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.

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 Supermobilizers with High CD34 + Cell Collection for Autologous Transplant and Impact on Survival Outcomes in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1837-1837
Author(s):  
Eyal Lebel ◽  
Katherine Lajkosz ◽  
Esther Masih-Khan ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Cd34 Cells

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for selected patients with newly diagnosed multiple myeloma (MM). Studies in MM and lymphoma have suggested that ability to mobilize and collect a higher yield of CD34 + cells predicts for improved survival outcomes, perhaps reflecting better bone marrow reserve (Bolwell 2007, Raschle 2011). We aimed to validate this hypothesis by correlating high CD34 + cell collection ("supermobilizers") and survival outcomes in a large myeloma cohort with long follow-up. Methods: We retrospectively reviewed MM patients (pts) who underwent ASCT at our centre 2000-2010, correlating number of CD34 + cells collected with post-transplant progression-free survival (PFS) and overall survival (OS). Stem cells were mobilized using cyclophosphamide 2.5 g/m 2 IV (day 1), G-CSF 10 ug/kg/day SC (starting on day 4), and leukapheresis (day 11), targeting 4x10 6/kg but accepting a minimum of 2x10 6/kg to support a single transplant. Using a cut-off used in previous studies, pts were categorized as "supermobilizers" if ≥8x10 6/kg CD34+ cells were collected. Results: 621 pts were analyzed. Most pts (422/605; 70%) received high dose dexamethasone (HDD) alone or in combination with vincristine and adriamycin (VAD) for pre-transplant induction therapy (pre-dating the novel agent era) with only 18% (110/605) receiving more contemporary bortezomib-based induction (mostly cyclophosphamide, bortezomib and dexamethasone; CyBORD). The median number of CD34 + cells collected for all pts was 13.9x10 6/kg (range 2.1-61.8). The median CD34 + cells re-infused was 6.2x10 6/kg (range 2.1-25), as some cells were reserved for 2 nd ASCT, but median CD34+ cells collected correlated with CD34 + cells infused (Pearson coefficient 0.81, p&lt;0.001). At a median follow-up of 74 months (m), we were surprised to report an inferior PFS of 24.1m for the supermobilizers collecting ≥8x10 6/kg vs 33.7m for the &lt;8 group (p=0.038, Figure 1a), without differences in OS (p=0.612, Figure 1b). No further discrimination in PFS was observed when using a more extreme supermobilizer cut-off of 15x10 6/kg. To further understand the counterintuitive result of shorter PFS with higher mobilization capacity, we explored the continuous relationship between CD34 + cells and PFS, identifying another optimal cut-off of 4.5x10 6/kg. Pts collecting in the mid-range (4.5-8; n=129) achieved the best PFS of 34.5m, significantly improved over 24.1m in the ≥8 group (n=478) and 11.4m in the small group at the extreme lower collection range (n=14; ≤4.5x10 6/kg)(Figure 1c). A similar pattern was seen with OS (Figure 1d). Clinical and laboratory parameters that may impact both collection capacity and survival, such as age, ISS, and kidney dysfunction, were investigated as confounders but were similar between collection groups and did not predict for PFS in multivariable analyses. Treatment variables, however, differed between groups: the lower collection groups more often received bortezomib-based induction (29%, 31% and 14% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p&lt;0.001) resulting in deeper responses pre-transplant (VGPR 50% in the ≥8 group vs 43% in the 4.5-8 group, p=0.024) (Table 1). Use of maintenance therapy post-ASCT also differed (50%, 40% and 28% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p=0.006). Discussion: In this large cohort of 621 MM patients, we report that "supermobilizers" who collected ≥8 x 10 6 CD34 + cells/kg exhibit inferior PFS from transplant than those with less robust mobilization. We suspected that this unexpected observation was due to confounding variables, and identified differences in treatment, primarily greater use of bortezomib-based induction and post-transplant maintenance therapy in the lower collection group. This group was able to achieve deeper responses (≥VGPR) even before transplant than the supermobilizer group, leading to improved PFS. Although bortezomib is routinely used as induction therapy pre-transplant currently and is not felt to be stem cell toxic, it may impair mobilization to a lesser degree, leading not to abject failure of collection but lowered capacity to achieve "supermobilizer" status. Although more research is needed to validate this hypothesis, we can at minimum conclude that high stem cell collection does not appear to predict for a long-term survival advantage. Figure 1 Figure 1. Disclosures Reece: Millennium: Research Funding; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Chen: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

scholarly journals Ixazomib-Based Induction Followed By Single-Agent Ixazomib Maintenance in Transplant Ineligible, Newly Diagnosed Multiple Myeloma Patients: Updated Results of the EMN10-Unito Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Roberto Mina ◽  
Alessandra Larocca ◽  
Paolo Corradini ◽  
Nicola Cascavilla ◽  
Anna Marina Liberati ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p&lt;0.05) and VGPR (46%-48% vs 24%; p&lt;0.05) rates as compared to Id. The median PFS was 10.3 months with Id, 17.9 with ICd, 12.3 with ITd, and 13.8 with IBd, with a 2-year PFS probability of 31%, 39%, 27% and 40%, respectively. Median OS was not reached in either arm, without significant differences in the 2-year OS across arms (Id: 85%; ICd: 75%; ITd: 78%; IBd: 89%). Grade 3-4 non-hematological AEs were more frequent in the ITd arm (45%) as compared to the Id (17%), ICd (17%) and IBd (36%) arms, as well as the risk of treatment discontinuation due to AEs: ITd 17% vs Id 10%, ICd 12%, IBd 9%. Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; Celgene: 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; Bristol-Myers Squibb: Honoraria; Karyopharm: 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. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

scholarly journals Preliminary Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 840-840
Author(s):  
Sheeba K. Thomas ◽  
Jatin J. Shah ◽  
Hans C. Lee ◽  
Elisabet E. Manasanch ◽  
Donna M. Weber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Best Response ◽  
Grade 3

Abstract Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) and after myeloablative AuSCT in patients (pts) with multiple myeloma (MM) (Attal et al. NEJM 2012, McCarthy et al. NEJM 2012,). Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of pts with MM who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report preliminary results of the primary (PFS) and secondary (overall survival and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 28 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2 and q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=27 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until progression. LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity &gt; grade 1 and significant cytopenias (ANC &lt; 1000/mL, platelet count &lt; 100,000/ml). For the 1st 8 weeks, pts &lt;75 yrs receive 28 mg of DEX 3-24 hours pre-infusion, while pts ≥75yrs receive 8mg; pts receive 4-10 mg iv DEX immediately pre-infusion for all cycles. Pts also receive herpes zoster prophylaxis and thromboprophylaxis commensurate with standard recommendations. The primary endpoint of the study is PFS, defined as the time from AuSCT to clinical progression or death (whichever occurs first), or the time of last contact. Secondary objectives include best response, overall survival, incidence of second primary malignancies and adverse event (AE) profile. Total enrollment of 100 pts is planned. Pts will be followed for 48 months after the last patient is enrolled in the trial. Eligible pts had received no more than 2 lines of induction therapy, and were between 60-210 days post-AuSCT. Results: Patients (n=55) have been treated for a median of 14 cycles (2-30). At study entry, 13 pts (24%) had complete response (CR), 27 (49%) had very good partial remission (VGPR), 14 (25%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 28 pts (51%), VGPR in 23 pts (42%) and PR in 4 pts (7%). For those who have converted to CR on study, median time to CR has been 5 months. Of 14 pts in CR who have been tested for MRD while on study, 13 are negative by flow cytometry (minimum of 2 million cells evaluated; sensitivity 10 -4-10-5). Two of these 13 have converted from VGPR to MRD negativity at 4 and 14 months on study, respectively. With a median follow up of 21 months, 95% of pts (n=52) remain alive. Three pts (all with high risk disease) had disease progression at 4 (del 17p), 9 (t [4;14]), and 13 (gain 1q) months; of these, 2 have died of progressive disease while receiving salvage therapy. One patient, in VGPR, died on study after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Two pts withdrew for logistical reasons; 2 have been taken off study per physician discretion (prolonged cytopenias (1), drug rash (1)). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 35% (16), thrombocytopenia 9% (4), febrile neutropenia 7% (3), and anemia 7% (3). Grade 3-4 non-Hematologic AEs (no. of pts): diarrhea 17% (8), fatigue 17% (8), pneumonia 15% (7), other infections 15% (7), peripheral neuropathy 11% (5), myalgias 9% (4), nausea/vomiting 7% (3), maculopapular rash 4% (2), dizziness 4% (2), edema 2% (1), memory impairment 2% (1). Renal cell carcinoma was diagnosed in 1 patient, 15 months after removal from study for disease progression. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 44% of 55 pts have had improvement in quality of response while on therapy, including 28% who have converted to CR and 24% who have tested MRD negative. The number of pts who have experienced improvement on study may, in fact, be underestimated in this analysis due to elotuzumab interference with measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Disclosures Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Shah: Kayopharm: Employment. Lee: Pimera Inc: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Manasanch: merck: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; celgene: Consultancy; takeda: Consultancy; quest diagnostics: Research Funding. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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.

scholarly journals Melphalan-Based Autologous Transplantation in the Octogenarian Multiple Myeloma Patient Population

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4608-4608 ◽  
Author(s):  
Neeraj Y Saini ◽  
Romil Patel ◽  
Ankur Varma ◽  
Qaiser Bashir ◽  
Ruby Delgado ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Hematopoietic Stem

Abstract Abstract: Background: Upfront autologous hematopoietic stem cell transplantation (auto-HCT) combined with novel anti-myeloma drugs is considered the standard of care for transplant-eligible patients with multiple myeloma (MM). However, this treatment is generally avoided in older patients due to concerns about toxicity. MM is primarily a disease of the elderly, with >35% patients being older than 70 years of age at diagnosis. We have previously reported on the role of auto-HCT in MM patients >70 years1. In this study, we evaluate the safety and feasibility of auto-HCT in patients ≥80 years who received auto-HCT at our institution. Methods: We retrospectively reviewed the outcomes of MM patients with age ≥80 years who underwent auto-HCT between January, 2007, and June, 2018. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of auto-HCT to the last follow up or the censored date. Kaplan-Meier method was used to estimate PFS and OS. Results: Between January, 2013, and December, 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥80 years. Also, between January, 2016, and June, 2018, a total of 210 MM patients with age ≥80 years were treated at our institution, and only 3(0.14%) underwent auto-HCT. Overall among 1740 patients with MM who received an auto-HCT at our institution between the beginning of 2007 to June, 2018, 9(0.5%) patients were ≥ 80 years of age (range 80-83). Table 1 summarizes the patient characteristics of these nine patients. All patients had an ECOG performance status of either 0 or 1. The median hematopoietic stem cell transplant - comorbidity index for the cohort was 3 (range, 0-5). Eight (89%) patients were in first remission, and 1 (11%) patient had relapsed disease at auto-HCT. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. Eight patients (89%) received maintenance therapy with lenalidomide. The median follow-up from auto-HCT was 18 months (range 0.5 - 50 months). No (0%) patient died within 100 days of auto-HCT. Out of 8 evaluable patients, 4 (50%) achieved a complete response, 2 (25%) very-good partial, and 2 (25%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. Median PFS was 31.5 months, while the median OS has not been reached (Fig1). 2-yr PFS and OS were 62.5% and 75% respectively. One patient died 22 months post-transplant due to non-transplant related cause. Conclusions: In selected MM patients ≥80 years old, auto-HCT was feasible, with 0% TRM, 100% response rate, and 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy. References: Qazilbash, M. H. et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplantation39, 279-283 (2007). Disclosures Shpall: Affirmed GmbH: Research Funding. Thomas:Celgene: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Orlowski:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

scholarly journals Interim Analyses of Overall Survival (OS) from the TOURMALINE MM3 & MM4 Studies of Ixazomib Maintenance Following Primary Therapy in Multiple Myeloma (MM)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1656-1656
Author(s):  
Meletios A. Dimopoulos ◽  
S. Vincent Rajkumar ◽  
Sagar Lonial ◽  
Wee-Joo Chng ◽  
Shinsuke Iida ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Interim Analyses ◽  
Kaplan Meier

Abstract Background: Two global, randomized, placebo (pbo)-controlled phase 3 studies of single-agent ixazomib (ixa) maintenance therapy are currently ongoing for newly diagnosed MM patients following primary therapy that included autologous stem cell transplantation (ASCT) (MM3, NCT02181413) or excluded ASCT (MM4, NCT02312258). Both trials have demonstrated statistically significant and clinically meaningful improvement in their primary endpoint of progression-free survival (PFS): for MM3, median 26.5 months (mos) ixa vs 21.3 mos pbo (hazard ratio [HR] 0.720, 95% confidence interval [CI] 0.582-0.890, P=0.002); for MM4, median 17.4 mos for ixa vs 9.4 mos for pbo (HR 0.659, 95% CI 0.542-0.801, P&lt;0.001). Data for the key secondary endpoint, OS, have not previously been published. Methods: Full methods have previously been reported (Dimopoulos, Lancet 2019; Dimopoulos, J Clin Oncol 2020). Eligible patients (MM3, N=656; MM4, N=706) were randomized 3:2 to receive maintenance therapy with single agent ixa or pbo for a maximum of approximately 24 mos (26 cycles, to the nearest complete cycle) or until progressive disease or unacceptable toxicity, whichever occurred first. Results: At the most recent data cut-off (MM3, 29 January 2021; MM4, 15 October 2020), with median follow up of 64 mos and 36 mos, respectively, 27% (MM3, 174/656) and 29% (MM4, 203/706) of the intention-to-treat (ITT) population had OS events. In MM3, the 5-year Kaplan-Meier estimate for OS was 74% for ixa and 73% for pbo, though the median OS had not yet been reached in either arm (HR 1.008, 95% CI 0.744-1.367, P=0.958; Figure). In MM4, the 5-year Kaplan-Meier OS estimate was 55% for ixa and 56% for pbo, though the median OS had also not yet been reached in either arm (HR 1.136, 95% CI 0.853-1.514, P=0.382; Figure). No new safety signals were identified, and the incidence of new primary malignancies in both studies was similar between ixa and pbo. Conclusions: These most current OS data for MM3 and MM4 have not demonstrated a statistically significant difference for the ixa or the pbo arm to date. After 64 mos of follow-up in MM3, the risk of OS does not differ between the study arms. After 36 mos of follow-up in MM4, the OS HR shows a trend that favors the pbo arm. Because interim analyses of OS may be overrepresented by deaths in patients who did not benefit from maintenance therapy, it is not known to what extent these results will be reflective of the ITT population at the time of the final analyses. As treatment options, including anti-CD38 mAb and other new mechanisms of action, for salvage therapies following progression continue to expand, OS is increasingly being confounded by subsequent therapies. Hence, demonstrating OS advantage for early line MM therapies is becoming increasingly challenging. OS data continue to be collected in these studies for later analyses. Figure 1 Figure 1. Disclosures Dimopoulos: Takeda: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria. Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Chng: Johnson and Johnson: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Iida: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: 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; AbbVie: Honoraria; Janssen: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Suryanarayan: Takeda: Current Employment. Vorog: Takeda: Current Employment. Fergus: Takeda: Current Employment. Labotka: Takeda: Current Employment. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance treatment for multiple myeloma following stem cell transplantation or induction therapy in newly diagnosed patients.

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 Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4451-4451
Author(s):  
Sarah A. Holstein ◽  
Sarah Cooley ◽  
Parameswaran Hari ◽  
Sundar Jagannath ◽  
Catherine R Balint ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Nk Cell ◽  
Single Infusion ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

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