ALBERT

Description: Introduction: Lenalidomide is approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients and used widely in practice for non-del(5q) MDS patients with anemia. Recently, subsequent primary malignancies (SPM) have been reported to be associated with lenalidomide treatment of multiple myeloma, and it is unclear if this observation is disease-specific or more broadly related to a particular therapy. The SPM risk in lenalidomide-treated MDS patients has not been evaluated previously. To investigate whether lenalidomide is associated with an increased risk of SPM in MDS patients, we conducted a large, retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC). Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC's enterprise wide data warehouse which combined clinical information from a variety of sources, including the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 41 cases of SPM were verified by two hematologists for confirmation of both the baseline MDS diagnosis and the SPM diagnosis. SPM incidence rates were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the age-adjusted association between lenalidomide treatment and SPM in the overall cohort, and stratified by lower versus higher risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all SPM cases in addition to a sample of MDS patients from the baseline cohort who had not developed SPM; these controls were matched to cases 1:1 on age at MDS diagnosis (

Description: INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

Description: Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts. Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff). Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM. Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated. Table 1. Incidence rates (per 100 PYa) by treatment exposure IR per 100 PY (95% CI) SPM LEN-Exposed (n = 977) Non–LEN Exposed (n = 466) Invasive 0.85 (0.61-1.19) 1.16 (0.72-1.86) Hematologic 0.17 (0.08-0.36) 0.47 (0.22-0.99) Solid tumor 0.67 (0.46-0.98) 0.68 (0.36-1.26) NMSC 0.50 (0.32-0.77) 0.41 (0.18-0.91) a PY of exposure is the sum of exposure of all pts. Disclosures Rifkin: Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees.

Description: Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

Description: Introduction: The incidence of subsequent primary malignancies (SPM) associated with lenalidomide treatment of multiple myeloma (MM) outside the context of maintenance therapy post-melphalan is unknown. Three clinical trials reported modest, statistically significant increased risks of SPM associated with lenalidomide treatment in MM patients (Palumbo et al, N Engl J Med, 2012; Attal et al, N Engl J Med, 2012; McCarthy et al, N Engl J Med, 2012). Although these randomized trials are well controlled for potential confounders, they represent a unique population of patients and a specific juxtaposition of lenalidomide use with melphalan; as such, their results are not necessarily generalizable to the broader MM patient population. To investigate whether lenalidomide is associated with an increased risk of SPM in MM patients within a clinical setting in the United States, we conducted a retrospective cohort study of 1,653 MM patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC) in Tampa, FL. Methods: Patients treated for MM at MCC from 2004-2012 were identified through Moffitt's enterprise wide data warehouse combining clinical information from several sources, including the Cancer Registry, electronic medical records and disease-specific databases. Among 1,653 MM patients, ages 18 and older, 51 cases of SPM were verified by two hematologists for confirmation of MM and SPM diagnoses. Incidence rates and 95% confidence intervals (CI) for SPM were estimated using a Poisson distribution. Cox proportional hazards ratios (HR) and 95% CIs were calculated to estimate the age-adjusted association between lenalidomide treatment and SPM in the overall cohort, and stratified by ISS. Additional details on lenalidomide treatment and potential confounders were obtained through medical chart abstraction for SPM cases and a subset of MM patients from the baseline cohort who had not developed SPM; these controls were matched to cases 2:1 on age at MM diagnosis (+/- 5 years), gender, follow-up time (+/- 6 months), and date of diagnosis (+/- 1 year). Associations between lenalidomide and SPM in the nested case-control analysis were estimated using odds ratios (OR) and 95% CIs adjusted for age at MM diagnosis, bone marrow transplantation, creatinine levels and personal history of cancer. Results: Overall, 1,653 MM patients were followed for an average of 40 months, including patients treated with (n=846) or without (n=807) lenalidomide. Incident SPMs were observed for 15 patients treated with lenalidomide (0.55 per 100 person-years) and 36 patients treated without lenalidomide (1.27 per 100 person-years), corresponding to an HR of 0.44 (95% CI=0.24-0.80) (Figure 1). Of the 51 SPMs observed, 37 were solid tumors comprising 14 different types, including 9 and 28 in the lenalidomide and no lenalidomide groups, respectively (HR=0.55, 95% CI=0.15-0.69). Of the 14 hematological SPMs observed, 8 were in the lenalidomide group versus 6 in the no lenalidomide group (HR=0.90, 95%CI = 0.31-2.63). Similar associations between lenalidomide and SPM were observed for MM patients with ISS = 1 (HR=0.26, 95% CI=0.06-1.21) and for MM patients with ISS = 2 or 3 (HR=0.20, 95% CI=0.02-1.62). Of the 51 SPM cases and 102 matched controls included in the nested case-control analysis, 33.3% and 74.5% were treated with lenalidomide, respectively (adjusted OR=0.03, 95% CI=0.002-0.34). Similar associations were observed for lenalidomide given as part of first line treatment versus subsequent treatment, and for lenalidomide given alone or in combination with other drugs. (8 cases and 46 controls received melphalan in addition to lenalidomide.) There was no association between lenalidomide and SPM among those treated for 〉9.1 months (OR=0.05, 95% CI=0.01-0.43), the median treatment duration among controls. Conclusion: Lenalidomide treatment was not associated with an increased risk of SPM among a large cohort of MM patients. It is important to note that in this clinical setting (in 2004-2012) the use of lenalidomide in combination with melphalan and in the maintenance setting was a rare event. This may be a critical factor in the contrast between the results of this study and in the increase in SPMs reported in randomized clinical trials. Figure 1: Incidence of SPM among patients treated for MM with or without lenalidomide, Moffitt Cancer Center, 2004-2012 Figure 1:. Incidence of SPM among patients treated for MM with or without lenalidomide, Moffitt Cancer Center, 2004-2012 Disclosures Rollison: Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide given as treatment for non-del(5q) MDS and/or multiple myeloma . Komrokji:Celgene: Consultancy, Research Funding. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fulp:Celgene, Inc.: Research Funding. Fisher:Celgene, Inc: Research Funding. Baz:Celgene: Research Funding; BMS: Research Funding; Millenium: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding. Olesnyckyj:Celgene: Employment, stock options Other. Kenvin:Celgene: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. Dalton:Celgene, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Shain:L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau; Envision/Celgene: Research Funding, Speakers Bureau.

Description: Background: Lenalidomide (Revlimid®) in combination with dexamethasone was approved in the US on June 29, 2006 for the treatment of subjects with multiple myeloma who had received at least one prior therapy. On February 28, 2005 based upon a positive interim analysis of two pivotal placebo-controlled Phase III studies, an independent Data Safety Monitoring Board recommended the studies be unblinded and all subjects in both studies be given access to lenalidomide. In April 2005, the FDA in association with myeloma patient advocacy groups requested Celgene establish an expanded access program to make lenalidomide plus dexamethasone available to subjects with relapsed or refractory multiple myeloma while the treatment was awaiting approval. Aim: To provide lenalidomide to multiple myeloma subjects with a high likelihood of benefit and to obtain additional safety data. Methods: Subjects with relapsed or refractory multiple myeloma that received at least 1 prior therapy were eligible. Subjects received 25 mg lenalidomide plus high-dose dexamethasone in 4-week cycles until disease progression was documented, study drug was discontinued, or lenalidomide became commercially available for this indication. Results: Between September 8, 2005 and July 25, 2006, approximately 1400 subjects in the US and Canada were enrolled into the study. A data snapshot taken March 17, 2006 demonstrated that 746 subjects had been enrolled, median age was 63 years, 60% were male, and 66.5% had Stage III disease. Median time on study was 7.1 weeks (0.1–24.4) and median daily dose was 20.5 mg. At least one Grade 3 or 4 adverse event was reported in 261 (35%) of the 746 subjects. Most commonly reported Grade 3–4 events were neutropenia (7.9% of subjects), thrombocytopenia (6.0%), fatigue (3.6%), anemia (3.5%), pneumonia (3.1%) and hyperglycemia (2.0%). These most commonly reported Grade 3–4 adverse events were the same as those found in the previous pivotal studies, however, their frequencies of occurrence were lower in the current study probably due to ongoing data collection and differences in study maturity. Likewise, the most commonly reported adverse events (all grades) were the same as those reported in the two previous pivotal studies. Conclusion: Preliminary data from this expanded access program in over 1400 subjects with multiple myeloma are consistent with results from two earlier Phase III pivotal studies. The EAP of lenalidomide plus dexamethasone in multiple myeloma represents a model of how government, advocacy groups, healthcare providers and industry can work together to quickly provide treatment to subjects in need while a clearly active treatment regimen is awaiting approval.