Lenalidomide-containing Regimens Research Articles

Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.

TPS7576 Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .

Hepatitis B Virus Infection Status and Reactivation Analysis in Multiple Myeloma in China

Background: China is a highly endemic area for Hepatitis B virus (HBV) infection and HBV reactivation is an event of concern in treating patients with hematologic malignancy. However, there were very few reports regarding HBV reactivation in patients with multiple myeloma (MM) in China. Since the approval of novel agents, especially immunotherapy such as monoclonal antibody and chimeric antigen T cell immunotherapy, the risk of HBV reactivation has increased. Therefore, the study aimed to evaluate the HBV infection status in MM and explore the incidence and risk factors of HBV reactivation in MM patients in China. Methods: Newly diagnosed MM patients with available serologic assays for HBV infection were retrospectively enrolled between June 30, 2008 and December 30, 2022 in West China Hospital, Sichuan University. Demographic and clinical data were obtained from the “HemaTank” Chinese Multiple Myeloma Database (HCMMD). Meanwhile, patients diagnosed with Waldenstrom Macroglobulinemia (WM) at the same time were enrolled as the control group. HBV reactivation was defined as the occurrence of one of the following: ≥ 2 log increase in HBV-DNA levels from baseline level, detection of HBV-DNA with level > 100 IU/ml in a person with undetectable HBV DNA at baseline or HBsAg-negative becoming positive. The penalized maximum likelihood logistic regression for rare events was applied to identify independent risk factors related to HBV reactivation. Results: The study recruited 3040 MM patients with a median age of 62 (range 14~98) and 240 WM patients with a median age of 63 (range 25~92). The HBsAg-positive rates were similar between MM and WM (9.4% vs 10.8%, P=0.49), but both the HBcAb-positive rates and HBeAb-positive rates in WM were significantly higher than MM (76.3% vs 60.7%, P<0.001; 37.5% vs 25.1%, P<0.001). The analysis of co-expression of HBV markers shows that the prevalence of HBsAg-/Anti-HBs+/anti-HBC- in MM was significantly higher than WM (16.7% vs 8.3%, P<0.001) and HBsAg-/Anti-HBs-/anti-HBC+ in MM was significantly lower than WM (18.3% vs 27.1%, P<0.001). However, he prevalence of HBsAg+/ HBeAg+/anti-HBC+ and HBsAg+/ anti-HBeAb+/anti-HBC+ were similar between MM and WM (0.5% vs 1.3%, P=0.158; 8.6% vs 8.8%, P=0.503). The baseline characteristics of HBsAg-positive MM and HBsAg-negative MM were summarized in Table 1. The rates of HBsAg-positive MM were significantly increased in young male patients (P<0.05). The level of ALT and AST, and the incidence of HBV reactivation, liver cirrhosis and pulmonary disease were significantly higher in HBsAg-positive MM than in HBsAg-negative MM (P<0.05). Of the 2147 MM patients who have received at least one line of chemotherapy (Table 1), 924 (43%) MM patients received bortezomib-containing or lenalidomide-containing regimens as the frontline therapy, while only 21 (1.0%) received a daratumumab-containing regimen as the frontline therapy. During hospital-documented follow-up visits, 26 (1.21%) MM patients have experienced HBV reactivation. According to the multivariate analysis of risk factors for HBV reactivation in MM, liver cirrhosis (OR 8.63, 95%CI 2.95-25.24, P<0.001), autologous stem cell transplantation (OR 6.03, 95%CI 2.47-14.72, P<0.001) and HBsAg-positive (OR 14.45, 95%CI 6.50-32.14, P<0.001) were independent risk factors associated with high prevalence of HBV reactivation. The ROC curve of the model integrating the three factors is shown in Figure 1, and the AUC was 0.8584. Conclusions: Among Chinese MM patients with multiple myeloma, a high proportion of MM patients presented with resolved hepatitis B virus infection, whereas HBV reactivation was pretty rare. However, long-term HBV DNA levels monitoring is still needed for MM patients at high risk for HBV reactivation.

Generic Lenalidomide Rivelime Versus Brand-name Revlimid® in the Treatment of Relapsed/Refractory Multiple Myeloma: A Retrospective Single-center Experience on Efficacy, Safety and Survival Outcome.

This study aimed to compare use of original brand-name lenalidomide (Revlimid®) vs. generic equivalent (Rivelime®) in terms of efficacy, safety and survival outcome in patients with relapsed/refractory multiple myeloma (RRMM) PATIENTS AND METHODS: A total of 184 patients RRMM (median age: 62 years, 60.9% were males) who received singlet, doublet or triplet lenalidomide-containing regimens including either Revlimid® (n=74) or Rivelime® (n=110) were included in this study. Treatment response was based on evaluation of objective response to treatment (ORR) including the sum of patients who achieved partial response (PR), very good partial responses (VGPR) or complete response (CR) to therapy. Progression-free survival (PFS), overall survival (OS) and safety data were also recorded. Revlimid® and Rivelime® groups were similar in terms of ORR (54.1 vs. 60.0%), CR (22.5 vs. 28.8%), VGPR (55.0 vs. 50.0%) and PR (22.5 vs. 21.2%) rates. Median (SE) PFS time were similar between Rivelime® vs. Revlimid® treated patients who were in the 2nd line (30.3(3.8) vs. 22.7(7.0) months, p=0.827) or 3rd line of therapy (38.1(12.1) vs. 20.1(0.9) months, p=0.147) at lenalidomide initiation. Two groups also had similar OS rate (83.8 vs. 73.6%) and OS time (mean 122.3 vs. 123.5 months). Side effects were manageable in both groups. In conclusion, replacing Revlimid® with its generic version Rivelime® in singlet, doublet or triplet lenalidomide containing RRMM regimens seems not to compromise the efficacy of treatment, and to yield a similarly improved response rates and survival outcome and no additional toxic effects, enabling a long-term therapy.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR=2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR=2.2, 95% CI=1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR=2.61, CI=1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Lenalidomide Dosing and Outcomes in Transplant-Ineligible Patients with Newly-Diagnosed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Lenalidomide Dosing and Outcomes in Transplant-Ineligible Patients with Newly-Diagnosed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Efficacy and Safety of Pomalidomide As a Replacement Therapy for Lenalidomide for Relapsed/Refractory Multiple Myeloma Patients Refractory to a Lenalidomide-Containing Combination Regimen

IntroductionPomalidomide (POM) is an immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) previously treated with bortezomib and lenalidomide. POM in combination with dexamethasone has been shown to overcome resistance and to be effective not only in RRMM pts but also in high risk myeloma cases. In this trial, we are evaluating the efficacy, safety and tolerability of POM replacing lenalidomide for pts who were refractory to a lenalidomide and steroid-containing regimen that includes at least one other agent.MethodsThis is a multicenter, open-label and non-randomized study. MM pts who were refractory to a combination regimen containing lenalidomide, steroids and at least one other agent were treated with the same regimen except POM replaced lenalidomide. For regimens containing bortezomib, carfilzomib, clarithromycin, cyclophosphamide, and/or pegylated liposomal doxorubicin, pts received 4 mg of POM from the beginning of the trial. Patients who had failed regimens containing ixazomib, elotuzumab or daratumumab for which the MTD of POM was unknown underwent intra-patient dose escalation from a POM dose of 2, 3 and 4 mg during Cycles 1, 2 and 3, respectively. POM was administered daily on days 1-21 of a 28-day cycle for a maximum of 8 cycles whereas the other drugs were administered using the same schedule(s), dose(s) and drug combination as the last lenalidomide-containing regimen that the patient received and failed. The planned enrollment for the study is 45 pts.ResultsTo date, a total of 32 pts have been enrolled. All pts have completed at least one full cycle of treatment. Currently, 11 pts are still active and 21 pts have discontinued treatment. The median age of all pts was 70 years (range, 52-81 years), and 20 (64%) were males. Pts received a median of 3 prior treatments (range, 1-7). The median follow-up time for all pts is 5.3 months (range, 0.9-8.1). Of the evaluable pts, 16 (50%) and 16 (50%) received 2 mg and 4 mg as their starting dose of POM, respectively. Of the 16 pts that received 4 mg of POM, 6 (38%), 8 (50%) and 2 (12%) were on bortezomib, clarithromycin, and carfilzomib-containing regimens, respectively. For thee 16 pts with the starting dose of 2 mg of POM, 13 (81%), 2 (13%) and 1 (6%) were on elotuzumab, daratumumab and ixazomib-containing treatments, respectively.Among all 32 evaluable pts, four (12.5%) pts achieved PR or better (1=CR, 1=PR and 2=VGPR), four (12.5%) pts achieved MR, 15 (47%) pts showed stable disease (SD), while 9 (28%) pts exhibited disease progression.At the time of data cutoff, the overall response (ORR) and clinical benefit rates (CBR) were 12.5% and 25%, respectively. ORR and CBR are expected to improve with further follow up among patients who have been recently enrolled on this trial. The median progression free survival was 7.6 months. Common ≥ Grade 3 adverse events were neutropenia (10%), hypomania (4%) and leukopenia (4%).ConclusionsWe show thatPOM replacement for lenalidomide among RRMM pts who are refractory to a lenalidomide and steroid-containing regimen that includes at least one other agent achieves clinical activity in some patients. DisclosuresBerenson:Incyte: Consultancy, Research Funding; OncoTracker, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Vescio:Celgene: Speakers Bureau.

Patients Responding to Any First Line Therapy for Multiple Myeloma Should Proceed to Autologous Stem Cell Transplantation Instead of Receiving Second Line Therapy to Deepen Response

Background: The current standard of care for transplant eligible patients with multiple myeloma, usually involves induction treatment with dexamethasone, a proteasome inhibitor and/or lenalidomide followed by autologous stem cell transplantation (ASCT). The optimal pre-transplant regimen and the extent to which we should try to deepen the pre-transplant remission remains undetermined. We therefore reviewed 496 patients with multiple myeloma who received ASCT at our institution with the goal of assessing predictors of outcome.Methods: 496 patient received 596 transplants between January 2005 and December 2015. The median age was 61 years (range 39 - 84), 58% were male and 26% had high risk features defined by cytogenetics, FISH and/or gene expression profiling (GEP). All patients received dexamethasone as part of initial myeloma therapy, 426 patients (86%) received a bortezomib-containing regimen, 347 patients (70%) received a lenalidomide-containing regimen, 302 patients (61%) received both bortezomib and lenalidomide, and 10 patients (2%) received a carfilzomib-containing regimen. A total of 25 patients did not receive lenalidomide, bortezomib or carfilzomib. The median time from diagnosis to transplantation was 7 months. The median follow-up time was 52.2 months (0.4 to 139.6). We analyzed the impact of the following on OS: age, disease type, stage and risk, pre-transplant dialysis, induction regimen, mobilization regimen, time to transplantation, transplantation regimen, CD34+ cell dose collected and administered, engraftment syndrome, response pre and post transplantation, and number of transplants.Results: We saw no difference in OS between patients receiving induction with lenalidomide, bortezomib or carfilzomib (either alone or in any combination) vs. no proteasome inhibitor or lenalidomide (p=0.4599). Having progressive disease at the time of transplantation predicted for a poorer OS (p=0.002) but all other responses (CR, VGPR, PR, SD) were not statistically different. These results apply to the entire cohort and individually for the low risk and high risk subsets. 11 patients had PD after first line therapy, of which only 1 was still in PD at the time of ASCT after receiving subsequent lines of therapy. However, of the 437 patients who were not in PD after first line therapy and continued treatment to deepen response, 29 patients evolved to PD at the time of transplantation. In multivariate analysis age > 60 (p=0.0059), high risk disease (p<0.0001), Mel 200 mg/m2 (p=0.0001) and PD response pre ASCT (p=0.0026) impacted OS.Conclusion: There was no impact on OS by the use of lenalidomide, bortezomib or carfilzomib pre-transplantation. Response depth prior to transplantation, with the exception of patients with PD, had no impact on OS. In our cohort, 7% of patients who were in CR, VGPR, PR or SD after first line therapy and received further lines of therapy to deepen response, evolved to PD prior ASCT. Since PD is determined to be a predictor of adverse outcome, our data supports continuing to second-line therapy only for patients in PD after first line. All other patients should proceed to mobilization and ASCT. [Display omitted] DisclosuresMcKiernan:Novartis: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Richter:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Goy:Genentech: Research Funding; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prolonged Lenalidomide Therapy Does Not Impact Autologous Peripheral Blood Stem Cell Mobilization and Collection in Multiple Myeloma Patients: A Single-Center Retrospective Analysis

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.

Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse.

Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P=0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6months (95% CI: 14·7-25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66-86%) and 74% (95% CI: 64-85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.

Comprehensive Geriatric Assessment in Consecutive Newly-Diagnosed Elderly Multiple Myeloma Patients in China: A Multicentered, Prospective, Non-Interventional Study

Background: Multiple Myeloma (MM) is a disease of the elderly, whose prognoses are highly heterogeneous. Hence International Myeloma Working Group (IMWG) proposed geriatric assessment (GA) in 2015, including daily activity and comorbidity status, to better discriminate between fit and frail patients (Palumbo et al, 2015). However, IMWG recruited patients from clinical trials instead of real world practices. Therefore we studied GA in elderly MM patients consecutively in China, along with other perspectives which are known to be problematic in elderly population that were previously left unnoticed, such as nutrition status, risk of cognitive impairment, risk of depression, and quality of life. Aim: Our study centers on the feasibility to perform a more comprehensive geriatric assessment (cGA) in elderly MM patients, current cGA status in elderly MM patients in China, and the cGA difference between Chinese patients and patients in the IMWG study. Method: From August 2017 to April 2019, we continuously recruited 336 newly diagnosed elderly (age ≥ 65) MM patients from 21 centers in China. cGA was performed at diagnosis, after treatment cycle 1, after cycle 4, and 1 year after treatment. cGA includes physical conditions (ECOG), activities of daily living (ADL), instrumental ADL (IADL), mini-nutritional assessment (MNA-SF), geriatric depression scale (GDS), mini-mental state examination (MMSE), quality of life (SF-36) and Charlson comorbidity index (CCI). Staging was assessed at baseline (International Staging System (ISS) &amp; Revised ISS) and hematological responses were evaluated along with each cGA timepoint. Results: We pool-analyzed data of 336 newly-diagnosed elderly MM patients. The median age was 70 (range 65-88) and 25.5% of patients were older than 75 years. 336 (100%) patients were able to complete cGA, and median assessment time was 40 minutes (range 20-70). Upon diagnosis, only 34% and 37.5% of patients had full ADL and IADL respectively. 38.5% of patients had moderate to high risk of depression (GDS ≥ 6). 13.2% of patients were malnourished (MNA-SF ≤ 7), while 46.3% of patients were at risk of malnutrition (8 ≤ MNA-SF ≤ 11). 41% of patients had at least one comorbidity (CCI ≥ 1). 45.7% of patients had moderate to intermediate risk of cognitive impairment (MMSE ≤ 26). Grouping by IMWG-GA index, our study identified 59.9% patients in frail group (vs 39% in IMWG study), 15.8% in intermediate (vs 31% in IMWG) and 24.3% in fit (vs 30% in IMWG). 69% of patients received proteasome inhibitor-containing regimens and 20.7% of patients received lenalidomide-containing regimens. Best hematological responses in fit and intermediate groups were better than responses in frail group (≥ PR rate: 88.5% in fit, 94.4% in intermediate vs 77.5% in frail). Median follow up time was 10 months. To date, 215 (64%) patients have finished the cGA after cycle 1; 164 (48.8%) patients have finished the cGA after cycle 4; 91 (27.1%) patients has finished all 4 planned cGA and improvements in cGA were observed in the majority of these patients. Conclusion: Our study showed significant CGA heterogeneity in elderly MM patients. Even in the IMWG-GA "fit" group, nutrition, depression and cognitive impairment remain problems. Frail patients took up a larger proportion in Chinese elderly MM patients compared to IMWG study. Our study strongly justifies the necessity for cGA in elderly patients with MM, more so in the real world MM patients than in the clinical trials. Disclosures No relevant conflicts of interest to declare.

Prolonged Lenalidomide Therapy in Multiple Myeloma Patients Does Not Impact Autologous PBSC Mobilization: A Single Center Retrospective Analysis

Background:Autologous stem cell transplantation (ASCT) is the standard of care for eligible patients with newly diagnosed multiple myeloma (MM). Typically, patients receive several cycles of induction therapy to achieve appropriate cytoreduction prior to ASCT. Since the introduction of lenalidomide into induction therapy, there have been conflicting reports about its impact on subsequent autologous peripheral blood stem cell (PBSC) mobilization. Early reports showed a trend of patients failing PBSC mobilization and collection after lenalidomide when granulocyte colony stimulating factor (GCSF) was employed as a single agent. More recent reports suggested that using chemotherapy in combination with growth factors including plerixafor can overcome failures of mobilization. To address these conflicting reports, we evaluated the impact of prior lenalidomide in a large cohort of MM patients undergoing mobilization and collection at a tertiary stem cell transplant center.Methods:The primary aim of this study was to identify the impact of prolonged lenalidomide therapy on mobilization of autologous PBSCs. We examined all patients 18 years of age and older, with a confirmed diagnosis of MM who attempted stem cell mobilization and collection between January 2012 and July 2015 at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Collected information included: demographics, staging according to the International Staging System, results of cytogenetics by conventional karyotype or FISH, prior treatments, number of cycles of lenalidomide received, mobilization method, receipt of plerixafor, number of stem cells collected, days of collection, and receipt of prior radiation therapy. Patients were also scored as successful or failed mobilization (defined as collecting < 2.5 x 106 CD34+ cells/kg). The patients were categorized into 3 groups (based on our recommendations for induction duration ≤ 6 cycles) for analysis: 1) Those patients with prior receipt of > 6 cycles lenalidomide, 2) Those patients with prior receipt of ≤ 6 cycles of lenalidomide, and 3) Patients without prior lenalidomide exposure.Results:We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 received > 6 cycles of lenalidomide (median of 8 cycles, range of 7 - 25), 156 received ≤ 6 cycles of lenalidomide (median of 4 cycles, range 1 - 6), and 106 received no lenalidomide (Table 1). Similar proportions of patients in each group of lenalidomide exposure received chemotherapy mobilization, chemotherapy with plerixafor, GCSF alone, and GCSF with plerixafor. There was no significant difference in receipt of plerixafor between these groups (p=0.41). A second mobilization attempt was made in 1 patient (2.9%) who received > 6 cycles of lenalidomide, 1.9% of patients who received ≤ 6 cycles of lenalidomide, and 0% of patients with no prior lenalidomide exposure. Only one patient, who had not received lenalidomide previously, failed to collect. In a multivariate linear regression analysis for association between receipt of > 6 cycles of lenalidomide with total number of PBSCs collected, with other covariates including prior radiation therapy, age, and number of prior regimens received, we did not observe a significant effect (regression coefficient of -3.37, p=0.166). We then examined whether receiving > 6 cycles of lenalidomide was associated with days of stem cell collection in a multivariate regression; other covariates included prior radiation therapy, age, mobilization regimen, and number of prior regimens, and did not see any association (regression coefficient -0.053, p=0.697).Discussion:In this retrospective analysis of MM patients undergoing autologous PBSC mobilization at a single center, we show that prior lenalidomide exposure did not meaningfully impact the total number of PBSC collected or the number of days of apheresis after controlling for clinically relevant features in a multivariate model. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response before transplant should not adversely impact the ability to collect PBSC, and that arbitrarily limiting lenalidomide use pre-mobilization does not appear warranted. The extensive use of chemotherapy with G-CSF and plerixafor for mobilization at our center may account in part for these findings. [Display omitted] DisclosuresCowan:Abbvie: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Sanofi: Research Funding. Becker:GlycoMimetics: Research Funding. Gopal:Incyte: Consultancy; Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; BMS: Research Funding; Teva: Research Funding; Brim: Consultancy; Asana: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Holmberg:Millenium-Takeda: Research Funding; Sanofi-Genzyme: Research Funding; Seattle Genetics: Research Funding; Merck Sharpe: Research Funding; Jazz Pharmaceuticals: Consultancy; NCCN: Consultancy.

Venous thromboembolism in patients with B-cell non-Hodgkin lymphoma treated with lenalidomide: a systematic review and meta-analysis

AbstractLenalidomide is associated with increased risk of thromboembolism (VTE) in patients with multiple myeloma. This risk has not previously been defined in B-cell non-Hodgkin lymphoma (NHL), for which lenalidomide is also an active agent. We conducted a systematic literature search in Ovid MEDLINE (1946 to February 2017), Ovid EMBASE (1974 to February 2017), The Cochrane Library (Wiley), and Web of Science Core Collection for prospective studies evaluating lenalidomide-containing regimens in B-cell NHL with adequate reporting of patient characteristics, total cycles received, and safety data including VTE rates. The primary outcome was VTE events per 100 patient-cycles by meta-analysis using random-effects models. Our literature search identified 1719 citations; 28 articles were included. For all patients with B-cell NHL receiving lenalidomide, the rate of VTE per 100 patient-cycles was 0.77 (95% confidence interval [CI], 0.48-1.12; I2, 67%). The rate for single-agent lenalidomide was 1.09 events per 100 patient-cycles (95% CI, 0.49-1.94; I2, 76%), the rate for lenalidomide plus biologics was 0.49 (95% CI, 0.17-0.97; I2, 59%), and the rate for lenalidomide plus chemotherapy was 0.89 (95% CI, 0.39-1.60; I2, 57%). Rate of VTE events in B-cell NHL patients treated with lenalidomide in clinical trials is similar to the rate in multiple myeloma. The VTE rate appears to be lowest for lenalidomide combined with a biologic compared with single-agent lenalidomide or its combination with chemotherapy. This protocol was registered at www.crd.york.ac.uk/prospero/ as #CRD42017056042.

Efficacy and safety of pomalidomide as a replacement therapy for lenalidomide for relapsed/refractory multiple myeloma patients refractory to a lenalidomide-containing combination regimen.

e20012Background: Pomalidomide (POM) is a third–generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) previ...

Bortezomib, Cyclophosphamide, Dexamethasone Versus Lenalidomide, Cyclophosphamide, Dexamethasone in Multiple Myeloma Patients at First Relapse

BACKGROUND: Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies for relapsed MM. METHODS: In this open-label, phase III study, we randomized MM patients at first relapse to receive either 9 cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) or lenalidomide-cyclophosphamide-dexamethasone (RCD). The primary endpoint was the achievement of a very good partial response (VGPR) or better at six weeks after 9 treatment cycles. FINDINGS: From March 2011 to February 2015, 155 patients were randomized. The primary endpoint was met by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (p=0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25.5) with RCD, and the 2-year overall survival (OS) was 75% (95% CI: 66%-86%) and 74% (95% CI: 64%-85%), respectively. By subgroup analysis, no differences in PFS were observed in bortezomib and lenalidomide- naive patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of bortezomib and lenalidomide. INTERPRETATION: Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse. Nevertheless, the two drugs have a different safety profile. Clinical Trial Number: This study is registered as EUDRACT 2010- 021557-40. Funding Statement: Associazione Italiana per la Ricerca sul Cancro - AIRC grant IG-10419; Associazione Italiana contro le Leucemie-Linfomi e Mieloma (AIL); Fondazione Adiuvare, Lugano. Declaration of Interests: VM has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb, Amgen. AC has not competing interests. MG has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb. IA has not competing interests. SP has not competing interests. CCarniti SP has not competing interests. FP has received honoraria and travel grants from Janssen and Celgene. FG has not competing interests. RZ has not competing interests. SS has not competing interests. MM has not competing interests. AN has not competing interests. CCrippa has not competing interests. AMC has received honoraria and travel grants from Janssen and Celgene. LB has not competing interests. PC has honoraria from advisory board and speaking fees from Celgene, Janssen, Novartis, Roche, Takeda, Sanofi, Abbvie, Amgen, Gilead, and Klowa Kirin. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees at each study site reviewed and approved the protocol.

Analysis of efficacy and safety of POM as a replacement therapy for lenalidomide for relapsed/refractory multiple myeloma pts refractory to a lenalidomide-containing combination regimen.

e19528 Background: Pomalidomide (POM) is a third –generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) for patients (pts) previously treated with bortezomib and lenalidomide (LEN) and in combination with dexamethasone it has been shown to overcome resistance in RRMM. In this phase 2 trial, we are evaluating the efficacy, safety and tolerability of POM as a replacement therapy for LEN for pts who have progressed receiving a LEN combination regimen. Methods: This is a phase 2, multicenter, open-label and non-randomized study. Pts who have failed a combination regimen containing LEN were treated with POM along with all of the other drugs previously used in the regimen. POM administered orally (dose is determined based on the previous regimen) on days 1-21 of a 28-day cycle, whereas other drugs are administered using the same schedule(s), dose(s) and drug combination as the last LEN-containing regimen that the patient received and failed. The planned enrollment on the study will be 45 pts. Results: To date, a total of 29 pts have been enrolled, 25 pts are evaluable and 12 pts have discontinued treatment. Of the evaluable pts, 9 (36%) and 16 (64%) received 3mg and 4mg of POM, respectively. The median age of all pts was 72 years (range, 52-81), and 17 (68%) were males. Pts have received a median of 3 prior treatments (range, 1-7). The median follow-up time for all pts is 3.1 months (range, 0.2-8.1). Amongst evaluable pts, 5 (23.8%) pts achieved at least a minimal response, 10 (47.6%) pts showed stable disease while 6 (28.6%) pts exhibited disease progression. At the time of data cutoff, only 17 pts have completed more than 1 full cycle of treatment; and, thus, the overall response and clinical benefit rates are fairly low (14.3% and 23.8%, respectively) but expected to improve with further follow up. The median PFS for the cohort was 7.6 months. Common ≥ Gr3 adverse events were neutropenia (8%), hypomania (4%) and leukopenia (4%). Conclusions: We show thatPOM appears to be promising replacement therapy for LEN in RRMM pts who have progressed within receiving a LEN combination regimen.

Effect of Lenalidomide on Hepatitis C Viremia in Cancer Patients: A Case Series

Background: T cells play an important role in controlling hepatitis C virus (HCV) infection. Immunomodulatory drugs affecting T cells such as thalidomide and lenalidomide are used in the treatment of some hematologic cancers (mainly multiple myeloma). Lenalidomide is up to 1000 times more potent than thalidomide in stimulating T cell proliferation, interferon-γ and interleukin-2 production. HCV reactivation (increase of HCV-RNA by at least 1 log10IU/mL) with hepatitis flare after thalidomide therapy was recently reported (Mahale et al., Open Forum Infect Dis. 2015); however, the effect of lenalidomide on HCV-viremia has not been studied yet.Methods: HCV-infected cancer patients treated with lenalidomide at MD Anderson Cancer Center (11/2012-3/2016) were studied. HCV-RNA levels were measured before and after lenalidomide use. Since chronically infected patients have stable HCV-RNA levels that only varies ∼0.5 log10 IU/m, a significant change in HCV viremia was defined as a change of HCV-RNA ≥ 1 log10IU/ml from baseline. Hepatitis flare was defined by an increase of ALT level to ≥ 3 times upper limit of normal (or >170 IU/ml).Results: Five HCV-infected cancer patients treated with lenalidomide were studied. All the patients were males with a median age of 56 years. They had multiple myeloma (n=4) or large B-cell lymphoma (n=1). Four patients had HCV genotype 1 (80%) and 1 had genotype 2 (20%). Two patients (40%) were cirrhotics. The 5 patients studied received 6 different lenalidomide-containing regimens: 2 with lenalidomide monotherapy, 2 lenalidomide + rituximab and 2 lenalidomide + steroids. HCV-RNA levels were measured between week 4 (1, 17%) and week 12 (5, 83%) on lenalidomide treatment. A decrease of HCV-RNA was seen with all the 6 regimens (100%) (Figs 1A, 1B and 1C). Nonetheless, a significant decrease (>1 log10IU/ml) was noted in 4 out of the 6 regimens: two on lenalidomide monotherapy (1.21 and 1.49 log10IU/ml) and two on lenalidomide + rituximab (1.15 and 1.3 log10IU/ml). Hepatitis flare was only seen in one patient treated with lenalidomide + rituximab but he did not have concomitant HCV-RNA changes.Conclusion: Unlike thalidomide,lenalidomide does not cause HCV reactivation. On the contrary, this agent seems to inhibit HCV replication. [Display omitted] DisclosuresSamaniego:Karus Therapeutics: Research Funding. Torres:Pfizer: Other: Scientific advisor; Theravance Biopharma: Other: Scientific advisor; Astellas Pharma: Other: Scientific advisor; Novartis: Other: Scientific advisor; Genentech: Other: Scientific advisor; Janssen Pharmaceuticals: Other: Scientific advisor; Vertex Pharmaceuticals: Other: Scientific advisor, Research Funding; Merck & Co.: Other: Scientific advisor, Research Funding; Gilead Sciences: Other: Scientific advisor, Research Funding.

Effectiveness of Lenalidomide in Patients with Mantle Cell Lymphoma Who Relapsed/Progressed after or Were Refractory/Intolerant to Ibrutinib: The MCL-004 Study

Effectiveness of Lenalidomide in Patients with Mantle Cell Lymphoma Who Relapsed/Progressed after or Were Refractory/Intolerant to Ibrutinib: The MCL-004 Study

Roar: A Phase Ib Trial of Oral Azacitidine (CC-486) in Combination with Lenalidomide and Dexamethasone (Rd) for Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma Who Have Failed a Prior Lenalidomide-Containing Regimen

IntroductionAzacitidine (AZA) is a DNA methyltransferase inhibitor and cytotoxic agent with survival benefits in higher-risk MDS and AML. We have demonstrated that AZA rapidly induces apoptosis of MM cells, and induces synergistic killing when combined with lenalidomide (LEN). This, coupled with development of an oral AZA formulation (CC-486), provides rationale for pursuing this combination in MM. The cereblon [CBRN]-Ikaros/Aiolos-IRF4/c-MYC signalling pathway has been implicated in the mechanism of action of cytotoxicity for IMiD®compounds. This pathway, as well as immune markers (CD8, PD-1) may represent potential biomarkers for predicting outcomes/response to IMiD® compounds.Aims:In R/R myeloma patients who previously failed a LEN-containing regimen: to determine the maximum tolerated dose (MTD) of CC-486 in combination with Rd; to characterise safety/tolerability; to assess efficacy: overall response rate (ORR), progression free survival (PFS), overall survival (OS).To correlate pre-treatment MM protein expression (CRBN, Ikaros, Aiolos, IRF4, c-MYC), as well as whole marrow expression of CD8/PD-1 with response and survival (PFS/OS) in patients receiving CC-489 plus Rd.Methods:Phase Ib, single centre, 3 x 3 dose escalation study. LEN 25mg d1-21 and dexamethasone 40mg d1, 8, 15, 22 of 28 day cycle were combined with escalating doses of CC-489: initial dose 100mg for d1-14, increasing by either 7 days or 50mg/cohort, to a maximum of 200mg d1-21. Dose limiting toxicity (DLT) was assessed during cycle 1. Treatment continued until toxicity/progression.Single- and dual-IHC assays were performed on pre-treatment trephines (Single: CD8, PD-1; Dual: CD138 paired with CRBN, Aiolos, Ikaros, IRF4, c-MYC). In samples with >10% CD138, presence and sub-cellular localisation of each stain was documented, and given an H score: product of % of tumour positive and intensity of staining (0-3). Single CD8 and PD-1 IHC assays were reported as positive cells/mm2. Samples were grouped according to quartiles (Group1: lower quartile, Group2: mid-range, Group3: upper quartile) and analysis was performed using SAS statistical platform v9.4.Results:22 patients commenced therapy (F=10, M=12), median age 67yrs (50-82yrs). Median prior lines of therapy: 5 (2-8), including 16 ASCT and 2 prior allogeneic transplant. All had failed LEN (R/R=18, primary refractory (PrimR)=4), 10/22 received and failed pomalidomide (POM) (R/R=4, PrimR=6). All had received bortezomib (R/R=10, PrimR=10), 18/22 were both bortezomib and LEN refractory.CC-486 dose reached was 200mg d1-21, with no DLTs observed at time of reporting.One patient died due to unrelated causes prior to end cycle 1, therefore was not evaluable for response. ORR (≥PR) was 43% (9/21): 8 PR, 1 VGPR. Of the remaining patients, 2 achieved MR, 5 SD, and 5 PD. (clinical benefit rate (≥MR) = 52%). Median time to best response in patients with ≥MR: 2.5m (1-3.7m). Responses were seen in cohorts: [100mg d1-14 (3PR=3), 100mg d1-21 (VGPR=1, PR=3), 150mg d1-21 (PR=2, MR=2)]. Median time on study: 3m; responders (≥MR): 6.3m (2.5-15m), non-responders: 1.7m (0.9-8m). Median PFS 3m, median OS 15m. One patient remains on study.3/6 patients treated with LEN in prior 1-2 treatment lines responded (PR=2, VGPR=1), 1/6 had SD. 1/10 patients treated with POM in prior 1-2 treatment lines responded (PR), with 2 achieving MR and 3 SD.Patients with a lower expression of cMYC and IRF4 had superior PFS compared with patients with higher expression (cMYC: Group1 vs Group3 p=0.052; IRF4: Group1 vs Group2 p=0.04). Patients with lower numbers of CD8+ T-cells had better PFS than those with higher (p=0.069). There was no association between degree of expression of CBRN, Ikaros, Aiolos or PD-1 and survival (PFS/OS).As CRBN expression increased, patients were more likely to respond (≥PR) (p=0.07) and patients with low PD-1 expression were more likely to respond (≥ MR) (Group1 vs Group3 p=0.05).ConclusionCC-489 combined with Rd is well tolerated and effective with durable responses in a subset of heavily pre-treated R/R MM patients, including those who recently failed IMiD® compound therapy, suggesting that CC-489 may overcome drug resistance. IHC may have utility in identifying subsets of patients more likely to respond to CC-489 and Rd (CRBN, PD-1) and predict survival (cMYC, IRF4 and CD8). This trial has been expanded to include other sites and less heavily pre-treated patients. DisclosuresThakurta:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment. Guzman:Celgene: Employment. Cuoto:Celgene: Employment. Ren:Celgene: Employment, Equity Ownership.

Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma

AbstractLenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma patients. We randomly assigned 662 patients who were age ≥65 years or transplantation-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd). The primary end point was progression-free survival (PFS) in triplet (MPR and CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the median PFS was 22 months for the triplet combinations and 21 months for the doublet (P = .284). The median overall survival (OS) was not reached in either arms, and the 4-year OS was 67% for the triplet and 58% for the doublet arms (P = .709). By considering the 3 treatment arms separately, no difference in outcome was detected among MPR, CPR, and Rd. The most common grade ≥3 toxicity was neutropenia: 64% in MPR, 29% in CPR, and 25% in Rd patients (P < .0001). Grade ≥3 nonhematologic toxicities were similar among arms and were mainly infections (6.5% to 11%), constitutional (3.5% to 9.5%), and cardiac (4.5% to 6%), with no difference among the arms. In conclusion, in the overall population, the alkylator-containing triplets MPR and CPR were not superior to the alkylator-free doublet Rd, which was associated with lower toxicity. This study was registered at www.clinicaltrials.gov as #NCT01093196.

Phase 1, multicenter, open-label, dose-escalation, combination study (NCT02103335) of pomalidomide (POM), marizomib (MRZ, NPI-0052), and dexamethasone (DEX) in patients with relapsed and refractory multiple myeloma (MM); study NPI-0052-107 preliminary results

toxic deaths. Methods: 1173 newly diagnosed MM patients entered the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012. Overall, 511 patients received bortezomiband 662 patients lenalidomide-containing regimens. Results: 1146 patients started therapy and could be evaluated for this analysis. Death within 24 months of start of therapy occurred in 207 patients (18%). Among them, 61 patients (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months. Thirty percent of deaths were attributable to cardiac complications (18 pts), 28% to infections (17 pts) and 15% to vascular complications (9 pts). There was no difference in the incidence of toxic deaths between patients receiving bortezomib (31 pts, 6%) or lenalidomide-containing regimens (30 pts, 5%, p1⁄40.32), nor in the proportions of toxic events. The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p1⁄40.005). In multivariate analysis, factors associated with increased risk of early mortality were age (HR 1.09 per 1 year increase, p1⁄40.002) and ISS stage (HR 3.81, p1⁄40.01 ISS 2 vs ISS 1; HR 5.69, p1⁄40.002 ISS 3 vs ISS 1). Poor performance status was not a predictor of early death (HR 1.25, p1⁄40.59). By analyzing the impact of response, toxic deaths within 6 months occurred in patients with a suboptimal response (overall response rate 29%). Conclusions: Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy. Nevertheless one-third of early deaths occurred due to cumulative specific drug-related toxicities. Cardio-vascular events and infections are the main causes. Greater tumor burden and activity (defined by ISS stage) increased the risk of death. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.