Lenalidomide Regimen Research Articles

Clinical Analysis of PD-1 Inhibitor Combined with Lenalidomide in Treatment of Relapsed CD5+ Diffuse Large B-Cell Lymphoma

To investigate the clinical characteristics and treatment of relapsed CD5+ diffuse large B-cell lymphoma (DLBCL). The data of a patient with CD5+ DLBCL was collected, and its clinical characteristics and treatment outcome were analyzed. The patient developed hemophagocytic syndrome and achieved complete remission (CR) after 6 cycles of R-ECHOP chemotherapy, then relapsed. After 2 cycles of PD-1 inhibitor combined with lenalidomide treatment, the patient achieved CR again accompanied by a decrease of interleukin (IL)-10 expression level. After a total of 15 cycles of chemotherapy, the patient remained in CR for 24 months, and the level of IL-10 remained in the normal range. PD-1 inhibitor combined with lenalidomide regimen may be a new treatment for relapsed CD5+ DLBCL.

Mitoxantrone Hydrochloride Liposome, Bortezomib, and Dexamethasone- Based Regimen in Multiple Myeloma Patients with Extramedullary Plasmacytoma: A Pilot Study

Background Extramedullary plasmacytoma (EMP) is frequently presented in multiple myeloma (MM), especially in relapsed/refractory MM (RRMM), indicating a high-risk state of disease with inferior survival. Even in novel agent era, most anti-myeloma therapeutics demonstrated limited efficacy in EMP. Since there are no randomized controlled studies specifically addressing this complicated situation, standard treatment recommendations still lacked in this setting. Mitoxantrone hydrochloride liposome (Lipo-MIT) has shown higher concentration in tumor tissues and extended half-life, which exhibited clinical benefits in leukemia and solid tumors. Herein we designed a pilot study to explore the efficacy and safety of Lipo-MIT, bortezomib, and dexamethasone (MVD)- based regimen in MM with EMP. Methods MM patients with measurable EMP were enrolled in this study. Patients were planned to receive a maximum of 8 cycles of Lipo-MIT, bortezomib, and dexamethasone (MVD)- based regimen. Other combination agents were chosen based on previous treatments and the tolerance of patients, according to the clinician's decision. For patients who were refractory or intolerant to bortezomib, carfilzomib could be an alternative option. The dose of Lipo-MIT was 12mg/m 2 on the first day of every cycle. Both hematological response and EMP response were assessed by the International Myeloma Working Group (IMWG) criteria. Results Between Nov 4, 2022 and Jun 25, 2023, fifteen patients were enrolled from Beijing Chaoyang Hospital, with a median age of 65 years (range: 46-77). All patients had at least one kind of EMP, of which 12 (80.0%) patients had paraskeletal plasmacytoma, 7 (46.7%) had soft-tissue plasmacytoma, and 4 (26.7) had plasma cell leukemia. Four (26.7%) patients were newly diagnosed MM (NDMM), three (20.0%) were first relapse, and eight (53.3%) were previously heavily treated (2-12 lines). All of the 11 RRMM patients had been previously treated with proteasome inhibitors and immunomodulatory drugs (IMiDs), seven of them (46.7%) had been treated with CD38 antibodies, five (33.3%) had been treated with anthracyclines, and three (20.0%) had received CAR-T therapy (Table 1). By the data cut-off date of July 30, 2023, enrolled patients received a median of 2 cycles of Lipo-MIT treatment (range: 1-4). Specific regimens included: Lipo-MIT- bortezomib/carfilzomib- dexamethasone (MVD) triplet regimen (20.0%), MVD plus lenalidomide regimen (M-VRD) (20.0%), MVD plus IMiDs and etoposide regimen (M-VTED) (40.0%), and MVD plus other cytotoxic drugs (cyclophosphamide or cisplatin) (20.0%). The overall response rate (ORR) of EMP was 53.3%. Among the 9 patients who had measurable hematological disease at baseline, the hematological ORR was 77.8% (22.2% ≥VGPR, 33.3% PR, 22.2% MR) (Table 1). The most common adverse effects (AEs) at all grades (incidence >10%) were myelosuppression, including leukocytopenia (80.0%) and thrombocytopenia (53.3%), as well as respiratory infection (46.7%), diarrhea (13.3%), blue skin (13.3%), dizzy (13.3%), and fatigue (13.3%). Common grade ≥3 AEs including leukocytopenia (46.7%), thrombocytopenia (26.7%) and respiratory infection (26.7%) (Table 2). Median follow-up time was 4.5 months. Five patients had died, among which 3 died of disease progression, 1 died of severe respiratory infection, and 1 died of Covid-19 infection. Median PFS and OS have not been reached in this cohort. Conclusion This study revealed promising results of early response and efficacy of MVD-based regimen in MM with EMP, which could be further explored in prospective phase 2 studies.

Azacitidine Combination with Lenalidomide in Treating Higher-Risk Myelodysplastic Syndromes: A Single-Center, Phase 2 Trial

Background: Azacitidine, which works through the proteosomic destruction of DNA methyltransferase and resultant chromatin decondensation, is used primarily in patients with higher-risk myelodysplastic syndromes (MDS). Lenalidomide has been approved by the US Food and Drug Administration for the treatment of MDS patients with del(5q) cytogenetic abnormality. It has also shown activity in patients with higher-risk MDS and acute myeloid leukemia. In this trial, we assessed the efficacy and safety of combining azacytidine and lenalidomide in higher-risk MDS. Methods: This is a single-center, phase 2 trial. Aza (75mg/m 2/d on days 1-7 of a 28-day cycle) was administered in combination with lenalidomide (10 mg/day on days 1 to 21 every 28 days) for patients. The primary endpoint was the overall response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). An MDS targeted-exome-seq panel including 37 driver genes was used for screening. Results: Between Oct 2020 to Apr 2023, a total of 41 MDS patients were enrolled. 32 patients were evaluable for efficacy. 23 (71.875%) responded to therapy: 7 achieved a complete response (CR) (21.875%), 12 a marrow CR (mCR) (37.5%), and 4 a hematologic improvement (HI) (12.5%), of whom 10 of the mCR patients also had a HI. The median follow-up was 5.6 months (1 to 27.4), the median overall survival (OS) was not reached, and the median progression-free survival was 12.2 months. The time to reach CR was 2 months (range, 1 to 4.5), and the median CR duration was 8+ months (range, 5 to 27.4) ( Table 1). 27 patients had at least one mutation, the most common being TET2 (n = 12), ASXL1 (n = 12), TP53 (n = 7), SRSF2 (n = 6), and RUNX1 (n = 6) ( Fig.1A). Compared with patients without mutations, CR/mCR rate was significantly higher for those with mutations in TP53 (100% v 48%; P =0 .025) ( Fig. 1B), ORR were numerically higher for those with TP53 (100% v 64%; P = 0.149) and TET2 (85% v 63%; P = 0.422) ( Fig. 1C). We also observed a reduction of VAF in TP53 and TET2 mutation after the combination treatment ( Fig. 1D & 1E). Common grade 3/4 nonhematologic adverse events included thrombocytopenia (18.75%), infection (12.5%), and febrile neutropenia (9.4%). Conclusion This trial demonstrated that the combination of azacytidine with a lenalidomide regimen is an effective therapy for higher-risk MDS patients, with high efficacy and well-tolerance. Patients with TP53 mutation appear more likely to achieve a CR/mCR.

Efficacy and Safety of Lenalidomide, Anti-PD-1 Antibody Combined with Orelabrutinib or Rituximab in the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma worldwide. Although most patients with DLBCL respond to first-line chemoimmunotherapy with R-CHOP, approximately 40% of patients will have relapsed or refractory disease. Currently, the second-line therapeutic regimen is chemoimmunotherapy followed by consolidative autologous hematopoietic stem cell transplantation (AHCT) for relapsed/refractory DLBCL (R/R DLBCL). However, the prognosis has remained poor. (Sawalha. J Pers Med. 2021). Thus, discovering effective treatment regimens for patients with R/R DLBCL has become extremely crucial. Recently, a combination regimen of lenalidomide, anti-programmed cell death protein-1 (PD-1) antibody, and rituximab demonstrated a good efficacy with an overall response rate (ORR) of 40% in R/R DLBCL (Sethi et al. Blood. 2019). Activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway is a hallmark of DLBCL (Kapoor et al. Cell Death Dis. 2019). Orelabrutinib, a novel and potent irreversible BTK inhibitor, has shown encouraging efficacy with an ORR of 61.5% in combination with a new generation anti-CD20 antibody MIL62 in R/R DLBCL (Xu et al. Blood. 2020; Thus, we assessed the efficacy and safety of lenalidomide, anti-PD-1 antibody combined with orelabrutinib or rituximab in R/R DLBCL. Methods: This was a prospective, multicenter, single-arm, open-label, phase II study (ChiCTR2200056256). Patients aged 18 to 75 years were eligible if they had histologically confirmed R/R DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ and bone marrow function, and survival time ≥ 6 months. Eligible patients received a combination regimen (21-day/cycle) of lenalidomide (10-25 mg, days 1-10, QD, oral), Tislelizumab (200 mg, day 1, intravenous), and orelabrutinib (150 mg, QD, oral) or rituximab (375 mg/m2, day 1, intravenous). The primary endpoint was ORR. Secondary endpoints included complete response (CR), progression-free survival (PFS), duration of response (DOR), time to response (TTR) and adverse events (AEs). Efficacy was assessed using Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC, 2016). AEs were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Results: Between August 2021 and March 2022, 9 patients (6 males; median age, 73 years, range 65-76) were enrolled. Among them, 8 patients were non-germinal center B-cell-like and 1 was unknown. Most patients had comorbidities (n=8, 88.9%), an Ann Arbor stage of III or IV (n=4, 44.4%), International Prognostic Index (IPI) ≥ 3 (n=4, 44.4%). All patients received lenalidomide, anti-PD-1 antibody combined with orelabrutinib regimen, and the median duration of treatment was 5 cycles (range 3-6). Among them, 4 patients (44.4%) received a second-line therapy, and 5 patients (55.5%) received ≥ third-line therapy. Before enrollment, 3 patients attained a CR as their best response during the previous therapies. Eight patients were included in the efficacy analysis. The ORR, CR and median TTR were 87.5%, 25.0%, and 2.45 months (range 1.97-2.73), respectively. Among them, 3 patients completed 6 cycles of therapy with ORR of 100% (Figure 1). The PFS and DOR were not completely mature due to the short follow-up period at the end of follow-up. Eight (80%) patients reported AEs. The most common hematological AEs were anemia (77.8%), platelet count reduced (55.6%), neutrophil count decreased (33.3%) and white blood cell count decreased (22.2%). Three patients (33.3%) discontinued treatment due to AEs (atrioventricular block, n=1; rash, n=2). In addition, the most common AEs were grade 1 or 2, and no grade 4 AEs. One patient died due to electrolyte disturbances and depression. Conclusion: Lenalidomide, anti-PD-1 antibody combined with orelabrutinib or rituximab regimen is effective and well-tolerated for patients with R/R DLBCL in this phase II study. This study provides a potential novel strategy for the treatment of R/R DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient Characteristics and Survival Outcomes of Lenalidomide Exposed non- Refractory vs. Lenalidomide Refractory Multiple Myeloma Patients in the HONEUR Federated Data Network

Background: Treatment options that became available over the past two decades, including proteasome inhibitors (PI) and immunomodulatory agents (IMIDs), have significantly improved survival outcomes of patients with multiple myeloma (MM). However, MM is still an incurable disease and patients ultimately progress and become refractory to standard treatments. The increased use of Lenalidomide regimens in earlier lines of treatment has led to a higher number of Lenalidomide (Len) refractory patients (Moreau P, Blood Cancer J 2019). Description of characteristics and outcomes of patients who have become refractory to Len vs. those who have only been exposed but did not become refractory is limited especially with regards to data coming from different European healthcare systems. Methods: Data from two MM registries, the Registry of Monoclonal Gammopathies from the Czech Republic (Brozova L, Klin Onkol. 2017) and the Oncology Information Service registry in Germany (Merz M, Cancers 2021), were analyzed in the Hematology Outcomes Network Europe (HONEUR). HONEUR is a federated data network with patient level data solely stored and governed at local sites with analysis executed centrally. MM patients exposed to both PI and Len, in 1-3 prior lines of therapy and with ECOG 0-1, treated between 2015 and 2021, were identified to compare outcomes of Len-exposed, non- refractory vs. Len-refractory patients. Refractoriness to Len was defined as disease progression while on Len and/or initiation of subsequent line of therapy not containing Len within 60 days after stopping the previous Len containing line of treatment. Index dates were defined as the date of treatment initiation after meeting above criteria. Patients fulfilling the eligibility criteria at multiple times in their longitudinal follow-up were included as separate observations with line of therapy as unit of analysis. Results: A total of 2415 treatment lines were included in the analysis. Of these, 2029 (84.0 %) treatment lines were from Len-refractory patients. Median follow-up from index date was 22.0 vs 23.5 months for the Len-exposed non- refractory and Len-refractory patients, respectively. Baseline characteristics of the Len-exposed non-refractory and Len-refractory patients are presented in table 1. For Len-exposed non-refractory and Len-refractory patients, median OS was 36.6 [95% CI: 31.74; 43.53] vs. 21.5 [95% CI :19.94; 23.06] months, respectively, with a Hazard Ratio (HR) of 0.53 [95% CI: 0.44; 0.64] in favor of Len exposed non-refractory patients. When accounting for line of treatment, the adjusted hazard ratio was 0.59 [95% CI 0.49; 0.70] in favor of Len-exposed non- refractory patients. Conclusions: An analysis of German and Czech registries in a federated data network shows that patients who have become refractory to Len have significantly poorer overall survival compared to Len-exposed non-refractory patients with MM. The Len-refractory population is a more difficult-to-treat patient population, with high unmet need for effective treatments that can prolong survival outcomes for these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PB1996: TREATMENT PATHWAYS AT FIRST RELAPSE POST-ASCT IN MULTIPLE MYELOMA: IMPACT OF MAINTENANCE THERAPY ON TREATMENT OPTIONS

Background: The introduction of new agents and treatment combinations has led to significant improvements in outcomes for multiple myeloma (MM) patients. In particular, lenalidomide maintenance therapy (LenM) following autologous stem cell transplant (ASCT) in younger/fitter MM patients has now become standard given the survival benefits associated with it. However, most MM patients will relapse post-ASCT and many effective relapse regimens have a lenalidomide backbone (e.g. KRD: carfilzomib, lenalidomide, dexamethasone, DRD: daratumumab-RD, IRD: ixazomib-RD) making choice of regimen at first relapse increasingly difficult in patients progressing during LenM therapy. Real world data reflecting these choices is needed to inform treatment decisions and consensus guidelines. Aims: We carried out an audit with an aim to: 1. Evaluate treatment and outcomes in MM patients undergoing ASCT from 2010-2020 2. Assess the impact of LenM post-ASCT and therapy choice after relapse. Methods: We carried out a retrospective audit of all patients with MM attending an Irish hospital who underwent ASCT from 2010-2020. Data was collected by chart/electronic record review. Endpoints included no. of ASCT/year and type of induction/maintenance therapy, relapse rates post-ASCT and choice of post-relapse therapy. Results: 71 patients at our centre underwent ASCT for MM between 2010-2020 (24 female,47 male) with median age of 67 and most common isotype IgG Kappa (n=33). The most frequently used induction was cyclophosphamide(C), bortezomib(V) and dexamethasone(D) (>60%, VCD). Use of maintenance therapy increased markedly over this decade, with 0% receiving maintenance in 2010, 44% in 2014 and 83% in 2020. LenM was most common, >75% (n=28).Other maintenance therapies included bortezomib n=4, daratumumab (dara)n=3 and lenalidomide + bortezomib (RV) combination n=4. First relapse treatment data was available for 36 patients. Regimens included carfilzomib/dexamethasone (KD) n=16 +/- lenalidomide (KRD) n=1, pomalidomide (PD), n=1, ixazomib (ID) n=1, dara (n=3) and dara combinations, including daraVD, n=1, and daraPD, n=1. 26 patients did not receive maintenance containing lenalidomide and the majority of these patients received ASCT pre-2015. There were n=13 relapses in this group: n=4 received lenalidomide regimens (RVD/VCD) at relapse. KD n=4, dara n=1, and ID n=1 were also used. First relapse therapy for 17 patients who progressed during LenM included: KD(n=11) 64.7%, dara(n=2) 11.7%, pomalidomide(n=1) 5.8%, and RV(n=2) 11.7% and VCD(n=1) 5.8%. Overall, carfilzomib-based therapy (without lenalidomide) was the most commonly prescribed therapy on first relapse. We observed a clear increase in its use from 2015-2020, in parallel with increased use of LenM. We also noted reducing rates of lenalidomide-based relapse therapies in later years, correlating with increased LenM. Importantly, neither DRD or PVD combinations were reimbursed for prescription in Irish healthcare during the period of audit and are notable absences from the relapse treatment regimens used. Summary/Conclusion: This audit highlights the treatment pathway and outcomes for all patients with MM undergoing ASCT over 10 years in our centre. We have noted significant changes in choice of therapy upon relapse, with carfilzomib prescription rates increasing and lenalidomide-based regimen use decreasing. Our real world data provides direct insight into the effect of widespread LenM therapy on choice of agent upon relapse and highlights the need for consensus treatment guidelines to reflect this evolution in treatment for MM patients.

The Efficacy of Plerixafor Plus Recombinant Human Granulocyte Colony-Stimulating Factor for Autologous Stem-Cell Mobilization and Transplantation for Patients with Lymphoma and Plasma Cell Diseases

Objective: Plerixafor is a small-molecule inhibitor of CXCR4. This study evaluates the efficacy of plerixafor combined with recombinant human granulocytic colony stimulating factor(G-CSF), in mobilizing hematopoietic stem cells for autologous stem-cell transplantation (ASCT) in patients with lymphoma and plasma cell diseases.Methods: A retrospective analysis was performed on 41 patients with Plerixafor combined with G-CSF admitted to the Department of Hematology, Nanfang Hospital, Southern Medical University,China from July 2019 to February 2021. Mobilization protocol: all patients were given G-CSF 10μg/kg d1-4 and Plerixafor 20mg (all patients weighed less than 83kg) 11 hours before collection on day 5 (night of day 4).Results: The median age of 41 patients was 52 years (25-66 years), the median body weight was 57kg (41-80kg), and the male to female ratio was 1.16:1(22/19). The patients of plerixafor used in combination with G-CSF include Multiple Myeloma 75.6%(31/41), Diffuse Large B Cell Lymphoma was 9.8%(4/41), Peripheral T Cell Lymphoma (4.9%, 2/41), Angioimmunoblastic T Cell Lymphoma (2.4% ,1/41), Systemic light chain (AL) amyloidosis (2.4% ,1/41), POEMS syndrome (2.4%,1/41), and plasma cell leukemia (2.4%, 1/41). Above the patients got partial remission（PR） before mobilization. 17 patients got complete remission（CR）, 4 patients got very good PR(VGPR) and ten got PR. There were 5 lymphoma patients with CR and 2 with PR. The majority of patients, 25, received first-line chemotherapy. 11 patients received second-line chemotherapy, and five received third-line myeloma therapy or above. The median cycle of chemotherapy was 4 (range 4-41). Twenty-two patients with multiple myeloma received treatment with lenalidomide regimens. 26 of all (63.4%) had optimum mobilization (CD34 positive cell count ≥5 × 10 6 cells/kg), and 36 (87.8%) had minimum mobilization (CD34 positive cell count ≥2 × 10 6 cells/kg). The minimum and optimum mobilization rate of first-line chemotherapy regimen was 92% and 72% respectively. The rate of the minimum mobilization of the second line chemotherapy was 100%, the optimum mobilization rate was 63.6%. The minimum and the optimum mobilization rate were 60% and 20% for the third line chemotherapy and above. The minimum mobilization rate was 94.7% and the optimum mobilization rate was 57.9% in patients receiving lenalidomide containing chemotherapy less than the 4 cycles. The minimum and optimum mobilization rate were 66.7% and 66.7% for patients with more than 4 cycles of lenalidomide chemotherapy. Thirty-four patients received autologous hematopoietic stem cell transplantation. Conditioning regimens was TBI (total-body irradiation) + CY (CTX)+ VP-16 or BUCY+ Me-CCNU protocol in lymphoma patients, and Melphala 200mg/m 2 in Multiple myeloma patients. A reduction of melphalan dose(140mg/m 2) in patients with severe renal failure, here defined as iohexol clerarance <30 ml/min, is suggested. Neutrophil engraftment was defined as neutrophil count ≥ 0.5 × 10 9/L for 3 days or ≥ 1.0 × 10 9/L for 1 day. Platelet engraftment was defined as platelet count ≥ 20 × 10 9/L without a transfusion from the preceding 7 days. All patients who received transplantation had successful neutrophil engraftment and 94.1% had successful platelet engraftment. The median time to engraftment was 10 days(9-13 days) for neutrophil and 11 days (9-48 days) for platelet. Using all available laboratory measurements and clinical information to determine graft failures, there were two platelet graft failures in at 1 month follow-up visit. However they had successful platelet engraftment after treatment with Eltrombopag or Avatrombopag(43 days, 48 days).Conclusions: The mobilized cells after G-CSF plus Plerixafor contained high numbers of hematopoietic stem cells, and engrafted very efficiently. G-CSF plus Plerixafor may be preferred for ASCT in patients with lymphoma and plasma cell diseases. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study of Lenalidomide, Ixazomib, Dexamethasone, and Daratumumab in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (AFT-41)

Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab.Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation.The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities.1Kapoor et al. Blood (2019) 134 (Supplement_1): 864.Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org [Display omitted] DisclosuresO'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Risk of Serious Infections with Lenalidomide Based Regimens in Multiple Myeloma: A Network Meta-Analysis

Background: Lenalidomide is an immune modulator, approved for use since 2005 for the treatment of multiple myeloma (MM) patients. Its use is associated with an increased risk of infections. Combination of lenalidomide with other drugs, monoclonal antibodies, proteasome inhibitors, dexamethasone, and alkylators, can enhance the risk of serious infections. We conducted a network meta-analysis to compare the incidence of ≥Grade 3 infections among lenalidomide based regimens used in MM that can help clinicians to monitor patients for the risk of infections. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "lenalidomide" AND "multiple myeloma" from the inception of literature till 06/10/2020. We screened 14,684 articles and included 23 randomized clinical trials (RCT) (N=11,174) in network meta-analysis. We extracted the data for serious (≥Grade 3) infections in lenalidomide based regimens. We excluded case reports, case series, preclinical trials, non-randomized clinical trials, observational studies, review articles, meta-analysis, and RCTs not providing any information about ≥Grade 3 infections. We used the "netmeta" package by Rucker et al. in the R programming language (version 4.0.2) to conduct frequentist network meta-analysis. Results: In 23 RCTs, the median age was ≥65years in 11 RCTs (N=5585) and ≤65 in 12 RCTs (5589). 9 RCTs were performed on relapsed/refractory multiple myeloma (RRMM) patients (N=4254), while 13 RCTs were performed on newly diagnosed multiple myeloma (NDMM) patients (N=6920). Lenalidomide regimen was used as maintenance therapy in 8 RCT (N=4255). Table 1 reviews the baseline characteristics. The pooled incidence of high-grade infections in trials with a median age of ≥65 and ≤65 years is 1010/5585 and 634/5589, respectively. The incidence of high-grade infections is 693/4254 in RRMM patients, 951/6920 in NDMM patients, and 466/4255 in NDMM patients with maintenance therapy. P-score in table 2 represents the mean extent of certainty with which a regimen is better in terms of the incidence of high-grade infections, i.e., higher P-score means a lower risk of serious infections. According to P-score, lenalidomide with carfilzomib and dexamethasone is worst in terms of the incidence of infections. Indirect comparison of placebo with lenalidomide shows a risk ratio of high-grade infections of 2.87 (95% CI: 1.96; 4.23) in favor of placebo. Fig 1 outlines the indirect comparison of the incidence of high-grade infections with different lenalidomide based regimens vs. placebo. Table 3. shows the calculated indirect comparison of high-grade infections in each lenalidomide based regimen. Heterogeneity was not statistically significant. For serious infections, lenalidomide dexamethasone showed a risk ratio of 0.86, 0.70*, 0.76*, 0.78*, 0.77, and 0.77 in comparison with the combination of lenalidomide dexamethasone with bortezomib, carfilzomib, daratumumab, elotuzumab, ixazomib, and pembrolizumab respectively (*statistically significant). Conclusion: This network meta-analysis suggests an increase in the risk of high-grade infections with the addition of bortezomib, monoclonal antibodies, ixazomib, and carfilzomib to lenalidomide in multiple myeloma patients with the highest increase in risk with the addition of carfilzomib. Additional randomized clinical trials are needed on the toxicity of lenalidomide based regimens to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Outcomes of lenalidomide- or bortezomib-based regimens in older patients with plasma cell myeloma.

The "triplet" regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide-dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib-dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first-line regimens using real-world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event-free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72-0.95) and EFS (HR = 0.68; 95% CI, 0.61-0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68-0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83-0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide-dexamethasone may be the preferred line doublet considering its advantage over VD.

Streamlining bortezomib regimen: A quality improvement project for cost-effective and patient-friendly protocol.

94 Background: Bortezomib is a novel first-in-class proteasome inhibitor and received it’s FDA approval with twice weekly dosing on day 1, 4, 8 and 11 of a 21-day cycle with weekly complete blood count (CBC). However, subsequent studies have shown that weekly dosing has equal drug efficacy. Our clinical practice at Feist-Weiller cancer center is to administer weekly subcutaneous bortezomib injection after reviewing the CBC. Objective: To analyze hematological toxicities with weekly bortezomib and assess the need for CBC prior to administration of bortezomib. Methods: A retrospective analysis of CBC results was done for every patient receiving bortezomib as part of bortezomib and dexamethasone +/- lenalidomide regimens in a 2-year period (2017-2018). The data extraction was done using Epic Clarity database using an SQL script which identified each treatment duration in minutes between check in and check out, Absolute neutrophil count (ANC) and platelet count on each treatment day. Results: A total of 38 patients received 626 treatment doses of bortezomib. The average patient stay between check-in and check-out was 227 mins. There was very low incidence of grade 3 thrombocytopenia (0.64%) and grade 3 neutropenia (0.32%). There is no evidence of grade 4 cytopenia’s or any dose changes from cytopenia’s. This data suggests that weekly lab monitoring may not be necessary prior to drug administration. Conclusions: Using this data, we have streamlined our approach for monitoring patients receiving weekly bortezomib. During weekly bortezomib administration, we propose to obtain a CBC on day 1 of every 4 weeks. If either platelet count is less than 75,000 /μl and ANC is less than 1000/μl on day 1, we will monitor labs weekly until count recovery. We believe that this new protocol may result in 75% reduction in the average patient stay for the treatment. It will reduce the need for phlebotomy and lab services. We believe that this change will improve patient satisfaction and an another step forward to efficient and safe patient care at our institute.

A case of primary gastric diffuse large B-cell lymphoma occurring in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) and Non-Hodgkin Lymphoma (NHL) are two different origins of hematological malignancies, which rarely occur at the same time. Moreover, NHL secondary to CML is common in T cell lymphoma, while NHL of B cell origin is rare. Since 1999, only 22 cases with B cell lymphoma have been reported, of which 4 cases have diffuse large B-cell lymphoma (DLBCL). The lesions of DLBCL were in lymph node, liver, jejunum, and soft palate. To our knowledge, it has no report for the primary gastric DLBCL (PG-DLBCL) occurring in CML. Here we reported a 63-year-old man of chronic phase (CP) CML associated with PG-DLBCL. The patient was diagnosed with CML nearly eight years ago and was treated with imatinib and nilotinib successively. However, gastroscopy found malignant lesions in the patient’s stomach in March 2018, and the masses were diagnosed as PG-DLBCL. Subsequently, with the treatment of the RCOP + lenalidomide regimen chemotherapy for 3 cycles, the patient achieved nearly complete remission (CR).

PB2145 POMALIDOMIDE AND DEXAMETHASONE IN RELAPSING POEMS SYNDROME: A FRENCH REPORT OF 5 CASES

Background:Significant improvements have been made in the management of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy and skin changes) syndrome, but patients (pts) still experience relapses or refractoriness. Immunomodulatory drugs are effective agents in the treatment of plasma cells dyscrasias. Lenalidomide has shown interesting activity in POEMS syndrome, but no data on pomalidomide have been published so far.Aims:We report the use of pomalidomide and dexamethasone in five patients with relapsing POEMS syndrome after lenalidomide regimen.MethodsDemographics: 5 patients (3 men), median age 74 years old (range, 67–77), median of 2,6 previous lines received (range, 2–4). All patients had received lenalidomide as previous therapy.Results:Hematological overall response rate (ORR) was 3/5 (60%): all 3‐responding patients experienced complete response (CR) according to local evaluation based on IMWG criteria, leading to clinical improvement of neuropathy in all of them, endocrinopathy and peripheral edema (2 of 2 pts). Other clinical responses concerned resolution of papilledema (2 of 2 pts) and improvement of pulmonary hypertension (1 of 1 pt). Noteworthy, serum Vascular Endothelial Growth Factor (sVEGF) level normalized after only one cycle of treatment in those 3‐responding patients (figure 1). No emergent toxicity was observed. As expected, adverse events were mainly hematological but of mild intensity and easily manageable. At this time, the 3‐responding patients are alive, including 2 without relapse after 11 months of follow‐up for both of them. The 2 other patients died, one of them from rapidly progressing disease, the other from heart disease not related to POEMS.Summary/Conclusion:In conclusion, pomalidomide and dexamethasone appears to be a safe and effective option in relapsing POEMS syndrome after lenalidomide regimen, demonstrating rapid and durable responses.image

Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (Axi-cel): Results from the U.S. Lymphoma CAR-T Consortium.

7517 Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG &gt;1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed &lt;3 months after axi-cel and did not receive therapy with median OS 17 days (95% CI 7-49); 33 pts relapsed &lt;3 months and received therapy with 114 day median OS (95% LCL 82). In contrast, 30 pts who relapsed &gt;3 months post axi-cel and received therapy had estimated median OS &gt;220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse &gt;3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.

Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials

Background:For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly.Methods:We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018).Results:From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p<0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea.Conclusion:The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. DisclosuresNo relevant conflicts of interest to declare.

Response-Adapted Therapy for Newly Diagnosed Myeloma

Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints.Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed.Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin.Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. [Display omitted] DisclosuresReu:Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BackgroundIxazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide–dexamethasone (ixazomib group) or placebo plus lenalidomide–dexamethasone (placebo group). The primary end point was progression-free survival.ResultsProgression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups.ConclusionsThe addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.)

Is There a Best Initial Treatment for a New Patient With Low Grade Follicular Lymphoma.

The treatment landscape for newly diagnosed follicular lymphoma (FL) has dramatically changed over the past decade, first with the advent of rituximab and then with the activity of old and new drugs, like bendamustine and lenalidomide, in this disease. The efficacy and tolerability of rituximab has led to a paradigm shift for the management of patients with low volume FL for many oncologists. Despite the lack of a survival benefit seen with this approach, many now use this single agent in patients who had historically been observed. Likewise, its use as maintenance therapy following successful front-line induction therapy of patients with symptomatic FL, with either rituximab alone or specific chemoimmunotherapy regimens, has improved remission duration and widely been adopted. As newer chemoimmunotherapy regimens, like bendamustine and rituximab, have superior outcomes with improved tolerability, upfront treatment options are redefined and questions emerge: whom do maintenance strategies benefit, and what is the optimal sequencing of therapies? Finally, as newer targeted and potentially better tolerated therapies demonstrate efficacy in the relapsed setting, their use, both in combination with and in place of chemotherapy, is being explored. The promising regimen of lenalidomide with rituximab is being compared with chemoimmunotherapy in a randomized fashion. Cure remains elusive, however, in advanced stage disease and so safety and tolerability, in addition to efficacy, remain important endpoints.

Real-world treatment patterns, comorbidities, and disease-related complications in patients with multiple myeloma in the United States

Objectives:To describe multiple myeloma (MM) treatment patterns and comorbidities over time in the US.Research design and methods:Study patients were newly diagnosed with MM (ICD-9-CM 203.0x) between 1 July 2006 and 31 March 2014 and had ≥6 months of data prior to the initial MM diagnosis in MarketScan Research Databases. Patients were followed until inpatient death or the end of data. First-line, second-line, and third-line treatment regimens were identified following diagnosis and were described over time based upon the start date of the first line of therapy (2006–2007, 2008–2014, 2013–2014). Comorbid conditions and disease-related complications were examined during the 6 months prior to the line of therapy start dates.Results:A total of 24,507 MM patients were examined (mean age: 65.2 years, 54.1% male, mean follow-up: 23 months, 16.2% transplant). Across all lines of therapy, the proportion of patients on thalidomide-based regimens decreased over time. In the first line, bortezomib-based regimens became more common from 2006–2007 to 2008–2014 (2006–2007: 17.0%, 2008–2014: 44.3%, 2013–2014: 49.4%). In the second line, lenalidomide- and bortezomib-based regimens were the most common (2013–2014: lenalidomide: 28.9%, bortezomib: 26.2%). The combination regimen of lenalidomide + bortezomib became more common in the first and second lines. In the third line, carfilzomib- and/or pomalidomide-based regimens were 37.0% in 2013–2014. Skeletal-related events, hypertension, anemia, and chronic kidney disease were the most prevalent comorbidities and disease-related complications. During the 6 months prior to each line of therapy, the prevalence of the majority of the comorbidities and complications increased as patients progressed to higher lines of therapy.Conclusions:MM treatment patterns have been dynamic over time. Comorbid conditions and myeloma-related complications increase as patients progress and may worsen MM patients’ prognoses over time. Combination regimens such as lenalidomide + bortezomib are more widely used as first- and second-line therapy. Newly approved agents (carfilzomib, pomalidomide) are the prevailing treatments in the third line and are under further investigation for earlier lines of therapy.

Efficacy and Safety of Lenalidomide in the Treatment of Multiple Myeloma

Background:Lenalidomide has emerged as an important treatment for patients with multiple myeloma (MM). However, its role in the management of MM is still controversial and requires further clarification. The aim of this study was to evaluate efficacy and safety of lenalidomide for MM using a meta-analysis.Methods:We searched the electronic databases including: PubMed, EMBASE and the Cochrane Center Register of Controlled Trials. Seven randomized clinical trials were identified, which included a total of 2357 patients with MM who received lenalidomide-containing, noncontaining lenalidomide regimens or placebo as induction therapy or maintenance therapy. The outcomes included overall response (OR) rate, complete response (CR) rate, 3-year progression-free survival (PFS) rate, 3-year overall survival (OS) rate, and different types of treatment-related adverse events. We calculated the risk ratios (RRs) as well as their 95% confidence intervals of these outcomes and pooled the results using RevMan 5.2 software.Results:For patients with previously untreated MM, OR rate and CR rate was significantly higher in lenalidomide-containing group than the control group. For relapsed or refractory MM patients, lenalidomide-containing regimens significantly improved the OR rate, CR rate, 3-year PFS rate and 3-year OS rate. With regard to MM patients after autologous stem cell transplantation, lenalidomide maintenance therapy significantly improved 3-year PFS rate but did not result in improved 3-year OS rate. In terms of toxicities, lenalidomide therapy has a higher rate of Grade 3–4 grade cytopenias, infection, deep-vein thrombosis, and diarrhea. Furthermore, the incidence of second primary malignancies was significantly higher in the lenalidomide group.Conclusions:The lenalidomide-containing regimens as induction therapy clearly increased response rates and improved intervals of survival with acceptable toxicity rates for patients with MM. However, when physicians choose to use the lenalidomide as maintenance therapy, whether the benefits outweigh the risks should be taken into account.