Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Maria-Victoria Mateos ◽  
Rohan Medhekar ◽  
Istvan Majer ◽  
Mehmet Turgut
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Literature Review ◽  
Board Of Directors ◽  
Unmet Need ◽  
Publicly Traded ◽  
First Line ◽  
Advisory Committees ◽  
Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Risk Factors Associated with Development of Extramedullary Disease in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5596-5596
Author(s):  
Martin Stork ◽  
Sabina Sevcikova ◽  
Marta Krejci ◽  
Zdenek Adam ◽  
Viera Sandecka ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
First Line ◽  
Advisory Committees ◽  
Line Of Therapy

Abstract Background Multiple myeloma (MM) is the second most common hematological malignancy characterized by plasma cell (PC) infiltration of the bone marrow. Unfortunately, better imaging techniques convey multiple reports about increased incidence of the so-called extramedullary disease of MM (EM), an aggressive, mostly resistant entity with poor prognosis for patients. EM probably develops because of 'bone marrow escape' of PC subclone that migrates out of the BM infiltrating soft tissues losing dependence on the BM microenvironment, either partially or completely. There are two types of EM - primary, found at the time of MM diagnosis, and secondary, found at the time of MM relapse. However, there are very few reports about EM. Aims This study aims to analyze risk factors connected to EM development. Methods Data from the Registry of Monoclonal Gammopathies (RMG) were analyzed. The RMG represents a database for collection of clinical data concerning diagnosis, treatment and follow-up of Czech MM and other monoclonal gammopathies patients. In total, data of 4985 MM patients were collected into the RMG database between 2007 and June 2017. Our analysis compared patients who developed EM at initiation of first or higher line of therapy with patients without EM during at least 5-year-long follow-up (patients who died earlier included). Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with EM occurrence at first line and relapse, respectively. Results In total, 4985 MM patients data were collected into the RMG database between 2007 and 2017. Patients were treated with bortezomib, lenalidomide, thalidomide, pomalidomide, ixazomib and daratumumab. Regardless of treatment, EM patients responded worse than MM patients did to any form of treatment. While primary EM patients had similar PFS as MM patients, OS was significantly worse (48.7 vs 60.6 months, resp.). Secondary EM patients did even worse, with PFS 8.7 months and OS 23.8 months only. We found 543 MM patients (10.9%) who developed EM during the entire follow-up. Out of these EM patients, we found 309 patients who were diagnosed with primary EM at initiation of first line of therapy. At initiation of 2nd line of treatment, we found 111 secondary EM patients. At 3rd, 4th and 5th, we found 61, 39 and 23 EM patients, resp. Finally, 309 patients who developed EM at initiation of 1st line and 234 patients who developed EM at initiation of further treatments were compared to 2092 patients who did not develop EM during the entire course of the disease. Overall, occurrence of EM at 1st or higher lines of treatment was associated with younger age, male sex, low ISS, D-S substage A, low B2 microglobulin, low creatinine, high hemoglobin, elevated thrombocytes, other types of M-Ig than IgG and presence of bone lesions. For EM cases found only at initiation of 1st line (primary EM), we found association with high ECOG status, low LDH, low M-protein quantity and low % of plasma cells infiltration in the bone marrow. For EM cases found at MM relapse (secondary EM), we found association with high D-S stage, high LDH, high CRP, high Ca, del13q and gain1q. Conclusion EM remains an aggressive disease with poor prognosis regardless of use of novel drugs. Surprisingly, in our group of patients, most EM disease developed early in the course of the disease - more than 60% at first relapse. We analyzed risk factors connected to development of EM and found that LDH, hemoglobin, thrombocytes and M-Ig status were associated with EM development. We suggest that in such patients, PET/CT or whole body MRI should be performed regularly to ensure early detection of EM. Grant support: AZV 17-29343A. Disclosures Maisnar: BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Patient Profile and Treatment Patterns in a Commercially Insured Population with Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5880-5880
Author(s):  
Nathan H Fowler ◽  
Yanni Hao ◽  
Stephen Lim ◽  
Guifang Chen ◽  
Frank Li ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Second Line ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Third Line ◽  
Line Of Therapy

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. Patient characteristics and burden of FL are incomplete and vary from previous studies. This study evaluated patient profile, including patient characteristics, treatment patterns, and duration using real-world data. Methods: Using the Truven MarketScan® databases, patients with FL who were newly initiated with FL indicated regimens were identified from 1/1/2010-12/31/2013 (initial treatment identification period). Patients were selected if they were ≥18 years old, had 1 FL ICD-9 code (202.0) as primary or secondary diagnosis, at least 1 FL commonly prescribed systemic anti-cancer therapy after the diagnosis, and did not use any FL indicated regimen in the past 6 months prior to first agent included in the initial treatment identification period. These patents were followed ≥3 months or to June 30, 2018. Primary outcomes were the distribution of regimens by line, the number of patients who switched from first- to second-line therapies, and from second- to third-line therapies. The treatment duration by line of therapy and regimen were also analyzed. Discontinuation was defined as 3 months without receiving a regimen after treatment. Results: This study identified 4,970 patients who initiated treatment for FL. Of these patients, 48.1% were female (n=2,390), with a mean age of 62.0 (SD: 14.0) years. The average follow-up time was approximately 2 years (median: 733 days). In this analysis, 4,970 patients with FL received first-line therapy for 153 days (median: 94 days), 1,985 received second-line therapy (39.9% of patients who received first-line therapy) for 208 days (median: 80 days), and 664 received third-line therapy (13.4% of patients who received first-line therapy) for 117 days (median: 43 days). Of the 4,970 patients on first-line therapy, 453 (9.1%) remained on first-line therapy, 2,532 (51.0%) discontinued treatment, and 1,985 (39.9%) patients switched to the next line of therapy during the follow-up period. Of the 1,985 patients who switched to second-line therapy, 328 (16.5%) remained by the end of follow-up period, 993 (50.0%) discontinued, and 664 (33.4%) switched to the next line of therapy during the follow-up period. Of the 664 patients who switched to third-line therapy, 125 (18.8%) remained, 269 (40.5%) discontinued, and 270 (40.7%) switched to the next line of therapy. The most common first-line regimens in descending order received by patients were rituximab (n=1,478, 29.7%), R-CHOP (n=1,368, 27.5%), BR (n=1,050, 21.1%), R-CVP (n=371, 7.5%), and FCR (n=63, 1.3%). Second-line treatment regimens were (N=1,985) rituximab (n=992, 50.0%), BR (n=202, 10.2%), R-CHOP (n=138, 7.0%), and R-CVP (n=120, 6.1%). Third-line treatment regimens were (N=664) rituximab (n=228, 34.3%), BR (n=91, 13.7%), R-CHOP (n=75, 11.3%), cyclophosphamide (n=35, 5.3%) and R-CVP (n=31, 4.7%). Conclusion: This data set describes the percentage of patients that transition from first- to second-line and second- to third-line treatment for FL. The primary regimens used across the treatment lines conform to those recommended by the NCCN guidelines. In addition, smaller numbers of non-recommended regimens were reported. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lim:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Consultancy, Employment. Li:Novartis Pharmaceuticals Corporation: Employment. Arcona:Novartis Pharmaceuticals Corporation: Employment.

scholarly journals The Prognostic Significance of Acquired 1q22 Gain in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Hadiyah Y. Audil ◽  
Joselle Cook ◽  
Patricia Greipp ◽  
Prashant Kapoor ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Significance ◽  
Advisory Board ◽  
Control Group ◽  
First Line ◽  
Advisory Committees

Background: Within the heterogeneous genomic landscape of multiple myeloma (MM), clonal evolution including the acquisition of risk-defining mutations and chromosomal abnormalities is a recurrent event and can be detected by fluorescence in situ hybridization (FISH). The effects of acquired abnormalities on clinical outcomes have not been well defined. We previously reported that patients who acquired 17p deletion [del(17p)] during the course of their disease had a significantly reduced overall survival (OS) by 38 months compared to patients who did not acquire del17p (Lakshman et al 2019). Similarly, while de novo gain of the long arm of chromosome 1 (1q22 gain) is a known high-risk aberration associated with significantly shorter OS and progression-free survival (PFS) in MM, the prognostic significance of acquired 1q22 gain has not been described. The primary objective of this study was to analyze factors predictive for acquired 1q22 gain and determine its impact on survival. Methods: We identified MM patients from the Mayo Clinic Dysproteinemia Database who had at least one follow up FISH performed ≥6 months from diagnosis. The clinical characteristics, concomitant cytogenetic abnormalities, first line treatments administered, and OS were compared between patients with acquired 1q22 gain and patients who did not acquire this abnormality. The Mayo Clinic IRB approved this study. Results: A total of 1041 MM patients met the inclusion criteria. Of these, 63 patients (6.1%) had acquired 1q22 gain, defined as being negative for 1q22 gain on initial FISH at diagnosis and having this abnormality detected on subsequent FISH. Median age at diagnosis was 59 years and 56% were male. Median time to acquisition of 1q22 gain was 60 months (range 8-140 months). We identified one control patient for each case who was diagnosed within one year of the case and had a subsequent FISH performed at a similar duration from diagnosis. Patients with acquired 1q22 gain had similar baseline characteristics except for a higher proportion of high-risk (HR) FISH at diagnosis [t(4;14), t(14;16), t(14;20), and del(17p13)] when compared to controls (27% HR FISH versus 6% HR FISH; P<0.01). 1q22 gain was concomitantly present with trisomies in 33 patients (54%), monosomy 13 in 24 patients (39%), t(4;14) in 8 patients (13%), and del(17p13) in 7 patients (12%). All patients received treatment prior to acquisition of 1q22 gain. Of the 63 patients, first line induction therapy consisted of proteasome inhibitor (PI) with steroid in 43%, immunomodulatory drugs (IMiD) with steroid in 40%, and PI + IMiD with steroid in 17% of patients. 54 patients (85%) received upfront stem cell transplant (SCT) (median 5.9 months to SCT), compared to 50 patients (79%) in the control group who received SCT. The median follow up of all 126 patients was 6.8 years. There was a statistically significant reduction in median OS from diagnosis in patients with acquired 1q22 gain compared to the control group (10.8 years versus 13.0 years; P = 0.02; Figure 1). Predictors of acquisition of 1q22 gain were identified using a case-control method. Age ≥70 at diagnosis and presence of HR FISH at baseline appeared to increase the risk of acquiring 1q22 gain. Conclusion: Acquisition of 1q22 gain is a relatively uncommon occurrence, but notably reduced OS by 2.2 years compared to patients who did not acquire 1q22 during the course of their disease (P = 0.02). Older age and the presence of HR FISH at diagnosis increased the risk of acquisition of 1q22 gain. The presence of high-risk translocations at baseline suggests that acquisition of 1q22 gain occurs in the context of more aggressive disease biology. Disclosures Kapoor: Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Alnylam: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Intellia: Research Funding; Janssen: Research Funding. Gertz:Prothena: Consultancy; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Dingli:Apellis: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Janssen: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Cellectar: Other; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Carsgen: Other, Research Funding; Tenebio: Other, Research Funding.

scholarly journals Outcomes in Multiple Myeloma Patients Progressing on Lenalidomide Maintenance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1779-1779
Author(s):  
Larysa Sanchez ◽  
Erin Moshier ◽  
Alexander Coltoff ◽  
Ali Mustafa ◽  
Darren Pan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Retrospective Study ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Total Change ◽  
Advisory Committees ◽  
Line Of Therapy

Introduction: Lenalidomide (R) maintenance therapy in multiple myeloma (MM) has been shown to improve progression-free survival (PFS) and overall survival (OS) after autologous stem-cell transplantation (ASCT). Even in the transplant ineligible population, R until progression is associated with improved PFS. The ever-increasing use of R maintenance therapy, however, eventually leads to refractoriness to R at maintenance doses. Moreover, clinical trials with len-dex (Rd) backbone regimens including daratumumab, elotuzumab, ixazomib, and carfilzomib have all excluded such patients (pts). This is particularly an issue for elotuzumab and ixazomib, which have no single agent approval. There are currently no published data on the outcomes of full dose Rd or Rd backbone containing regimens in pts refractory to R maintenance. A prospective randomized trial would be difficult to perform given variability in pt factors (i.e. R tolerance, age, renal function) and disease factors (i.e. molecular risk and clinical vs biochemical progression). We therefore performed a retrospective study to characterize outcomes of pts on R maintenance therapy. Methods: This is a single-institution, retrospective study in which we reviewed the records of all consecutive pts with a diagnosis of MM at the Mount Sinai Hospital between February 2010 and October 2016. There were 465 pts identified who had maintenance R as a single agent or in combination with low-dose dexamethasone or prednisone. Pts were excluded if insufficient data were available or < 3 month (mo) follow up from time of initiation of R maintenance. Time to progression (TTP) on R maintenance, next line of therapy, and PFS on next line of therapy were determined using Kaplan Meyer analysis. Results: A total of 350 pts were included in this study. Baseline characteristics are summarized in Table 1. The median follow up time was 59 mos and median time on R maintenance was 21.0 mos. 172 pts (49%) progressed while on R maintenance or within 60 days of R discontinuation. 51 pts (15%) remain on R maintenance as of last follow up. The remaining 127 pts (36%) discontinued R for reasons other than progression and either progressed after 60 days (median 658 days, range 91-2053 days) or have not progressed. The median TTP on R maintenance was 34.2 mos (Fig 1A) and the majority of these were characterized by the treating physician as biochemical (65% during maintenance and 56% after R discontinuation). Of the patients with serologic and symptomatic progression, the majority were by bone disease (24% and 37%, respectively). 234 pts had data available on next line of therapy and the median PFS on this next line was 16.8 mo (95% CI: 13.2-20.1), however the PFS was shorter for those who had progressed while on R maintenance versus those who had progressed after R maintenance had been discontinued (13.2 mos vs. 28.9 mos, respectively, p 0.0001). The median PFS according to next line of therapy for those who received an increase in R dose + dex vs 3rd agent added to Rd backbone vs total change in therapy was 9.5 mos vs 21.0 mos vs 14.2 mos, respectively (Fig 1B). The most common drugs added to an Rd backbone were bortezomib and elotuzumab with an associated PFS of 19.0 and 40.1 mos, respectively. The majority of those receiving elotuzumab + Rd had progressed on R maintenance (15/18 = 83%). The most common regimens for those with a total change in therapy are summarized in Table 2. Conclusions: The median TTP on R maintenance was 34.2 mos and while most progression was felt to be biochemical, of those with symptomatic progression as well, the primary manifestation was bone disease (approximately 30% of patients), highlighting the importance of surveillance osseous imaging in MM. While an increase in R dose with steroids was associated with an additional 9.5 mos PFS and a total change in regimen with 14.2 mos PFS, those who received an Rd containing triplet had impressive results. In particular, Rd + elotuzumab resulted in a PFS of 40.1 mos. Multivariate analysis accounting for the potential confounding patient and disease factors inherent to treatment selection in retrospective studies will be presented at the meeting. Disclosures Cho: BMS: Consultancy; GSK: Consultancy; Takeda: Research Funding; The Multiple Myeloma Research Foundation: Employment; Genentech: Honoraria, Research Funding; Agenus: Research Funding; Celgene: Honoraria, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy. Madduri:Abbvie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; undation Medicine: Consultancy. Parekh:Celgene Corporation: Research Funding; Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy. Richter:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Chari:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase II Study of Elotuzumab in Combination with Pomalidomide, Bortezomib, and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3169-3169 ◽  
Author(s):  
Andrew J. Yee ◽  
Jacob P. Laubach ◽  
Erica L. Campagnaro ◽  
Brea C. Lipe ◽  
Omar Nadeem ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Grade 3 ◽  
Line Of Therapy

Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.

Allogeneic Hematopoietic Stem Cell Transplantation in First Line High Risk Multiple Myeloma Patients: Evolving Strategies with the Immunomodulating Drugs.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3116-3116
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Jean El-Cheikh ◽  
Stéphane Morisset ◽  
Anne Sirvent ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Induction Treatment ◽  
High Dose ◽  
First Line ◽  
Advisory Committees ◽  
Β2 Microglobulin

Abstract Abstract 3116 We evaluated in this study the efficacy and toxicity of a pilot tandem auto-HSCT strategy followed by reduced intensity conditioning (RIC) and allogeneic HSCT with the post-allo-HSCT introduction of bortezomib and donor lymphocyte infusion (DLI) in high risk multiple myeloma (MM) patients (Group1). We compared our results to those observed after traditional tandem auto-RIC-allo-HSCT without bortezomib after allo-HSCT (Group2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the IFM previous prospective studies. Matching variables were: diagnosis date, age, gender, β2 microglobulin, cytogenetics and induction treatment, the matching ratio was 1:3. Groups 1 & 2 included MM patients of age ≤ 65 years who previously received vincristine, doxorubicin and high-dose dexamethasone (VAD) or bortezomib plus dexamethasone (VD) as induction treatment followed by auto-HSCT. Only patients who achieved at least a partial response (PR) after auto-HSCT were included. Patients must have an HLA identical related or unrelated donor, and at least one of the following factors: β2 microglobulin level >3mg/L, del13, t(4;14) or del17p. The conditioning regimen combined fludarabine 30 mg/m2/d (d-5→d-1), busilvex IV 3.2 mg/kg/d (d-4, d-3) and ATG 2.5 mg/kg/d (d-2, d-1). GVHD prophylaxis consisted on cyclosporine A 3mg/Kg from day -1 with the addition of methotrexate at days 1, 3 and 6 in case of ABO incompatibility. In group1, by day 90 post-allo-HSCT, patients not in CR received 4 cycles of bortezomib 1.3 mg/kg (21 days cycle, on days 1, 4, 8 and 11); if the CR was not achieved, increasing doses of DLI were administered. Allo-HSCT groups included 25 patients (12 in group1 and 13 in group2), 18 males and 7 females with a median age of 51 years [28–67], there were 15 IgG, 6 IgA and 4 light chains MM. Fourteen (56%) patients had del13, 7 (28%) del17 and 17 (68%) had β2 microglobulin level >3mg/L. Induction treatment was VAD in 16 (64%) patients and VD in 9 (36%). Twenty-one (84%) patients received high dose melphalan (200 mg/m2) while the rest received a dose of 140 mg/m2; auto-HSCT was performed after a median time of 5.5 months [3.6–15.3] from diagnosis. The median time between auto-HSCT and allo-HSCT was 3.8 months [2.5–8.5]. The stem cell source was peripheral HSC in 22 (88%) of cases and the median number of infused CD34+ cells was 6.1×106cells/Kg (range: 2–13) from 16 identical siblings and 9 HLA (10/10) matched unrelated donors. Sex matching was as follow: F→M:9, F→F:3, M→F: 4 and M→M:9 and for ABO compatibility, 18 (72%) were compatible, 1 had minor incompatibility and 6 major incompatibility. At allo-HSCT, one patient was in CR, 4 in very good partial response (VGPR) and 20 patients were in PR. The matched population included 36 controls for group1 and 39 for group2. At Day 90 after allo-HSCT, all patients engrafted, 10 patients were in CR and 15 patients were in less than CR. Nine patients in group1 received bortezomib, 3 reached a CR while the 6 others were still in PR and received increasing doses of DLI. There were 8 acute GVHD [7 grade II (3 in group1) and 1 grade III in group1] and 11 chronic GVHD [3 lim. (all in group1) and 8 ext. (1 in group 1)]. No GVHD reactivation was observed after DLI. At the last follow-up, 14 patients are alive (9 in group1 and 5 in group2), 10 patients were in durable CR1 post-allo-HSCT and 4 patients in PR after DLI; 11 patients died (3 in group1: all from progression; 8 in group2: 5 from progression and 3 from TRM). After a median follow-up of 55 months [3–142], the median OS was not reached in group1 vs. 65 months (51-NR) in its matched patients (p=0.027); and it was 96 months (49-NR) in group2 vs. 91 months (32-NR) in its matched patients (p=0.77). The median PFS was 49 months (29-NA) in group1 vs. 25 months (21–35) in its matched patients (p=0.0045); and it was 31 months (22-NR) in group2 vs. 28 months (21–40) in its matched patients (p=0.0776). The encouraging results observed in group1, in terms of OS, PFS and toxicity are due to the introduction of IV busilvex and better ATG administration schedule in addition to the immunomodulating role of bortezomib in the elimination of the residual disease. In addition, we showed a good GVL effect after DLI with a durable stability of the disease without any important GVHD complication. According to our promising results, we should reconsider the allo-HSCT in the context of first line treatment for high risk MM patients. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals High-Dose Melphalan Significantly Increases Mutational Burden in Multiple Myeloma Cells at Relapse: Results from a Randomized Study in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Mehmet K. Samur ◽  
Marco Roncador ◽  
Anil Aktas-Samur ◽  
Mariateresa Fulciniti ◽  
Abdul Hamid Bazarbachi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Publicly Traded ◽  
Private Company ◽  
Advisory Committees ◽  
High Dose Melphalan ◽  
New Mutations

We recently shown that high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) as first line therapy in young (&lt;66 yrs) multiple myeloma (MM) patients significantly improves progression-free survival (IFM/DFCI 2009 study). However, the impact of alkylating agent melphalan inducing N-alkylpurine-monoadducts forming interstrand crosslinks (ICLs) in surviving myeloma cells remains an important biological question. We here profiled samples from the IFM/DFCI 2009 study, where patients were randomized to RVD+HDM vs RVD alone, to identify genomic changes induced by HDM and observed at relapse. We analyzed paired purified MM cells collected at diagnosis and at relapse from 68 patients using deep (75X) whole genome sequencing. Forty-five patients were treated with RVD only, while 23 patients received RVD followed by HDM. There was no significant difference between the 2 groups in regard to disease characteristics including sex, age, cytogenetic risk, and best response. Median follow-up was similar (29 vs 31 months, respectively), removing longer follow up as a confounding variable. The number of mutations at diagnosis was similar on both arms (7137 [IQR=3742] vs. 7230 [IQR=3702], p value = 0.67). Although mutational load increased in both arms; there was a significantly higher increase in number of mutations and indels in the HDM arm compared to RVD alone (mutations 5686 vs 1745, p=1.4e-5; and indels 467 vs 360, p= 0.02, respectively). Using a model incorporating number of new mutations, depth, and purity, we found that HDM causes a 4.1 fold higher mutation accumulation rate per month than RVD only (158.3 vs 38.3 mutations/ month; p=0.003). Importantly, newly acquired mutations were localized to regions which overlap with transcribed regions, and accumulated at significantly higher rate in the HDM group (p=0.009). In contrast, we did not observe any significant changes in copy number alterations (CNAs) and structural variants, including translocations, between both arms. A significant change in frequency of driver mutations including RAS/RAF, FAM46C, TP53, and DIS3 was not observed at the time of relapse. Clonality level was increased only for KRAS (p=0.054), while all other specific driver genes had similar clonality level at diagnosis and relapse. Interestingly, a significant increase in mutations involving MYO16 and SLC7A8 genes was observed at relapse in both arms, implicating components of the induction regimen (RVD). Investigating the mutational signature utilization in only newly acquired mutations identified 4 signatures: APOBEC, HR Double Strand Repair, clock-like signature, and unknown. k-means clustering analysis of samples based on signature utilization showed four distinct clusters. All patients clustering with high DNA repair signature utilization were in the HDM arm (65% HDM patients), the majority of whom achieved CR or sCR (74%); these patients acquired 8308 (range 3302-19107) new mutations between diagnosis and relapse. None of the RVD only treated patients were in this cluster. The remaining 35% HDM group patients were clustered with RVD samples and showed unknown signature utilization. Furthermore, motif enrichment analysis identified CYWR and ATGAGATV (p &lt; 1e-130) as enriched motifs around the new mutations in HDM compared to RVD cohort. Importantly and as expected, DNA damage repair pathway genes were frequently targeted in the HDM group: 72% HDM samples accumulated DDR gene mutations vs. only 17% in the RVD alone arm (p &lt; 0.001). At the time of relapse, 100% HDM arm patients had at least one DDR gene mutation and 80% had two or more, while only 37% RVD only group had one or more such mutation. Finally, we have reconstructed phylogenetic and evolutionary trajectories based on mutation and copy-number data from samples at diagnosis and relapse. The clonal composition in both arms was similar at diagnosis; however, HDM caused a significant shift to more subclonal mutations at relapse. chromothripsis and chromoplexy events were detected in 30% patients at diagnosis, which remained constant at relapse regardless of treatment. In summary, we describe significant accumulation of mutations following high dose melphalan. This fundamental molecular change in the disease at relapse, suggests the need for reappraisal of the optimal use and sequencing of high dose melphalan in the era of novel agents. Disclosures Fulciniti: NIH: Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Moreau:Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Anderson:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Parmigiani:Phaeno Biotehnologies: Current equity holder in publicly-traded company; CRA Health: Current equity holder in publicly-traded company; Foundation Medicine Institute: Consultancy; Delphi Diagnostics: Consultancy; BayesMendel Laboratory: Other: Co-lead. Munshi:Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; C4: Current equity holder in private company; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy.

scholarly journals Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL) for Relapsed/Refractory Waldenström Macroglobulinemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1607-1607 ◽  
Author(s):  
Giulia Benevolo ◽  
Simone Ferrero ◽  
Alessandro Andriani ◽  
Anna Castiglione ◽  
Anna Baraldi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Salvage Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Grade 3 ◽  
Line Of Therapy

Abstract BACKGROUND: Standard rituximab plus chemotherapy salvage treatment has shown moderate activity in patients with relapsed/refractory Waldenström's macroglobulinemia (RR-WM), with 18-months progression free survival (18-PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi (F.I.L.) we designed a multicenter phase II study to assess the efficacy of a combination of bendamustine, rituximab and bortezomib (BRB) in improving these results. METHODS and PATIENTS: This single-arm phase II study tested the hypothesis that 18-PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan was: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months. Patients with RR-WM after first line of therapy were enrolled in 18 F.I.L. centers, from October 2014 to November 2017. In the last 23 patients MYD88L265Pwas tested by the recently described droplet digital PCR (ddPCR) assay both on bone marrow (BM) and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). RESULTS: At the time of analysis, 29 patients completed the six cycles of therapy, six patients stopped therapy for toxicity, two patients died and one had just finished therapy and was not yet evaluated. 18-PFS was 84% (95%CI: 61-94%), with two progressions and two deaths without evidence of progression (one cerebrovascular accident during the fifth cycle and one pulmonary embolism at three months follow up). On an intention-to-treat analysis (N=37), overall response rate was 70%, (N=26) including 4 (11%) complete, 11 (30%) very good partial, 10 (27%) partial responses and 1 (3%) minimal response according to IWM response criteria. Overall, treatment was well tolerated, the most common adverse events of any grade included 13 patients (34%) experiencing grade 3-4 neutropenia, especially in cycle 4 (leading in four cases to treatment discontinuation). Peripheral nervous system toxicity was observed in five patients (13%; 4 of grade 1-2 and 1 of grade 3-4), with no discontinuations. Serious adverse events were observed only in three patients, mainly rash, all resolved. All the 23 patients assessed for MYD88L265Pat baseline scored positive in BM, while only 18/23 (78%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. Among the 21 patients monitored for MRD after treatment 5 scored MRD negative in BM and 13 in PB, highlighting the deep activity of the BRB regimen in clearing the disease. CONCLUSIONS: Among patients with RR-WM after first line of therapy, BRB regimen is a well-tolerated salvage treatment, resulting in high rates of PFS at 18 months. Moreover, the deep anti-tumor activity of this regimen is highlighted by the promising rates of both clinical and molecular responses. More complete and mature results will be presented during the meeting. (ClinicalTrials.gov number: NCT02371148). Disclosures Gaidano: AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Physicians' Behavior, Diagnostics and Treatment Patterns in Multiple Myeloma Management in Belarus: Nation-Wide Survey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5853-5853
Author(s):  
Ihar Iskrou ◽  
Anatoly Uss ◽  
Sergey Golubev ◽  
Vitali Papok
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Plasma Cells ◽  
Treatment Patterns ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Advisory Committees ◽  
First Line Treatment

Abstract Background: Although multiple myeloma (MM) remains an incurable disease, its management progressed during the last decade owing to novelties in diagnostics and new therapeutic options. There is a general belief in heterogeneity of the novel technologies penetration among countries and regions, such differences should be studied. Information on physicians' knowledge, preferences and satisfaction is limited worldwide and may provide important insights for explanation of differences in clinical decision making in routine practice. Moreover, data on typical diagnostic and treatment patterns in real-world clinical setting are particular scarce in the Eastern European and Eurasian region. Methods: A cross-sectional national survey of physicians treating MM in Belarus was performed from October 2017 till January 2018. Among 51 hematologists registered in the country 43 physicians involved in MM management in real clinical settings were approached. Printed forms of 21-item questionnaire containing multiple choice questions were used. We anonymously collected physicians' opinions on typical diagnostics and treatment patterns as well as their clinical reasoning, preferences and satisfaction. We assessed whether practice place and type, practical experience (length of service and average number of MM patients seen per year) and attitude to participation in clinical trials influence answers. Univariate analysis was conducted with Fisher's exact test. Results: All approached physicians completed the survey. Among respondents 17 (40%) belonged to republican specialized centers, 37 (86%) were hospital-based physicians, 23 (53%) had more than 10 years of service, 28 (65%) seen more than 20 MM patients per year. 10 (23%) declared their experience in clinical trials and 20 (46%) had no experience but expressed readiness to be involved in. The clinical uptake of revised ISS for MM was 33%, among adopters physicians with more than 10 years in practice and who sees more than 20 patients per year dominated. The proportions of ISS users which believed that median survival for low-risk, standard-risk and high-risk MM patients to be > 12 months were 100%, 100% and 36%, respectively. For primary MM diagnosis 40% of respondents used MRI and 49% - CT-imaging. Physicians used the next criteria for treatment response : < 5% plasma cells (PCs) in bone marrow (88%), Ig level normalization (74%), absence of clonal PCs in BM (60%), and absence of new lesions (37%). The possibility to perform autologous stem-cells transplantation (ASCT) was revealed as a key factor for first-line treatment choice. Various bortezomib-based regimens were predominant treatment options for first-line treatment of patients eligible for ASCT. Melphalan-containing regimens were more widely spread as first-line treatment of ASCT-ineligible patients. The majority of respondents (52%) practiced first-line treatment of more than 4 months of duration, while 41% of clinicians used second-line therapy of short duration (less than 6 months). In the relapse setting after ASCT the most common regimens were still bortezomib-based as well as schemes with bendamustine. In the second-line setting in patients who did not receive ASCT monotherapy was more commonly reported. In absence of high dose dexamethasone for oral use Belarusian physicians preferred treatment schemes with combination of drugs for IV and per os routes of administration. The predominant factors of drug choice were efficacy (91%) and cost (97%). The respondents reported satisfaction with current situation in diagnostics and treatment in 74% and 65% of cases, respectively. The factors influencing readiness for disease management change were clinical experience, hospital-based practice position and positive attitude to/participation in clinical trials. Conclusions: The study covers the gaps of information about real-world MM management in Belarus. The Belarusian physicians are aware about the modern place of ASCT in MM. Targeted education in specific aspects of MM management (disease biology understanding, clinical guidelines updates, risk evaluation and stratification) may result in wider adoption of innovative diagnostic approaches and treatment technologies. MM management should be further concentrated in large specialized clinical centers for plasma cells disorders. The survey results make possible and warranted further intercountry comparisons. Disclosures Iskrou: Takeda Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Belarus: Consultancy, Honoraria, Speakers Bureau; Novartis Belarus: Consultancy, Honoraria, Speakers Bureau; Nativita Belarus: Consultancy, Honoraria, Speakers Bureau; Octapharma Belarus: Consultancy, Honoraria, Speakers Bureau. Uss:Roche Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Golubev:Medical department of Takeda Belarus: Employment. Papok:Medical department of Takeda Belarus: Employment.

T-Bird (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], Dexamethasone) Therapy in Newly Diagnosed Symptomatic Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2937-2937
Author(s):  
Tomer M Mark ◽  
Manan Shah ◽  
Melissa Rodriguez ◽  
Ryann Quinn ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival ◽  
Line Therapy ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Abstract 2937 Background: The addition of thalidomide to BiRD therapy (clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) may enhance anti-myeloma activity of the combination while not adding to overall regimen toxicity, given the different side effect profiles of thalidomide and lenalidomide. We now report an update of the phase 2 trial of T-BiRD (thalidomide/Thalomid®, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) in up-front treatment of symptomatic multiple myeloma (MM). Methods: Twenty-six patients with newly diagnosed symptomatic MM received T-BiRD. T-BiRD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1, 8, 15, 22; and lenalidomide 25mg for days 1–21 of a 28-day cycle. Thalidomide was given at a dose of 50mg daily for the first week and thereafter at 100mg daily. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patients until disease progression. Results: Twenty-six patients were enrolled. The median number of T-BiRD cycles delivered was 6.5 (range 0–17). The overall response rate (ORR) to T-BiRD (audited at time of autologous stem cell transplant [ASCT] or other planned change in therapy) was 77% (4% progressive disease (PD), 19% stable disease (SD), 42% partial response (PR), 31% very good partial response (VGPR), 4% CR). Eight patients (31%) withdrew from study, including 4 (15%) early withdrawals prior to completion of cycle 2 (1 due to Grade 4 rash, 2 due to Grade 3 rash, and 1 due to renal failure secondary to MM). Excluding these early withdrawals, ORR was 86% (5% PD, 10% SD, 45% PR, 36% VGPR, 5% CR). In these patients, median time to PR was 1 cycle [range 1–5]; the median time to max response was 4 cycles [range 1–7]. All eighteen patients who electively underwent autologous stem cell collection were successful, with median 16.317 CD34+ cells/kg collected [range 5.8–43.9] over a median of 1.5 apheresis sessions [range 1–5]. Eleven subjects underwent ASCT as part of a first line of therapy with T-BiRD induction; ORR to first line therapy in these subjects was 100%, with 18% PR, 46% VGPR, and 36% CR. At 4 years of study follow-up for 1st line therapy, median progression free survival (PFS) and event free survival (EFS) was 135.6 and 65.3 weeks respectively. Median overall survival (OS) was not reached; at 4-year follow-up, 4 patients had died of progressive myeloma, giving an overall survival rate of 84.5%. Twelve patients experienced grade 3 non-hematologic toxicity (weakness: 4; rash: 3; popliteal vein thrombosis: 2; respiratory infection: 1; hyperglycemia: 1; anorexia/dysgeusia: 1; renal insufficiency: 1; dizziness: 1; psychomotor agitation: 1; myocardial infarction: 1). One subject had grade 4 rash during cycle 1. 1 subject died of progressive myeloma prior to completion of 10 days of cycle 1. Conclusions: T-BiRD is a highly active regimen in treatment-naïve multiple myeloma, with prolonged responses achieved; however, early treatment toxicity precluded extended use in up to a third of patients. Responding patients achieved PR within 1 cycle, indicating that this regimen may be useful when a swift drop in paraprotein is desired. T-BiRD allows for successful autologous stem cell collection and transplant outcomes. These data support the use of immunomodulatory-based regimens in the upfront treatment of MM and highlight the potential additive toxicities of the simultaneous administration of thalidomide and lenalidomide. Disclosures: Mark: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The combination of thalidomide and lenalidomide was tested in relapsed myeloma; the combination is not FDA-approved. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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