scholarly journals ELOTUZUMAB FOR THE TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO ITS MODES OF ACTION AND SLAMF7 SIGNALING

2018 ◽  
Vol 10 (1) ◽  
pp. e2018014 ◽  
Author(s):  
Masafumi Taniwaki ◽  
Mihoko Yoshida ◽  
Yosuke Matsumoto ◽  
Kazuho Shimura ◽  
Junya Kuroda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cell ◽  
Cell Activity ◽  
Adaptor Protein ◽  
Progression Free Survival ◽  
Sh2 Domain ◽  
Phase Iii ◽  
Refractory Multiple Myeloma ◽  
Pathway Activation ◽  
Signaling Lymphocytic Activation Molecule

Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone   (ELd)   for relapsed/refractory  multiple myeloma (MM) based on the findings of the phase III randomized trial  ELOQUENT-2 (NCT01239797). Four-year  follow-up  analyses  of  ELOQUENT-2 have demonstrated  that  progression-free survival was 21%  in  ELd  versus  14%  in  Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of  action:  natural  killer  (NK)  cell-mediated  antibody-dependent  cellular  cytotoxicity  (ADCC) and  enhancement  of  NK  cell  activity.  The  ADCC  is  mediated  through  engagement  between  Fc portion  of  elotuzumab  and  FcgRIIIa/CD16  on  NK  cells. Enhanced NK cell cytotoxicity results fromm phosphorylation  of  the  immunoreceptor  tyrosine-based  switch  motif  (ITSM)  that  is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2.The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+. Influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis inNK  cells. Elotuzumab  does not stimulate the  proliferation of MM cells due to a lack of EAT-2.The  inhibitory  effects  of  elotuzumab  on  MM  cell  growth  are  not  induced by  the lack  of  CD45, even  though  SHP-2,  SHP-1,  SHIP-1,  and  Csk may be  recruited  to  phosphorylated  ITSM  of SLAMF7.  ELd  improves PFS in patients  with  high-risk  cytogenetics,  i.e.  t(4;14),  del(17p),  and 1q21  gain/amplification. Since  the immune  state  is  paralytic  in  advanced  MM,  the  efficacy  of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.

Comparison of lenalidomide plus dexamethasone therapy used at first relapse versus later salvage therapy in relapsed or refractory multiple myeloma patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8594-8594
Author(s):  
E. A. Stadtmauer ◽  
D. M. Weber ◽  
R. Nieszvizky ◽  
A. Belch ◽  
H. M. Prince ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Salvage Therapy ◽  
Response Rate ◽  
Early Stage ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Duration Of Treatment ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
First Relapse

8594 Background: The benefit of initiating lenalidomide plus dexamethasone at first relapsed was evaluated in this subset analysis from phase III studies in patients with relapsed or refractory multiple myeloma (MM). Methods: Patients from the randomized, multicenter clinical trials MM-009 and MM-010 who had received at least 1 prior treatment and were not resistant to dexamethasone were treated with lenalidomide (25 mg daily for 21 days of every 28 day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 every 28 days for 4 months, then 40 mg on days 1–4 every cycle thereafter until disease progression or intolerance), or dexamethasone (same dose and schedule) plus placebo. Baseline characteristics such as age, sex, ECOG score, and baseline β2-microglobulin levels between the 2 patient groups were similar, however, median time from diagnosis and prior therapy were statistically different. Results: Multivariate analysis showed that more prior therapies is associated with shorter time-to-progression (TTP). Patients who received 1 prior therapy demonstrated a significant improvement in outcomes such as TTP, progression-free survival (PFS), overall response rate (ORR), complete response/very good partial response rate (CR/VGPR), median duration of treatment and overall survival (OS) after first relapse compared with those who received ≥ 2 prior therapies ( Table ). Toxicity, rate of dose reduction, or treatment discontinuation in the cohort with 1 prior therapy did not increase, despite longer treatment. Conclusions: When used at first relapse compared with salvage therapy, lenalidomide plus dexamethasone treatment resulted in significantly prolonged TTP, PFS, and OS, and an improved quality of response. Lenalidomide plus dexamethasone should be considered at an early stage of therapy for patients with MM. [Table: see text] [Table: see text]

scholarly journals OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma

2020 ◽  
Vol 16 (11) ◽  
pp. 631-641 ◽  
Author(s):  
Fredrik Schjesvold ◽  
Pawel Robak ◽  
Ludek Pour ◽  
Johan Aschan ◽  
Pieter Sonneveld
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Phase Iii Study

Melflufen is a novel peptide–drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2–4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

Daratumumab, pomalidomide, and dexamethasone in relapsed refractory multiple myeloma (RRMM): A comparison with contemporary clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20011-e20011
Author(s):  
Barry Paul ◽  
Myra M. Robinson ◽  
Jordan Robinson ◽  
Ami Ndiaye ◽  
Manisha Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Median Number ◽  
Phase Iii ◽  
Published Data ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Previously Treated

e20011 Background: Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells. The combination of pomalidomide/dexamethasone with either daratumumab or isatuximab is FDA approved for relapsed refractory multiple myeloma (RRMM) based on randomized phase III trial data. Herein, we compare our center’s experience with published data to help identify the most appropriate patient population for this regimen outside of the context of clinical trials. Methods: We interrogated our internal plasma cell disorder database to identify all patients with RRMM at our institution who were treated with the combination of daratumumab, pomalidomide, and dexamethasone (Dara-Pd). We evaluated the best response achieved, overall response rate (ORR), progression free survival (PFS), and overall survival (OS) measured from initiation on Dara-Pd. Kaplan Meier methods were used to estimate PFS and OS curves. Fisher’s exact tests and log rank tests were used to determine the association between outcomes and variables of interest. Results: Between Dec 2015 and Dec 2020, 98 patients were identified, of which 97 were evaluable for response. Median number of prior lines of therapy was 2 (range 1-12), with 23 patients (23%) previously treated with 3 prior lines and 24 patients (25%) previously treated with ≥4 lines of therapy. Most patients were refractory to an IMiD (79.6%), a PI (65.3%), or both (56.1%). The ORR was 69.1%, > VGPR rate was 33%. ORR was significantly improved for patients who received Dara-Pd after 1 line (p = 0.03), but depth of response (≥VGPR), was similar (p = 0.62). At a median follow up of 10.8 months, 1-year PFS was 76.6% in patients after 1 line, 38.8% in patients after 2-3 lines, and 35% in patients after > 4 lines. Overall response rates appear comparable to published phase III trials comparing the combination of Pd with or without an anti-CD38 monoclonal antibody (Table 1). While PFS was somewhat lower in our population, subset analysis showed that PFS was significantly lower in patients who were PI refractory (10.8 months vs 6 months; p = 0.014), and in patients who were both IMiD and PI refractory (20.4 months vs 6 months p = 0.01), but OS was similar in these populations. Conclusions: Our data suggests that the combination of Dara-Pd has activity in heavily pretreated patients, including patients who are both IMiD and PI refractory and remains a viable option for these patients outside the context of a clinical trial.[Table: see text]

scholarly journals Isatuximab for relapsed/refractory multiple myeloma: review of key subgroup analyses from the Phase III ICARIA-MM study

2021 ◽  
Author(s):  
Paul G Richardson ◽  
Simon J Harrison ◽  
Sara Bringhen ◽  
Fredrik Schjesvold ◽  
Kwee Yong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Response Rates ◽  
Phase Iii ◽  
Free Survival ◽  
Treatment Need ◽  
Disease Response ◽  
Refractory Multiple Myeloma ◽  
Subgroup Analyses ◽  
Unmet Treatment Need

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.

scholarly journals Treatment of double-refractory multiple myeloma

2021 ◽  
Vol 16 (3) ◽  
pp. 58-73
Author(s):  
S. V. Semochkin
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
High Risk ◽  
Confidence Interval ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Median Progression Free Survival

In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-­Pd, Isa-­Pd, Dara-­Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-­Pd, Isa-­Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-­Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-­Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-­Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-­Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-­Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-­Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-­Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.

scholarly journals Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design

2020 ◽  
Vol 16 (2) ◽  
pp. 4347-4358 ◽  
Author(s):  
Philippe Moreau ◽  
Meletios A Dimopoulos ◽  
Kwee Yong ◽  
Joseph Mikhael ◽  
Marie-Laure Risse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Review Committee ◽  
Clinical Trial Registration ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
The Past ◽  
Independent Review ◽  
Phase Iii Study

Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus carfilzomib and low-dose dexamethasone, versus carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. Clinical trial registration: NCT03275285

scholarly journals Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments

2021 ◽  
Vol 10 ◽  
Author(s):  
Massimo Offidani ◽  
Laura Corvatta ◽  
Sonia Morè ◽  
Davide Nappi ◽  
Giovanni Martinelli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Human Monoclonal Antibody ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Two Phase ◽  
Refractory Multiple Myeloma ◽  
Phase Iii Trials ◽  
Line Of Therapy

Immunotherapy is changing the paradigm of multiple myeloma (MM) management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved for the treatment of this malignancy. Daratumumab exerts anti-myeloma activity by different mechanisms of action as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulation. After GEN501 and SIRIUS trials showed efficacy of daratumumab monotherapy in heavily pretreated relapsed-refractory multiple myeloma (RRMM), in patients with at least two previous line of therapy, two phase III trials demonstrated superior overall response rate (ORR) and progression free survival (PFS) using triplets daratumumab–bortezomib–dexamethasone (DVd) vs Vd (CASTOR) or daratumumab–lenalidomide–dexamethasone (DRd) vs Rd (POLLUX) in relapsed-refractory MM patients; so these combinations have been approved and introduced in clinical practice. The ongoing phase III CANDOR is evaluating the triplet daratumumab–carfilzomib–dexamethasone (DKd) vs Kd whereas phase III APOLLO trial is exploring daratumumab–pomalidomide–dexamethasone (DPd) vs PD. Many other trials exploring daratumumab combinations in relapsed-refractory MM are ongoing, and they will provide other interesting results. In newly diagnosed transplant-eligible patients, phase III CASSIOPEIA trial found the combination daratumumab–bortezomib–thalidomide–dexamethasone (Dara-VTd) significantly improves stringent Complete Response (sCR) rate and PFS compared with VTD, whereas in the phase II GRIFFIN study, comparing daratumumab–bortezomib–lenalidomide–dexamethasone (Dara-VRD) vs VRD, sCR rate was significantly higher using quadruplet combination. Many studies are evaluating daratumumab in consolidation and maintenance therapy after autologous stem cell transplantation (ASCT). As regard patients ineligible for ASCT, a great efficacy of daratumumab-containing combinations was reported by the phase III trials ALCYONE and MAIA, exploring daratumumab–bortezomib–melphalan–prednisone (DVMP) vs VMP and daratumumab–lenalidomide–dexamethasone (DRd) vs Rd, respectively. These studies provided results never seen before in this setting. The aim of this paper is to critically review the results obtained with regimens containing daratumumab both in relapsed-refractory and in newly diagnosed MM.

Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial

2011 ◽  
Vol 29 (32) ◽  
pp. 4243-4249 ◽  
Author(s):  
Paul G. Richardson ◽  
Jeff Wolf ◽  
Andrzej Jakubowiak ◽  
Jeff Zonder ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progression Free Survival ◽  
Phase Iii ◽  
The Novel ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Heavily Pretreated ◽  
Previously Treated

Purpose Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. Patients and Methods In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m2, with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. Results An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). Conclusion Perifosine–bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine–bortezomib plus dexamethasone with bortezomib–dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

The Combination of Pegylated Liposomal Doxorubicin and Bortezomib Significantly Improves Time to Progression of Patients with Relapsed/Refractory Multiple Myeloma Compared with Bortezomib Alone: Results from a Planned Interim Analysis of a Randomized Phase III Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 404-404 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Sen H. Zhuang ◽  
Trilok Parekh ◽  
Liang Xiu ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Interim Analysis ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Introduction: Proteasome inhibition with bortezomib (VELCADE®) is a standard of care for patients with relapsed/refractory multiple myeloma (MM) who have received at least one prior therapy. Pre-clinical studies have shown that bortezomib acts synergistically with anthracyclines, and clinical trials have shown encouraging evidence of enhanced anti-myeloma activity for the combination of bortezomib with pegylated liposomal doxorubicin (PLD; DOXIL®). We therefore sought to test the hypothesis that the bortezomib/PLD regimen would improve clinical outcome measures in this patient population. Methods: Between December, 2004 and March, 2006, 646 patients with relapsed or refractory MM after at least one prior line of therapy were randomized on the DOXIL-MMY-3001 study conducted at 144 sites in 18 countries. Patients were eligible if they had not previously received bortezomib, progressed on an anthracycline-containing regimen, or received more than 240 mg/m2 of doxorubicin, or the equivalent amount of another anthracycline. Subjects were randomized in a 1:1 ratio to receive either bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle, or the same dose and schedule of bortezomib but with the addition of PLD at 30 mg/m2 given on day 4 of each cycle. Treatment was to continue for up to a total of 8 cycles unless a complete response (CR) was attained, or disease progression occurred, or unacceptable treatment-related toxicity was noted. Exceptions included patients achieving CR at any time, who were treated with an additional two cycles, and patients experiencing a continued paraprotein response after 8 cycles, who were allowed to continue for as long as treatment was tolerated, and they continued to respond. Disease assessments were to occur at the start of each cycle, beginning at cycle 2, and were made according to the stringent criteria recommended by the European Group for Blood & Marrow Transplantation. Subjects who did not progress after the initial 42-week period were assessed every 6 weeks until disease progression was documented. Results: During the course of the study, an Independent Data Monitoring Committee (IDMC) reviewed safety data every 3 months, and a planned interim analysis (IA) was performed after at least 230 progression events were collected. Upon review, the IDMC concluded that, based on the IA, there was a significant benefit to patients randomized to the bortezomib/PLD arm of the trial in the primary study endpoint, time to progression, as well as in progression-free survival. No survival advantage had yet been demonstrated to date. While there was an increase in adverse events associated with the combination therapy, this increase was judged to be acceptable in the context of the benefits. In light of these results, the IDMC recommended that study results be communicated. Toxicity, time to progression, and progression free survival data will be available for presentation at the time of the annual meeting. Conclusions: At the IA, PLD plus bortezomib was significantly more effective than bortezomib monotherapy for patients with previously treated multiple myeloma.

Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8509-8509 ◽  
Author(s):  
Shaji Kumar ◽  
Simon J. Harrison ◽  
Michele Cavo ◽  
Javier de La Rubia ◽  
Rakesh Popat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Double Blind ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
D 20

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

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