal failure.
LESSONS: This report, highlighting the protean presentation of paraprotein-mediated injuries, provides additional information on the ocular anomalies not previously described that may be associated with crystal-storing histiocytosis.

Jelínek T, Mihályová J, Hájek R
CD38 targeted treatment for multiple myeloma.
Vnitr Lek. Fall 2018; 64(10):939-948 [PubMed] Related Publications
CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs). Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications, nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug. Anti-CD38 possess pleiotropic mechanism of action that have been described also in other mAbs, but quite specific, novel and very important seems to be the immunomodulatory effect provided by depletion of several CD38+ immunosuppressive immune cell populations. CD38-targeted mAbs induce partial response or better in approximately 30 % of heavily pre-treated myeloma patients as monotherapy. Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already approved as a part of three distinct combination regimens in relapsed setting. The combination of daratumumab with lenalidomide and dexamethasone is considered to be the best treatment option in relapsed myeloma with unprecedented prolongation of median PFS, including high rate of good quality responses. CD38 targeted therapy is rapidly moving toward the first line treatment. Anti-CD38 mAbs have been also successfully tested in other plasma cell dyscrasias (such as AL amyloidosis), and they are examined in other hematological malignancies (such as CLL, ALL, AML, etc.) and even in solid oncology as well as in autoimmune disorders. Implementation of CD38 targeted mAbs have been significant milestone in the treatment of MM, similar to that of CD20 targeted mAbs in CLL or non-Hodgkin lymphomas. We believe that this drug may eventually help to reach the cure at least in a subset of MM patients in the near future. Key words: acute myeloid leukemia - CD38 - daratumumab - isatuximab - multiple myeloma.

Paquin AR, Kumar SK, Buadi FK, et al.
Overall survival of transplant eligible patients with newly diagnosed multiple myeloma: comparative effectiveness analysis of modern induction regimens on outcome.
Blood Cancer J. 2018; 8(12):125 [PubMed] Free Access to Full Article Related Publications
Overall survival (OS) of multiple myeloma has improved remarkably over time, with the recent Intergroupe Francophone du Myelome (IFM) 2009 randomized trial reporting a 4-year OS rate of approximately 82% in patients receiving modern therapy. However, survival estimates from clinical trials may overestimate outcomes seen in clinical practice even with the adjustment for age and other key characteristics. The purpose of this study was to determine the OS of myeloma patients seen in routine clinical practice who resembled the cohort studied in the IFM 2009 trial. A second goal was to conduct a brief comparative effectiveness analysis of bortezomib, lenalidomide, dexamethasone, and other major induction regimens used during the study period. We studied all patients with myeloma 65 years of age and younger, seen at the Mayo Clinic between January 1, 2010 and August 31, 2015, who had a stem cell harvest performed within 12 months of initial diagnosis. Patients with baseline serum creatinine >2 mg/dL were excluded. Five hundred and eighteen patients were studied. The 4-year OS rate was 82.3%, comparable to results achieved in the contemporaneous IFM randomized trial. The 4-year OS rates for standard and high-risk myeloma were 86.3% and 68.2%, respectively.

Flowers CR, Leonard JP, Nastoupil LJ
Novel immunotherapy approaches to follicular lymphoma.
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):194-199 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Follicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies. Lenalidomide and phosphatidylinositol 3-kinase inhibitors are emerging as agents that can be applied in the relapsed setting. Other immunotherapy approaches, including checkpoint inhibitors and chimeric antigen receptor T cells, appear promising but remain experimental. Utilization of all forms of immunotherapy requires careful consideration of the unique toxicities associated with these agents and the means to mitigate them by selection of appropriate patients, optimal timing, and the use of supportive care.

Manasanch EE, Shah JJ, Lee HC, et al.
Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial.
Lancet Haematol. 2018; 5(12):e628-e640 [PubMed] Related Publications
BACKGROUND: Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma.
METHODS: In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m
FINDINGS: Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m
INTERPRETATION: The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results.
FUNDING: Novartis and MD Anderson Cancer Center Support Grant.

Sato S, Kambe E, Tamai Y
Disseminated Cryptococcosis in a Patient with Multiple Myeloma Treated with Daratumumab, Lenalidomide, and Dexamethasone.
Intern Med. 2019; 58(6):843-847 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
We report a case of disseminated cryptococcosis in a patient with multiple myeloma (MM) during treatment with daratumumab, lenalidomide, and dexamethasone (DRd). A 62-year-old woman, who was diagnosed with IgGλ type MM, was treated with three cycles of bortezomib and dexamethasone and subsequently treated with three cycles of DRd before admission. She reached a stringent complete response and presented with lethargy and seizure. Laboratory findings revealed severe CD4 lymphopenia, and Cryptococcus neoformans was detected in her cerebrospinal fluid and blood culture. The risk of developing an opportunistic infection should be considered in patients treated with daratumumab.

Fernández-Caballero M, Salmerón D, Dolores Chirlaque M, et al.
Increasing therapy-related myeloid neoplasms in multiple myeloma.
Eur J Clin Invest. 2019; 49(2):e13050 [PubMed] Related Publications
BACKGROUND: Despite the longer survival achieved in multiple myeloma (MM) patients due to new therapy strategies, a concern is emerging regarding an increased risk of secondary primary malignancies (SPMs) and how to characterize those patients at risk. We performed a retrospective study covering a 28-year follow-up period (1991-2018) in a tertiary single institution.
MATERIAL AND METHODS: Data of 403 MM patients were recorded and compared with the epidemiologic register of the population area covered by our centre, calculating the standardize incidence ratio (SIR) for the different types of SPMs diagnosed in the MM cohort. Fine and Gray regression models were used to identify risk factors for SPMs.
RESULTS: Out of the 403 MM patients, 23 (5.7%) developed SPMs: 13 therapy-related myeloid (TRM) malignancies (10 of them (77%) myelodysplastic syndrome (MDS), 1 acute lymphoid leukaemia and 9 solid neoplasms. In the MM cohort, the relative risk of MDS was significantly higher than in the general population. Survival of patients with TRM malignancies was poor with a median of 4 months from the diagnosis, and most of them showed complex karyotype. Within the MM subset, multivariable analysis showed a higher risk of TRM malignancies in patients that previously received prolonged treatment with lenalidomide (>18 months).
CONCLUSIONS: Though the improvement in MM outcome during the last decades is an unprecedented achievement, it has been accompanied by the rise in TRM malignancies with complex cytogenetic profile and poor prognosis that are in the need of an improved biologic and therapeutic approach.

Richardson PG, Zweegman S, O'Donnell EK, et al.
Ixazomib for the treatment of multiple myeloma.
Expert Opin Pharmacother. 2018; 19(17):1949-1968 [PubMed] Related Publications
INTRODUCTION: Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy. Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications. Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including 'poor prognosis' patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens.

Koo RM, Crispin P, Craft M, Lalloo S
Successful treatment of central nervous system myeloma manifesting as cauda equina nodules with intrathecal chemotherapy, lenalidomide and dexamethasone.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
We report a case of central nervous system myeloma manifesting as cauda equina nodules, successfully treated with triple intrathecal (IT) chemotherapy, lenalidomide and dexamethasone. After presenting with multiple plasmacytomas which led to a diagnosis of non-secretory myeloma at age 56, the patient underwent multiple episodes of treatment for relapsing myeloma over a 7-year period. In March 2017, he presented with declining gait over a month with bilateral hip flexion weakness, absent lower limb reflexes and dorsal column loss. MRI of the spine revealed multiple enhancing cauda equina nodules at L1-L3. Cerebrospinal fluid (CSF) examination confirmed a clonal plasma cell population and disease was not found elsewhere. He was treated with radiotherapy, IT and intravenous methotrexate and cytarabine. However, repeat lumbar puncture revealed persistent disease. Clearance of CSF plasma cells was achieved with two times a week IT cytarabine, methotrexate and dexamethasone. He was started on lenalidomide and dexamethasone with no evidence of disease progression at 12 months.

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