Phase III Intergroup Study of Lenalidomide (CC-5013) Versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant for Multiple Myeloma (CALGB 100104): Initial Report of Patient Accrual and Adverse Events.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3416-3416 ◽  
Author(s):  
Philip L. McCarthy ◽  
Kouros Owzar ◽  
Edward A. Stadtmauer ◽  
Sergio Giralt ◽  
David D Hurd ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Progressive Disease ◽  
Study Drug ◽  
Phase Iii ◽  
Cell Transplant ◽  
Grade 5 ◽  
Grade 3

Abstract Abstract 3416 Poster Board III-304 Relapse and/or progression of disease are the primary causes of treatment failure after autologous hematopoietic stem cell transplant (ASCT) for multiple myeloma (MM). The primary objective of CALGB 100104 was to investigate whether adding maintenance therapy would improve the time to progression (TTP). The study was powered to detect an improvement of 9.6 months (prolongation of TTP from 24 months to 33.6 months) in MM patients undergoing a single ASCT. Secondary objectives were the Complete Response conversion rate following maintenance initiation, the Overall Survival and the feasibility of long term lenalidomide maintenance therapy. Eligible MM patients were Durie-Salmon Stage I-III patients within 1 year of diagnosis, receiving at least 2 months of any induction therapy with response (Stable Disease (SD) or better) and ≤ 70 years of age. Patients with progressive disease prior to ASCT were not eligible for study. Patients underwent stem cell mobilization followed by Melphalan 200 mg/m2 and ASCT with a minimum of 2 × 106 CD34 cells/kg for stem cell infusion. Responding patients with SD or better were randomized at day 100 to 110 post ASCT to study drug versus placebo. Patients with progressive disease were not randomized. Randomized patients were stratified by elevated β2 microglobulin at diagnosis and prior thalidomide or lenalidomide use during induction therapy. The starting dose was 10 mg daily with an escalation at 3 months to 15 mg if tolerated. Study drug could be de-escalated by 5 mg daily if not tolerated. Patients could be maintained at 5, 10 or 15 mg as tolerated and were followed with monthly complete blood counts. Drug was held for neutropenia (Absolute Neutrophil Count (ANC) < 500/μl or thrombocytopenia (<30,000/ μl) and restarted after resolution of cytopenia(s). Patients were re-staged by blood and urine testing every 3 months, by skeletal survey and bone marrow testing yearly and remained on maintenance therapy until progression. A total of 568 pts were registered at centers from the following cooperative groups: CALGB (n=377), ECOG (n=132), and BMT-CTN (n=59). The study opened in 12/2004 with increasing annual accrual: 2005, n=33, (6%); 2006, n=62, (11%); 2007, n=137, (24%); 2008, n=214, (38%); 2009, n=122, (21%) and study closure on 07/03/09. The drop out rate before randomization at day 100 to 110 was projected to be 10-15% with an expected randomization of 462 patients. Among the 568 registered patients, 424 have been randomized, 81 have dropped out pre-randomization and 63 are pending randomization as of 08/06/09. Projected final randomization is approximately 475. Pooled Hematologic and Non-Hematologic Adverse Events (AEs) are available from 275 patients in both arms. Individual patients experiencing Hematologic AEs are as follows: Grade 3 (severe) n=43 (16%); Grade 4 (life-threatening) n=26 (9%); and no Grade 5 (lethal). Individual patients experiencing Non-Hematologic AEs are as follows: Grade 3 n=74 (27%); Grade 4 n=9 (3%); Grade 5 n=5 (2%). The most common Non-Hematologic AEs were infection, fever, rash and fatigue. The Data Safety and Monitoring Board (DSMB) will continue to monitor the study for AEs and determination of progression. This large Phase III study has successfully completed patient registration and is nearing completion of patient randomization at day 100 to 110 post ASCT through the cooperation of the Intergroup oncology and transplant clinical research groups. Further analysis will determine if maintenance therapy with lenalidomide (CC-5013) is of benefit for MM patients following single ASCT. Disclosures McCarthy: Celgene: Speakers Bureau. Off Label Use: Lenalidomide for maintenance therapy following autotransplant for multiple myeloma. Stadtmauer:Celgene: Speakers Bureau. Richardson:Millenium (Research Funding and Advisory Board), Celgene, Keryx, BMS, Merck, Johnson and Johnson (All Advisory Board): Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

scholarly journals Safety Analysis of Intra-Patient Dose- Study of Crenolanib Maintenance Therapy in Patients with FLT3 Mutant AML Following Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3426-3426 ◽  
Author(s):  
Betul Oran ◽  
Stefan O. Ciurea ◽  
David Marin ◽  
Jessica M McCarty ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Side Effects ◽  
Maintenance Therapy ◽  
Dose Escalation ◽  
Research Funding ◽  
Patient Dose ◽  
Phase Iii ◽  
Cell Transplant ◽  
Grade 3 ◽  
Active Disease

Abstract Background: FLT3 inhibitors (like sorafenib and midostaurin) have been administered as maintenance therapy post allogeneic stem cell transplantation (SCT) to reduce persistent relapse risks in FLT3-mutant AML patients. Reduced doses of both sorafenib and midostaurin have been found to be tolerable in the post-HSCT setting. Crenolanib is a highly potent and selective FLT3-targeted TKI that has activity as a single-agent and combined with chemotherapy in patients with FLT3-ITD and/or FLT3-TKD mutations. We here report the outcomes of safety and tolerability of crenolanib maintenance in FLT3 mutant AML patients after allo-HSCT (NCT02400255). Methods: To assess the tolerability of crenolanib maintenance in post-SCT AML patients and evaluate the appropriate dose for such patient population, a clinical trial of crenolanib maintenance therapy was performed in patients (age ≥ 18) with FLT3 mutant AML who had undergone SCT. Enrollment criteria included patients with FLT3-ITD, or FLT3-TKD positive disease at any point prior to SCT, having first SCT, with ≥ 50% T cell donor chimerism, adequate engraftment with complete remission (CR) at post-SCT evaluations. Patients needed to enroll between 42 and 90 days post-transplant without uncontrolled infection and graft versus host disease (GvHD). Initially, the study was designed for patients to be treated with crenolanib 80 mg TID (240 mg daily. Due to initial tolerability in the first patients (n=4), the design was changed to an intra-patient dose-escalation, in which patients received crenolanib starting at a dose of 60 mg BID for a month and then escalated to 80 mg BID and finally 80 mg TID as tolerated. As of July 2018, 24 patients, median age 53.5 years (range 31-74) have been enrolled and received crenolanib maintenance therapy. Disease status at SCT was CR (n=10, 42%), CR without count recovery (CRi, n=12, 50%), and active disease (n=2, 8%). The minimal residual disease (MRD) by multicolor flow cytometry was evaluable in 22 CR/CRi patients at SCT and was deemed to positive in 5 (23%). Conditioning regimen was myeloablative (20, 83%) or reduced intensity (4, 17%). Donors were matched related (n=11, 46%), matched unrelated (n=11, 46%) or haploidentical (n=2, 8%). After 4 patients enrolled, the trial design was altered to allow for intra-patient dose escalation. Ten patients were never able to escalate above 60mg BID, one patient stayed at 60 mg TID, 12 patients escalated to 80 mg BID, of those 12, 7 were able to escalate to 80 mg TID. The median days on crenolanib was 474 days (4-728 days) and median number of cycles was 17.5 cycles (1-26 cycles). Of the 21 patients no longer on study, 6 were due to relapse with median time to progression of 17 days (7-76 days) after first dose of crenolanib. Of the 6 relapses, four patients were positive for MRD prior to transplant and two had active disease. Two patients came off study due to noncompliance with study procedures, two were due to withdrawal of consent, 7 were patient decision due to side effects, one was due to suicidal ideation, and one was for insurance non-payment. Only one patient completed the planned 24 cycles of treatment with crenolanib 60 mg BID. Currently, four patients remain on study. Observed side effects were predominantly grade 1 and 2 with the most common (regardless of attribution) being nausea (62%), vomiting (38%), and diarrhea (33%), 13 adverse events that were grade 3 were reported likely attributable to crenolanib, no grade 4 side effects reported. There were two grade 2 GVHD-AEs, one grade 1 and one ungraded GVHD-AEs reported. One patient had a grade 3 rash that was confirmed as GVHD. Conclusion: These interim results suggest that crenolanib can be safely given at a dose of 160 mg to 240 mg total daily in the post-SCT setting. Two randomized phase III trials have been initiated to investigate the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML as well as crenolanib vs midostaurin following chemotherapy in newly diagnosed FLT3 mutated AML (NCT03250338, EudraCT 2017-001600-29; NCT03258931). Post HSCT crenolanib maintenance will be offered at 100 mg BID (200 mg daily) in both trials. Disclosures Oran: AROG pharmaceuticals: Research Funding; ASTEX: Research Funding; Celgene: Consultancy, Research Funding. Shpall:Affirmed GmbH: Research Funding. Agrawal:Arog: Employment. Champlin:Sanofi: Research Funding; Otsuka: Research Funding.

Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 407-407 ◽  
Author(s):  
Preet Paul Singh ◽  
Shaji K Kumar ◽  
Betsy R. LaPlant ◽  
Morie A Gertz ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Cell Transplant ◽  
Grade 3 ◽  
Substantial Heterogeneity

Abstract Background Conflicting results have emerged, especially with respect to the impact on overall survival (OS), from trials evaluating lenalidomide maintenance (LM) therapy after induction therapy alone or post-autologous stem cell transplant (ASCT) in multiple myeloma (MM). We performed a systematic review and meta-analysis of existing outcome data from LM trials to evaluate role of lenalidomide as maintenance strategy in MM. Patients and methods A comprehensive search of electronic databases and abstracts through June 2013 was performed to identify randomized controlled trials (RCTs) that compared LM vs. placebo/no maintenance. Single arm studies were excluded. Pooled hazard ratio (HR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) were calculated using the random-effects model for clinical endpoints of progression free survival (PFS), OS, response rate (RR) and adverse events (AEs), including second primary malignancies (SPMs). Analyses were performed using Comprehensive Meta-Analysis Software Version 2. We assessed between-study heterogeneity with the Cochran Q test and quantified its extent with the I2 statistic. Results Overall, five RCTs, with data extractable from four phase III trials (3 publications and 1 abstract) were identified (n= 1935). All studies were RCTs with an adequate randomization. MRC MM XI study was excluded from analyses as survival data are not available. Two placebo controlled trials (IFM 05-02, CALGB 100104) addressed the role of LM post-ASCT, one placebo-controlled trial (MM-015) studied LM therapy in the non-transplant setting and the remaining trial (RV-MM-PI209) had a 2 X 2 design comprising of both ASCT and non-transplant randomized arms followed by a second randomization of LM versus no maintenance. There was no heterogeneity for estimate of PFS results (Cochran Q, p=0.68; I2=0%), but considerable heterogeneity for estimate of OS (Cochran Q, p=0.09; I2= 55%), among the studies. There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance (Figure 1). Best response during maintenance was reported only in 2 studies and odds of responding (very good partial response or better) were not significantly different with LM (OR 1.28, p=0.3). Grade 3-4 AEs data were available from 3 trials for calculation of pooled OR with LM compared with placebo. We observed a nearly two-fold increase in the risk of SPMs with LM (OR 1.99; 95% CI, 1.31–3.04; p=0.001). Patients on LM were more likely to have grade 3-4 AEs than placebo: neutropenia (OR 4.9, p<0.001), thrombocytopenia (OR 2.7, p<0.001), fatigue (OR 2.3, p=0.01) and venous thromboembolism (OR 3.2, p=0.02). Odds of discontinuing treatment were also significantly higher in patients on lenalidomide (OR 2.9, p<0.001). Conclusions Meta-analysis of RCTs demonstrates significant improvement in PFS and modest improvement in OS with LM. There is an increased risk of grade 3-4 adverse effects, including SPMs with LM. Substantial heterogeneity for estimate of OS among protocols is a limitation of this analysis. Lack of uniform access to lenalidomide upon disease progression in the placebo/no maintenance arms of the constituent studies should be taken into account while interpreting aggregate effect estimates for OS in this meta-analysis. OS: Cochran Q p=0.09, I2=55%, substantial heterogeneity PFS: Cochran Q p=0.68, I2=0%, minimal heterogeneity Disclosures: Off Label Use: Lenalidomide for maintenance therapy in multiple myeloma. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Bergsagel:Onyx: Consultancy. Lacy:Celgene Corporation: Research Funding.

scholarly journals Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

scholarly journals Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 339-339 ◽  
Author(s):  
Jeanette K Doorduijn ◽  
Monique C. Minnema ◽  
Marie Jose Kersten ◽  
Pieternella J Lugtenburg ◽  
Martin R. Schipperus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Induction Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Mabel Rodriguez ◽  
Nelly G. Adel ◽  
Sean Devlin ◽  
Sergio A Giralt ◽  
Heather Landau
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Hospital Days ◽  
Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

scholarly journals The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3439-3439
Author(s):  
Brandon B. Wang ◽  
Mark A. Fiala ◽  
Mark A. Schroeder ◽  
Tanya Wildes ◽  
Armin Ghobadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
The Impact

Abstract Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear. Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results. Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID). The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1. Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months. Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT. Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance. At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed. In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002). Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Multiple Myeloma: CALGB 100104

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 37-37 ◽  
Author(s):  
Philip L. McCarthy ◽  
Kouros Owzar ◽  
Kenneth C. Anderson ◽  
Craig C. Hofmeister ◽  
David Duane Hurd ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Disease Progression ◽  
Board Of Directors ◽  
Stable Disease ◽  
Interim Analysis ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Advisory Committees

Abstract Abstract 37 The primary objective of CALGB 100104 was to determine if maintenance lenalidomide would prolong time to progression (TTP) after single AHSCT for multiple myeloma. Eligibility included: Stage I-III multiple myeloma, ≤ 1 year from diagnosis, ≥ 2 months of induction with stable disease or better and age < 70 years. AHSCT regimen was melphalan 200 mg/m2. Patients (pts) with stable disease or better were randomized double-blinded at day 100–110 post-AHSCT to lenalidomide or placebo, after stratification by diagnostic β2-microglobulin (β2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months and continued until disease progression. Drug was stopped and dose reduced according to the development of toxicity. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and de-escalated by 5 mg or maintained as tolerated at 15, 10, 5 mg daily or 5 mg daily for 21 of 28 days per month. All pts required some form of anticoagulation including aspirin, warfarin or heparin compounds. There was no consolidation therapy. Results: 568 pts were enrolled before AHSCT (04/15/05-07/03/09) from 47 centers. Of 108 pts (19%) not randomized, reasons were: progressive disease/no response 16%, adverse events (AEs) 5%, died during therapy 2%, refusal 26 %, other disease 1%, other therapy 4 %, other reasons 33%, unknown 14%. Pt characteristics in the lenalidomide arm and placebo arm respectively were: median age (range) 58 (29-70) and 57 (39-70); male gender 48% and 52%; β2M >2.5 mg/L, 28% and 27%. For 554 pts with complete data, induction regimens were thalidomide based (27%), lenalidomide based (22%), bortezomib based (20%), bortezomib and thalidomide based (12%), bortezomib and lenalidomide based (9%), dexamethasone based (4%), lenalidomide and thalidomide (3%), lenalidomide, thalidomide and bortezomib (1%), other (1%) and missing (1%); hence 74% of pts received either lenalidomide or thalidomide prior to enrollment. The primary endpoint of the study, TTP was met in a planned protocol interim analysis in the 3rd quarter of 2009 and the study results were released on 12/17/09. This updated 3rd interim analysis for TTP includes further events up until 12/17/09 after which study pts were un-blinded. This interim analysis is based on 460 randomized pts with approximately 33% of the required number of events (progression or death before progression) observed. The median follow-up is 17.5 months from ASHCT. The number of events among 231 pts randomized to lenalidomide was 44 compared to 91 among 229 pts randomized to placebo. The one-sided unadjusted P-value was <0.0001. Pts receiving lenalidomide experienced a 61% reduction in the risk of disease progression or death when compared to pts receiving placebo. The estimated hazard ratio was 0.39 (95% CI,0.27-0.56 p < 0.0001). The preliminary estimated median TTP is 42.3 months for the lenalidomide arm and the estimated median TTP is 21.8 months for the placebo arm. Deaths in the lenalidomide and placebo arms were 19 and 28 respectively (p=0.13) and as of this analysis, there is no difference between these two arms. Significant improvements in TTP were observed in the lenalidomide maintenance arm regardless of β2M level or prior thalidomide or lenalidomide induction therapy. For 389 reported pts, the post-randomization, hematologic AEs were Gr 3 (32%), Gr 4 (13%) and Gr 5 (0) for the lenalidomide arm and Gr 3 (6%) Gr 4 (4%) and Gr 5 (0) for placebo (p=0.0001). The non-hematologic AEs were Gr 3 (30%), Gr 4 (3%) and Gr 5 (1%) for the lenalidomide arm and Gr 3 (19%), Gr 4 (3%), and Gr 5 (2%) for placebo (p=0.0048). Comparing lenalidomide versus placebo post-randomization pooled Gr 3–5 AEs, there were significantly more episodes of thrombocytopenia (11% versus 3%, p=0.01), neutropenia (44% vs 8%, p<0.0001) anemia (5% vs 1%, p=0.0082) and all infections (16% vs 3%, p<0.0001) with lenalidomide. There were no significant differences in incidence of fatigue, neuropathy, rash and thromboembolism. A minority of patients discontinued therapy due to AEs (12%, 28 of 231 on lenalidomide vs 2%, 5 of 229 on placebo) and for other reasons (13%, 29 of 231 on lenalidomide vs 6%, 14 of 231 on placebo). Conclusions: Long term administration of lenalidomide is feasible. When compared to placebo controls, lenalidomide initiated at day 100–110 post-AHSCT in multiple myeloma patients significantly delays TTP. Disclosures: McCarthy: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide maintenance therapy for myeloma following autologous hematopoietic cell transplant. Anderson:Millenium: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hurd:Celgene: Research Funding. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Speakers Bureau. Callander:Millenium: Research Funding. Maziarz:Millenium: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Novartis: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Shea:Millenium: Consultancy, Research Funding.

Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Yong Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2089-2089 ◽  
Author(s):  
Francesca Gay ◽  
Federica Cavallo ◽  
Tommaso Caravita ◽  
Maide Cavalli ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Solid Tumors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Abstract Background High-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. Aims To compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. Methods A 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. Results From November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance. After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001). A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics. The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects. During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200. During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. Conclusion The administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures: Gay: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

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