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Lenalidomide

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

Zuo W, Zhu X, Yang J, et al.
Bortezomib combined with lenalidomide as the first-line treatment for the rare synchronous occurrence of multiple myeloma and pulmonary adenocarcinoma: A case report.
Medicine (Baltimore). 2017; 96(1):e5787 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Simultaneous multiple myeloma (MM) and pulmonary adenocarcinoma is a rare occurrence, and thus, treatment is a challenge. This study reports on 1 such case of MM with concurrent lung cancer, where an accurate diagnosis was made and the patient underwent treatment for both cancers.
CASE SUMMARY: A 68-year-old man presented with 2 months of progressive lower back pain. Visualization with magnetic resonance imaging (MRI) revealed multiple collapsed vertebrae from T12 to S3, as well as an altered signal intensity at the T3 vertebra. The patient was diagnosed with MM upon examination. A chest computed tomography (CT) scan revealed a round mass in the left lower lobe of the lungs, and a CT-guided needle biopsy uncovered a moderately differentiated adenocarcinoma. There were no additional notable findings in the left lung using positron emission tomography computed tomography (PET-CT). Therefore, a diagnosis of MM with pulmonary adenocarcinoma was made. Surgery was performed to excise the lung cancer. Bortezomib was used as first-line induction therapy against both tumors and lenalidomide was used for maintenance. The patient went into complete remission. Using this combined chemotherapy, the patient has survived for over 3 years since a diagnosis was made despite relapsing twice after the first year.
CONCLUSION: This report clearly delineates the diagnosis and treatment of a rare case of synchronous MM and pulmonary adenocarcinoma, as well as depicts a potentially positive outcome for the patient. It also overviews some diagnostic and therapeutic implications for clinicians.

Berenson A, Vardanyan S, David M, et al.
Outcomes of multiple myeloma patients receiving bortezomib, lenalidomide, and carfilzomib.
Ann Hematol. 2017; 96(3):449-459 [PubMed] Related Publications
New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.

Berenson A, Vardanyan S, David M, et al.
Improved clinical outcomes for multiple myeloma patients treated at a single specialty clinic.
Ann Hematol. 2017; 96(3):441-448 [PubMed] Related Publications
Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients' quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (<65 years old) showed a longer OS. The results of this study should help physicians predict outcomes for MM patients and be encouraging for patients with this B cell malignancy.

Xia C, Ribeiro M, Scott S, Lonial S
Daratumumab: monoclonal antibody therapy to treat multiple myeloma.
Drugs Today (Barc). 2016; 52(10):551-560 [PubMed] Related Publications
Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed. Given the encouraging efficacy and acceptable safety profile, daratumumab has emerged as a novel treatment option for MM both as a monotherapy and in combination with conventional and novel anti-MM agents. This review will focus on preclinical pharmacology, pharmacokinetics, safety and clinical development of daratumumab in MM.

Offidani M, Corvatta L, Bringhen S, et al.
Salvage therapy in first relapse: a retrospective study in a large patient population with multiple myeloma.
Eur J Haematol. 2017; 98(3):289-295 [PubMed] Related Publications
OBJECTIVE: There is no strong evidence to guide therapeutic approach to multiple myeloma (MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide.
METHODS: In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy.
RESULTS: Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2ndPFS), PFS2, and overall survival (OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2ndPFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2ndPFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months.
CONCLUSION: Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM.

van de Velde H, Londhe A, Ataman O, et al.
Association between complete response and outcomes in transplant-eligible myeloma patients in the era of novel agents.
Eur J Haematol. 2017; 98(3):269-279 [PubMed] Related Publications
OBJECTIVES: Achieving complete response (CR) has been linked to improved progression-free (PFS) and overall (OS) survival in myeloma. A meta-analysis was conducted to investigate whether this holds true in the era of novel agents (bortezomib, lenalidomide, thalidomide).
METHODS: A total of 24 studies in newly diagnosed patients undergoing autologous stem cell transplantation (ASCT) that reported associations between responses and long-term outcomes (PFS/OS rates post-ASCT by response, or hazard ratios with 95% confidence intervals from Cox models) were identified and analyzed.
RESULTS: Achievement of CR vs. CONCLUSIONS: Achieving CR during first-line therapy remains important in the novel-agent era; magnitude of association between achieving CR and outcomes appears higher for CR obtained using novel vs. non-novel agents.

Schabel C, Horger M, Kum S, et al.
Simplified response monitoring criteria for multiple myeloma in patients undergoing therapy with novel agents using computed tomography.
Eur J Radiol. 2016; 85(12):2195-2199 [PubMed] Related Publications
INTRODUCTION: Multiple myeloma is a malignant hematological disorder of the mature B-cell lymphocytes originating in the bone marrow. While therapy monitoring is still mainly based on laboratory biomarkers, the additional use of imaging has been advocated due to inaccuracies of serological biomarkers or in a-secretory myelomas. Non-enhanced CT and MRI have similar sensitivities for lesions in yellow marrow-rich bone marrow cavities with a favourable risk and cost-effectiveness profile of CT. Nevertheless, these methods are still limited by frequently high numbers of medullary lesions and its time consumption for proper evaluation.
OBJECTIVE: To establish simplified response criteria by correlating size and CT attenuation changes of medullary multiple myeloma lesions in the appendicular skeleton with the course of lytic bone lesions in the entire skeleton. Furthermore to evaluate these criteria with respect to established hematological myeloma-specific parameters for the prediction of treatment response to bortezomib or lenalidomide.
MATERIALS AND METHODS: Non-enhanced reduced-dose whole-body CT examinations of 78 consecutive patients (43 male, 35 female, mean age 63.69±9.2years) with stage III multiple myeloma were retrospectively re-evaluated. On per patient basis, size and mean CT attenuation of 2-4 representative lesions in the limbs were measured at baseline and at a follow-up after a mean of 8 months. Results were compared with the course of lytical bone lesions as well with that of specific hematological biomarkers. Myeloma response was assessed according to the International Myeloma Working Group (IMWG) uniform response criteria. Testing for correlation between response of medullary lesions (Respmed) and response of all myeloma manifestations including osteolyses (Resptotal) was performed using the corrected contingency coefficient (Ccorr).
RESULTS: The correlation between Respmed based on length diameter and transverse diameter and Resptotal was perfect (Ccorr=1.0; p<0.0001) whereas the correlation based on density was moderate (Ccorr=0.54; p<0.0001). The evaluation of simplified response criteria with a measurement of only 2 medullary lesions yielded the best sensitivity and specificity valued for treatment-induced changes for the length diameter evaluation with 94.4%/95.7% for prediction of progressive disease and 78.6%/93.3% for prediction of therapy response. There were no significant differences between patients treated with bortezomib and lenalidomide (p>0.05).
CONCLUSION: Measurements of size of a minimum of two medullary lesions is sufficient for response assessment and correlates very well with the course of lytic bone lesions and that of hematologic parameters.

Sasaki M
Current treatment of refractory and relapsed multiple myeloma.
Rinsho Ketsueki. 2016; 57(10):2084-2095 [PubMed] Related Publications
In the past decade, previously approved novel agents, such as proteasome inhibitors (bortezomib) and immunomodulatory drugs ([IMiDs]; e.g., lenalidomide), have led to significant improvement in the treatment of multiple myeloma in Japan. However, almost all patients will ultimately relapse, even when they have achieved a deep and prolonged therapeutic response with initial treatment. Next-generation IMiDs (pomalidomide) and deacetylase inhibitors (panobinostat) were approved for use as salvage therapy for refractory and relapsed multiple myeloma [RRMM] within the last year. Long-term chemotherapy could result in the emergence of drug-resistant clones due to "intraclonal heterogeneity" and "clonal evolution by Darwinian selection." Though some recommendations on the management of RRMM have been detailed, no uniform treatment has yet been established for these patients. Relapse situations are heterogeneous. Therefore, relapse management requires an individual approach based on assessments of patient-, disease-, and treatment-related factors. The primary considerations when selecting an appropriate treatment are patient-related factors such as frailty, comorbidity, disability, quality of life, and the overall goals of care. We hope that these novel agents that appear promising in Japan, such as monoclonal antibodies (e.g., elotuzumab, daratumumab) and next-generation proteasome inhibitors (e.g., carfilzomib, ixazomib) will improve the outcomes of patients with this incurable disease in the near future.

Tamura H
Treatment strategy for transplant-ineligible patients with newly diagnosed multiple myeloma.
Rinsho Ketsueki. 2016; 57(10):2074-2083 [PubMed] Related Publications
The current therapeutic strategy for multiple myeloma has improved dramatically due to the use of novel agents. In newly diagnosed transplant-ineligible myeloma patients, the standard therapy until the 1990s had long been melphalan and prednisolone (MP), but the recent recommendation is the proteasome inhibitor bortezomib plus MP (MPB), the immunomodulatory drug thalidomide plus MP (MPT), and the thalidomide derivative lenalidomide (LEN)-based regimens such as LEN plus low-dose dexamethasone (Ld) and LEN plus MP (MPL). The overall response rate in patients treated with Ld, MPL, or MPB was reported to be approximately 70%. Achieving complete remission (CR) is important in elderly as well as younger patients. Therefore, MPB administration appears to be the most appropriate initial therapy because the MPB regimen results in high CR rates. However, in elderly patients, especially in those 75 years of age and older and those who are frail or with comorbidities, it is important to balance efficacy and toxicity as well as to maintain quality of life. Furthermore, continuous treatment results in longer survival than a fixed-duration regimen in this population.

Sunami K
Treatment strategy in untreated transplant-eligible multiple myeloma patients.
Rinsho Ketsueki. 2016; 57(10):2064-2073 [PubMed] Related Publications
Autologous stem cell transplantation (ASCT) is known to be superior to conventional chemotherapies and has been established as a standard of care for young patients with multiple myeloma. In the first decade of this century, novel agents such as thalidomide, bortezomib, and lenalidomide became clinically available, and several clinical trials using these drugs as induction therapies, conditioning regimens, and post-transplant consolidation and maintenance therapies have been reported, leading to increasing improvement in treatment results as compared to conventional therapies. Future changes in therapeutic strategies using these novel agents are anticipated to increase the complete response rate and prolong progression free survival and overall survival. This article describes the optimal treatment strategy for ASCT-eligible patients in Japan.

Mangiacavalli S, Pompa A, Ferretti V, et al.
The possible role of burden of therapy on the risk of myeloma extramedullary spread.
Ann Hematol. 2017; 96(1):73-80 [PubMed] Related Publications
Extramedullary relapse (EMR) represents a poor prognostic marker in the course of multiple myeloma (MM). We reviewed data from 329 patients, diagnosed between 2000 and 2010, without extramedullary disease at onset to explore possible risk factors for EMR. The median overall survival of our study cohort was 6.4 years. The risk of EMR was 28 % with a median time from diagnosis to first EMR of 2.2 years (0.2-9.1 years). Patients with soft tissue masses located in extra-osseous organs (EMR-S) showed the worst outcome, compared to those with tumor masses arising from adjacent bone (EMR-B) (median OS 1.6 vs 2.4 years, p = 0.006). In addition, patients with EMR-S showed a significant trend for further development of extramedullary masses in a very short time (3.7 vs 5.7 months for EMR-B, p = 0.043). Multivariate analysis failed to identify any clinically presenting features predictive for EMR. The occurrence of EMR was higher in patients with more complex treatment history, defined on the basis of longer treatment duration (≥6 vs <6 months) and on elevated number of treatment lines administered (>2 vs ≤2 lines) (HR = 4.5, p < 0.001 and HR = 9.0, p < 0.001, respectively, when one or both factors are present).In conclusion, increasing burden of treatment might be a possible risk factor for EMR. MM patients with multiple relapses should be comprehensively investigated including, when possible, a whole-body-targeted radiologic technique to accurately detect EMR. Treatment choice should take into account the very poor outcome for patients with soft tissue involvement.

Pavlikova L, Seres M, Imrichova D, et al.
The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin.
Gen Physiol Biophys. 2016; 35(4):497-510 [PubMed] Related Publications
In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA
Current treatments for renal failure due to multiple myeloma.
Expert Opin Pharmacother. 2016; 17(16):2165-2177 [PubMed] Related Publications
INTRODUCTION: Renal impairment (RI) is one of the most common complication of multiple myeloma (MM). RI is present in almost 20% of MM patients at diagnosis and in 40%-50% of patients during the course of their disease. Areas covered: Biology along with tools for diagnosis and management of RI are reported in this paper. Papers published in PubMed and reported abstracts up to May 2016 were used. Expert opinion: Moderate and severe RI increases the risk of early death; thus rapid intervention and initiation of anti-myeloma treatment is essential and improves renal outcomes in RI patients. Bortezomib and dexamethasone triplet combinations are the current standard of therapy for MM patients with acute kidney injury due to cast nephropathy; they offer high rates of both anti-myeloma response and renal recovery. Thalidomide and lenalidomide may be used in bortezomib refractory patients. In the relapsed/refractory setting additional treatment options such as carfilzomib, pomalidomide and monoclonal antibodies are available; however, there is limited data for their effects on patients with RI. High dose melphalan with autologous stem cell transplantation should be considered in otherwise eligible patients with RI. Finally, high cut-off hemodialysis membranes do not seem to offer significant additive effects on anti-myeloma therapies.

Dimopoulos MA, Oriol A, Nahi H, et al.
Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016; 375(14):1319-1331 [PubMed] Related Publications
Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10(5) white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. Conclusions The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

Voorhees PM, Usmani SZ
The role of high-dose melphalan and autologous stem cell transplant in the rapidly evolving era of modern multiple myeloma therapy.
Clin Adv Hematol Oncol. 2016; 14(9):719-28 [PubMed] Related Publications
The advent of the immunomodulatory drugs thalido-mide, lenalidomide, and pomalidomide; the proteasome inhib-itors bortezomib, carfilzomib, and ixazomib; the histone deacet-ylase inhibitor panobinostat; and the monoclonal antibodies elotuzumab and daratumumab has led to dramatic improvements in outcomes for patients with multiple myeloma. Along with progress in nontransplant therapy have come questions regarding the continued role of high-dose melphalan (HDM) supported by autologous stem cell transplant (ASCT) in the treatment of multiple myeloma. Emerging evidence from phase 3 studies demonstrates that consolidation therapy with HDM/ASCT further improves depth of response and progression-free survival in the context of modern therapy for multiple myeloma. Moreover, unprecedented survival data from ongoing phase 3 studies of patients treated with modern myeloma therapy followed by HDM/ASCT in first-line or second-line therapy reaffirm single and tandem HDM/ASCT as important standards of care for eligible patients. Herein, we review the evolving role of HDM/ASCT for the treatment of patients with newly diagnosed or relapsed multiple myeloma.

Tobinai K
Disease-oriented treatment of T/NK-cell lymphomas.
Rinsho Ketsueki. 2016; 57(8):1044-51 [PubMed] Related Publications
Recent clinical trials for T/NK-cell lymphomas are summarized herein, focusing on ATL and extranodal NK/T-cell lymphoma (ENKL). The outcomes of patients with these malignancies were the poorest among various peripheral T-cell lymphomas (PTCLs) in the International T-Cell Lymphoma Project. JCOG has conducted several clinical trials aimed at improving these poor outcomes. For aggressive ATL, JCOG is conducting a phase II trial of VCAP-AMP-VECP followed by allogeneic SCT. For localized ENKL, concurrent chemoradiotherapy has shown promising and durable efficacy in the phase I/II study. Among various new agents for PTCLs and ATL, mogamulizumab has shown promising efficacy for relapsed ATL. A subsequent phase II study of mogamulizumab using the same dose and schedule for relapsed PTCL/CTCL also showed promising efficacy. To establish a new standard for untreated aggressive ATL, a randomized phase II study of VCAP-AMP-VECP with or without mogamulizumab was conducted. Higher % CR was obtained (52% vs 33%) in the former arm, suggesting that VCAP-AMP-VECP plus mogamulizumab is a reasonable option. Lenalidomide recently showed promising efficacy for ATL in phase I and II studies.

de Morrée ES, Vogelzang NJ, Petrylak DP, et al.
Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study.
JAMA Oncol. 2017; 3(1):68-75 [PubMed] Related Publications
Importance: The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles.
Objective: To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial.
Design, Setting, and Participants: The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors.
Main Outcomes and Measures: Total number of docetaxel cycles delivered as an independent factor for OS.
Results: Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001).
Conclusions and Relevance: These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.

Iqbal N, Tariq MU, Shaikh MU, Majid H
Pleural effusion as a manifestation of multiple myeloma.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Multiple myeloma is a clonal B-cell malignancy, characterised by proliferation of plasma cells and secretion of paraproteins. These plasma cells accumulate predominantly in the bone marrow; rarely, they invade other areas, especially the thorax. Myeloma presenting with a pleural effusion is rare and reported in only 6% of patients with myeloma. Such patients generally present late and have a poor prognosis. Here, we describe a patient presenting with a lung mass, renal failure and a massive unilateral pleural effusion due to multiple myeloma who was treated successfully.

Gonsalves WI, Milani P, Derudas D, Buadi FK
The next generation of novel therapies for the management of relapsed multiple myeloma.
Future Oncol. 2017; 13(1):63-75 [PubMed] Article available free on PMC after 01/01/2018 Related Publications
The advent of various novel therapies such as immunomodulators and proteasome inhibitors has transformed the treatment paradigm for patients with multiple myeloma (MM). As a result, the overall survival has improved dramatically over the last decade. Despite these advances, MM remains mostly incurable and most patients experience disease relapse after enjoying a period of disease control or remission. Fortunately, the scientific community continues to make strides in developing 'next-generation' therapies for the management of patients with relapsed MM. This review will summarize the efficacy of some of the newest therapeutic agents available for the treatment of patients with relapsed MM after their upfront treatment with the original novel agents such as thalidomide, lenalidomide and bortezomib.

Kosugi S, Shibayama H, Nakatani E, et al.
Second primary malignancies among patients with myeloma-related-diseases in the KMF database.
Rinsho Ketsueki. 2016; 57(7):839-47 [PubMed] Related Publications
The incidence of second primary malignancies (SPMs) in Japanese patients with myeloma or myeloma-related diseases was studied by using the Kansai Myeloma Forum (KMF) database registered from November 2012 to March 2015. We studied 1,571 cases. Hematologic malignancies were documented in 10 patients, and solid tumors in 36 during this period. The cumulative 5-year incidence was estimated to be 1.0% for hematological malignancies and 3.7% for solid tumors. In the patients with smoldering myeloma or MGUS without treatment, solid tumors but not hematologic malignancies developed, though the cumulative incidence of each malignancy did not differ significantly from that in patients receiving treatment. Although statistical analysis showed that treatment with melphalan, bortezomib, lenalidomide, or thalidomide had no effect on the occurrence of hematological malignancies, lenalidomide administration was more frequent in the patients with solid tumors. To evaluate the SPMs in myeloma or myeloma-related diseases more accurately, accumulation of a larger number of patients and longer observation are needed.

Mitani Y, Usami E, Kimura M, et al.
Risk factors for neutropenia with lenalidomide plus dexamethasone therapy for multiple myeloma.
Pharmazie. 2016; 71(6):349-51 [PubMed] Related Publications
Neutropenia may develop as an adverse event in patients with multiple myeloma receiving lenalidomide (LEN) plus dexamethasone (DEX) therapy. In the present study, we examined the risk factors associated with grade 3/4 neutropenia during the first cycle of LEN plus DEX therapy. We observed that hemoglobin level (≤ 8.5 g/dl) was a significant risk factor for grade 3/4 neutropenia during the first cycle of therapy (odds ratio: 19.40; 95% confidence interval: 2.68-141.00; p < 0.01). thus, our findings suggest that determining the hemoglobin level could be useful in the risk management for neutropenia in patients receiving LEN plus DEX therapy.

Lovering S, Miao W, Bailie T, Amato D
Hair repigmentation associated with thalidomide use for the treatment of multiple myeloma.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A 75-year-old woman diagnosed with multiple myeloma in 2007 began treatment with monthly melphalan and prednisone for a total of 9 cycles in combination with thalidomide in 2009. The patient subsequently continued on thalidomide for long-term maintenance therapy. 3 years following initiation of thalidomide, the patient mentioned to her oncologist that her hair had become darker over the years. She attributed the change to thalidomide given the temporal relationship and progressive darkening over the course of therapy. The patient denies ever using any hair colouring treatments and had longstanding grey/white hair before beginning thalidomide in 2009. A case of hair repigmentation associated with the use of lenalidomide, a 4-amino-glutamyl analogue of thalidomide, in a patient with multiple myeloma was previously reported in the literature. We report herein the first case of hair repigmentation associated with the use of thalidomide, a related immunomodulatory drug.

Medinger M, Halter J, Heim D, et al.
Gene-expression Profiling in Patients with Plasma Cell Myeloma Treated with Novel Agents.
Cancer Genomics Proteomics. 2016 Jul-Aug; 13(4):275-9 [PubMed] Related Publications
BACKGROUND/AIM: Novel agents such as thalidomide, lenalidomide and bortezomib have in part anti-angiogenic properties. In this study, we examined gene expression of angiogenic molecules in patients with plasma cell myeloma (PCM).
MATERIALS AND METHODS: We included 93 patients with PCM treated with novel agents (immunomodulatory drugs (IMiDs), bortezomib or a combination of both). The mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 Profiler PCR Array. The response evaluation was performed after three cycles.
RESULTS: Regarding all 93 patients, gene expression of 15 out of 84 genes tested (pre- and post-treatment and changes in levels pre-treatment/post-treatment) were significantly different in responders compared to non-responders. Responders had a lower expression of pro-angiogenic factors and increased expression of antiangiogenic factors.
CONCLUSION: In the IMiD-treated groups we found significant changes of expression of angiogenic genes in responders compared to non-responders, whereas in the bortezomib-based group the difference in expression of angiogenic genes was not significant.

Jung SH, Choi HJ, Shin MG, et al.
Thalidomide-based induction regimens are as effective as bortezomib-based regimens in elderly patients with multiple myeloma with cereblon expression.
Ann Hematol. 2016; 95(10):1645-51 [PubMed] Related Publications
Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs and is considered a biomarker for the prediction of outcomes after thalidomide- or lenalidomide-based treatments. In this study, we evaluated CRBN expression in bone marrow (BM) tissue at diagnosis and investigated the relationship between CRBN expression and treatment outcomes after thalidomide- or bortezomib-based front-line therapies in 89 elderly patients with multiple myeloma (MM). CRBN expression at the time of diagnosis was evaluated with immunohistochemical (IHC) staining for myeloma cells in paraffin wax-embedded BM tissue. CRBN-immunostained slides were scored by intensity and diffuseness, and a total score of >6 was defined as CRBN-positive (CRBN(+)). Thirty-eight patients (45.2 %) were CRBN(+). Among patients treated with thalidomide-based regimens, CRBN(+) patients showed a better treatment response than did CRBN-negative patients (35.0 vs. 11.8 % complete response rate, respectively; HR = 4.038, P = 0.137). During a median follow-up of 31.8 months, patients treated with bortezomib-based regimens had a longer time to progression (TTP) than did patients treated with thalidomide-based regimens (15.6 vs. 13.2 months, respectively; P = 0.047), but early mortality occurred frequently in patients treated with bortezomib-based regimens. Additionally, there was no significant difference in survival outcomes between thalidomide- and bortezomib-based regimens in CRBN(+) patients (median TTP, 13.8 vs. 15.6 months, respectively; P = 0.842 and median OS, 39.3 vs. 30.1 months, respectively; P = 0.074). These data suggest that thalidomide-based regimens are as effective as bortezomib-based regimens in elderly patients with MM who are CRBN(+). Thus, CRBN positivity, by IHC staining, may be useful in deciding appropriate treatment options in elderly patients with MM.

LeBlanc R, Hollmann S, Tay J
Canadian cost analysis comparing maintenance therapy with bortezomib versus lenalidomide for patients with multiple myeloma post autologous stem cell transplant.
J Popul Ther Clin Pharmacol. 2016; 23(1):e103-13 [PubMed] Related Publications
BACKGROUND: Multiple myeloma (MM) is a cancer caused by malignant plasma cells that accumulate mostly in the bone marrow. In Canada, the most common maintenance therapy options after autologous stem cell transplant (ASCT) are bortezomib and lenalidomide.
OBJECTIVE: To determine the incremental cost between bortezomib and lenalidomide maintenance therapies for patients with MM post ASCT.
METHODS: Analyses were conducted to compare the annual costs of bortezomib and lenalidomide maintenance treatments for patients with MM post ASCT in Canada. The base case analysis included the acquisition costs of the drugs and administration costs. Additional analyses were conducted which considered the cost of experiencing adverse events (AEs) and the cost of treating second primary malignancies (SPMs).
RESULTS: In the Canadian healthcare system, the total annual per patient cost was $33,967 for bortezomib maintenance therapy versus $131,765 for lenalidomide maintenance therapy. One-way sensitivity analyses demonstrated that both AEs and SPMs had little impact on the incremental cost, and that differences between the two maintenance therapies were mainly due to the acquisition costs of the drugs.
CONCLUSIONS: Bortezomib is significantly less costly than lenalidomide, and is an economically reasonable maintenance treatment option for patients with MM post ASCT.

Liang L, Zhao M, Zhu YC, et al.
Efficacy of lenalidomide in relapsed/refractory chronic lymphocytic leukemia patient: a systematic review and meta-analysis.
Ann Hematol. 2016; 95(9):1473-82 [PubMed] Related Publications
Therapeutic results of relapsed/refractory chronic lymphocytic leukemia (CLL) are very disappointing at present. Lenalidomide has been proved to be effective for relapsed/refractory CLL as a single agent or in combination with various chemo-immunotherapeutic regimens. However, current clinical experience in its usage is still limited. Because of existing considerable variability in different studies, a systematic review and meta-analysis was conducted to describe overall response rate (ORR) of lenalidomide in patients with relapsed/refractory CLL. Pooled estimate of cumulative prevalence of total ORR was 42.23 % (95 % confidence interval [CI], 32.49-52.61 %), while pooled ORR in regimen with lenalidomide plus anti-CD20 monoclonal antibody (mAbs) and lenalidomide mono-therapy were 60.01 % (95 % CI, 53.86-65.86 %) and 24.38 % (95 % CI, 16.15-35.06 %), respectively. There was no significant difference between L + R (lenalidomide plus rituximab) group and L + O (lenalidomide plus ofatumumab) group, with pooled ORR of 66.38 % (95 % CI, 57.96-73.87 %) and 57.40 % (95 % CI, 46.46-67.65 %), respectively. When co-administrated with anti-CD20 mAbs, dosage of lenalidomide was not the key factor of ORR in combination therapy. Pooled ORR of patient with high-risk cytogenetic in L + anti-CD20 mAbs group was 56.74 % (95 % CI, 45.53-67.30 %). In comparison with patients without high-risk cytogenetic receiving the same treatment regimen, no significant difference was observed, with relative risk (RR) of 0.87 (95 % CI 0.68-1.11). Our finding demonstrated that lenalidomide plus anti-CD20 mAbs could be an efficient therapy regimen for relapsed/refractory CLL patients, especially for those with high-risk cytogenetic factor.

Touzeau C, Moreau P
Pomalidomide in the management of relapsed multiple myeloma.
Future Oncol. 2016; 12(17):1975-83 [PubMed] Related Publications
Pomalidomide, a very potent member of the immunomodulatory drug family, is considered a standard of care for patients with relapsed and refractory myeloma, who have previously been treated with bortezomib and lenalidomide. Pomalidomide induces both direct myeloma cell death, and indirect antimyeloma response through its impact on the microenvironment (modulation of immune response, inhibition of angiogenesis, inhibition of bone resorption). Pomalidomide in combination with dexamethasone is an approved regimen in Europe and USA based on the results of a Phase III randomized trial. In order to improve response rate and patient survival, pomalidomide is currently being assessed in triplet combinations with other antimyeloma agents. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients.

Kreiniz N, Khateeb A, Gino-Moor S, et al.
Acute Renal Failure Associated with Lenalidomide Treatment in Multiple Myeloma: A Rare Occurrence?
Anticancer Res. 2016; 36(6):2889-92 [PubMed] Related Publications
Renal failure is a frequent complication of multiple myeloma (MM). Recently, the combination of lenalidomide-dexamethasone has become one of the cornerstone regimens for the treatment of MM. Impairment of renal function exacerbation is a rare, but potential, complication of lenalidomide therapy in plasma cell dyscrasias. We present two patients who developed exacerbation of renal function during their first cycle of therapy with lenalidomide. In the first case, we present a 76-year-old-male with MM and impaired renal function, who declined two weeks after initiation of second-line therapy with lenalidomide. His renal functions improved after discontinuation of lenalidomide and with supportive care. In the second case, we describe a 61-year-old woman who was started on lenalidomide for relapsed MM and admitted to intensive care unit three weeks later due to severe renal failure. Despite intensive supportive care, her renal function deteriorated even more and she died. We conclude that renal failure is an uncommon, but serious, potential complication of lenalidomide therapy in plasma cell dyscrasias, particularly MM. Close monitoring of renal function is clearly recommended during this treatment.

Itoh T
Multiple myeloma developing in a patient with immune thrombocytopenia.
Rinsho Ketsueki. 2016; 57(5):630-3 [PubMed] Related Publications
A female diagnosed as having immune thrombocytopenic purpura (ITP) was found to be simultaneously suffering from monoclonal gammopathy of undetermined significance (IgGλ). Urine Bence-Jones protein was negative. During the course, plasma cells accounted for 21.6% of the bone marrow. Based on these clinical features in our case, the second disease was diagnosed as multiple myeloma (MM). Both ITP and MM were successfully treated with corticosteroids, bortezomib, lenalidomide with dexamethasone and eltrombopag olamine. MM with ITP may show the following features: 1) the great majority are IgG types, 2) λ chain types show marked light chain predominance when these two diseases appear simultaneously, 3) κ chain types are predominant in the cases with MM followed by ITP, and 4) MM cases with ITP are more often seen in Japan.

Uchida T, Inoue M, Hua J, Hagihara M
Achievement of hemodialysis discontinuation with lenalidomide and dexamethasone therapy in a refractory BJP-type multiple myeloma patient.
Rinsho Ketsueki. 2016; 57(5):613-7 [PubMed] Related Publications
A 63-year-old man with Bence Jones-κ multiple myeloma (MM) presented with renal impairment. First, we administered a bortezomib-containing regimen which is considered to be the first choice among therapeutic approaches for MM patients with renal failure. However, his condition was refractory to bortezomib, and the renal dysfunction worsened (creatinine 12.55mg/dl) necessitating the initiation of hemodialysis. Subsequently, we administered an adjusted dose of lenalidomide and dexamethasone. Dialysis could be discontinued after 3 cycles of lenalidomide therapy. After 4 cycles, he achieved a stringent complete response (sCR) with the creatinine level at 1.85mg/dl. This case suggests lenalidomide to be an effective drug for patients with multiple myeloma and renal impairment refractory to treatment with bortezomib.

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