Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8051-8051
Author(s):  
Sham Mailankody ◽  
Meghan Salcedo ◽  
Elizabet Tavitian ◽  
Neha Korde ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Overall Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Pilot Trial ◽  
Progression Free Survival ◽  
Overall Response ◽  
Smoldering Multiple Myeloma ◽  
Increased Risk

8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time < 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383.

scholarly journals A Phase 2 Study to Assess the Feasibility and Tolerance of the Combination of Elotuzumab, Lenalidomide, and Dexamethasone (ERd) in the Induction, Consolidation, and Maintenance Treatment of Transplant-Eligible Patients Newly Diagnosed with Multiple Myeloma (MM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 603-603 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Tara K. Gregory ◽  
Suman Kambhampati ◽  
Bertrand M. Anz ◽  
Stefano R. Tarantolo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Overall Response Rate ◽  
Response Rate ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Overall Response

Background: The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) with and without corticosteroids has revolutionized treatment (tx) and improved survival rates for MM. IMID/PI triplets such as VRD (bortezomib, lenalidomide, dexamethasone), VTD (bortezomib, thalidomide, dexamethasone), or KRD (carfilzomib, lenalidomide, dexamethasone) are preferred inductions for transplant-eligible patients (pts). Unfortunately, the PI often has unique safety events such as peripheral neuropathy (PN) or cardiac issues that can impact the quality of life. Elotuzumab is a mAb with a dual mechanism of action (tagging MM cells and activating NK cells by binding SLAMF7). The combination of elotuzumab, lenalidomide, and dexamethasone (ERd), is active, well-tolerated, and approved by the FDA for pts with relapsed MM. In this study, we will determine the feasibility of incorporating ERd into a transplant-eligible pt population. Methods: Pts with newly diagnosed MM requiring chemotherapy planning to undergo autologous stem cell transplantation (ASCT) were enrolled. Induction of elotuzumab at 10 mg/kg was administered IV on days (D) 1, 8, 15, 22 of the 1st 2 28-day cycles and days 1, 15 of the third and fourth 28-day cycles. Lenalidomide was dosed at 25 mg orally on D 1-21 of each 28 day induction cycle. Dexamethasone was administered IV concurrent with elotuzumab (28mg orally 3-24 hours prior to infusion and 8 mg IV with elotuzumab), with 40 mg orally administered on D 8 and 22 of cycles 3 and 4. After completion of the 4 induction cycles, pts proceeded to mobilization and ASCT though pts who refused transplantation were allowed to proceed directly to consolidation and maintenance if the investigator believed the pt was deriving benefit. 70-120 days after ASCT, 4 cycles of consolidation were administered (dosing similar to cycles 3-4 of induction but with lenalidomide at 15mg). Pts then went on to maintenance with elotuzumab 20 mg/kg IV on D 1, oral lenalidomide 10mg +/- 5 mg D 1-21 and dexamethasone 28mg oral/8 mg IV prior to elotuzumab infusion were dosed in 28-day cycles for up to 24 months. The primary endpoint was the induction feasibility rate (IFR) defined as the percentage of pts successfully completing 4 cycles of induction tx with ERd and able to start ASCT. Secondary end points were complete response rate (≥nCR), overall response rate (≥PR), progression-free survival (PFS) and overall survival (OS). AEs were assessed according to CTCAE V4 and responses were assessed using the revised IMWG criteria. Results: 52 pts were enrolled: 56% male, median age 61 ys, 12% RISS III, 21% high-risk cytogenetics [17p del, t(4;14), and/or t(14;16)]. To date, 26 (50%) pts remain on active tx. 4 pts refused transplantation despite being eligible and were excluded from the IFR calculation. The IFR was 69% and the best overall response rate (ORR) was 92% (69% ≥ VGPR). With a median follow up of 20 mos, median PFS and OS for all pts were not reached. The 18 mo PFS and OS were 83% and 89% respectively. The most common AEs were fatigue (59.6%), diarrhea (42.3%) and nausea (42.3%). PN was seen in 29%, and all events were ≤ G2. There were 28 SAEs in 20 pts, including 12 tx-related SAEs. There was 1 tx-related death due to heart failure in a pt with no history of prior cardiac issues who had subsequent therapy. 29% of pts met the high-risk (HR) criteria (defined as RISS III or high risk cytogenetics) and 29% of pts were considered standard-risk (RISS I and no high-risk cytogenetics). The best ORR was 87% (67% ≥ VGPR) for HR pts and 93% (53% ≥ VGPR) for SR pts and the IFR was 57% for HR pts and 64% for SR pts. The median PFS and OS were 20.5 mos and 22.0 mos respectively for HR pts and have not been reached for SR pts. Conclusions: ERd induction, consolidation and maintenance was feasible and well tolerated in conjunction with ASCT in transplant-eligible pts. Despite high ORR for all pts, HR patients had inferior PFS and OS. This study supports the continued evaluation of this regimen in SR pts. Disclosures Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; Poseida: Research Funding; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding. Gregory:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Poseida: Research Funding; Amgen: Speakers Bureau. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant-eligible patients newly diagnosed with multiple myeloma.

Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 140-140
Author(s):  
Inderjit Mehmi ◽  
Jordan Hill
Keyword(s):  
Metastatic Melanoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Standard Dose ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Overall Response ◽  
Reduced Dose ◽  
Increased Risk ◽  
Grade 3

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.

scholarly journals Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1231-1238 ◽  
Author(s):  
Gareth J. Morgan ◽  
Faith E. Davies ◽  
Walter M. Gregory ◽  
Nigel H. Russell ◽  
Sue E. Bell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Autologous Transplantation ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Overall Response ◽  
Depth Of Response

Abstract As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

scholarly journals Bortezomib in Combination with Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin (V-DCEP) for the Treatment of Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2139-2139 ◽  
Author(s):  
Kelly Valla ◽  
Jonathan L. Kaufman ◽  
Charise Gleason ◽  
Lawrence H. Boise ◽  
Leonard T Heffner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Median Time ◽  
Salvage Therapy ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
University Hospital ◽  
High Dose ◽  
Overall Response

Abstract Introduction Despite therapeutic advances in multiple myeloma, disease relapse is common. Combination therapy with dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has been utilized as an effective salvage regimen for over a decade, and a recent study reported that DCEP provided an overall response rate of 45.1% when used as salvage therapy in patients who had previously received novel agents (Park S, et al. 2014). Aside from hematologic toxicities, DCEP is generally well-tolerated. In fact, the toxicity profile of DCEP has been compared to high dose cyclophosphamide in the setting of stem cell mobilization and is considered less toxic than the latter. Based upon the synergy noted when proteasome inhibitors are combined with genotoxic therapy, we have combined bortezomib with DCEP in a series of relapsed myeloma patients. Herein we report our experience with the addition of bortezomib to DCEP in relapsed/refractory disease. Patients and Methods We performed a retrospective evaluation of patients with relapsed/refractory multiple myeloma treated at Emory University Hospital from October 2011 until March 2014. Patients received dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) at standard doses in combination with bortezomib at either a dose of 1 mg/m2 or 1.3 mg/m2 administered on Days 1 and 4 of each cycle given every 28 days. Indications for receiving V-DCEP are either cytoreduction prior to SCT (cohort 1) or as salvage therapy (cohort 2). Results Among the 51 patients (49% male and 51% female) included in analysis, the median age at the time of diagnosis is 58 years (range 30-78) and the time of treatment with V-DCEP is 62 years (range 33-79). Among patients that received V-DCEP as cytoreduction prior to SCT, median prior lines of therapy were 1 (0-8). Among the patients that received V-DCEP as salvage therapy, median number of prior lines of therapy was 3 (1-6). ISS 3 disease was seen in 70% of patients and high risk disease in 72.5% of pts (del 17p: 31%; PCL: 19%; extramedullary disease: 33%; complex CTG: 11%) and t(4;14): 6%). Median time from diagnosis to initiation of V-DCEP therapy among cohort 1 is 18 months (0-86) and among cohort 2 is 31 months (12-105) months. Median serum creatinine before C1D1 is 1.17 (0.61-6) and serum bilirubin is 0.6 (0.1-2.8). 31% of patients needed dose reductions from our standard protocol due to organ dysfunction. 47% of patients received ≥2 cycles. The median time to next cycle is 28 days (20-46) and time to next treatment after V-DCEP is 35 days (25-451) suggesting good hematologic recovery. The overall response rate (≥PR) amongst both cohorts with V-DCEP is 47.8% (40% and 51.6% overall response for cohorts 1 and 2, respectively). Figure 1 illustrates response rates. 10 patients that presented with renal insufficiency had renal response including 2 of the 5 patients on hemodialysis. While the median PFS for cohort 1, as expected has not reached, for cohort 2, it is 8 months (95% CI 5.7-10.3). At a median follow-up of 17 months, from the time of V-DCEP initiation, median OS for cohort 2 is 10 months (95% CI 5-14.9). Median overall survival for this predominantly high risk group of patients from diagnosis in cohort 1 is 78 months (95% CI 47-108) and 49 (95% CI 17-80.7) months in cohort 2, respectively. While only 1 patient with grade 2 peripheral neuropathy (PN) received V-DCEP, change from baseline existing PN was seen in 19% of patients (no grade 3/4 events). Conclusions During this era where minimizing alkylator therapy is a consideration, certain indications exist for using V-DCEP such as cytoreduction prior to SCT or as salvage therapy serving as bridge to next line of therapy. Addition of bortezomib to DCEP is deemed safe and is an effective cytoreductive regimen in the treatment of multiple myeloma. Figure 1 Figure 1. Disclosures Gleason: Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4445-4451 ◽  
Author(s):  
Michael Wang ◽  
Meletios A. Dimopoulos ◽  
Christine Chen ◽  
M. Teresa Cibeira ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Previously Treated ◽  
Survival Studies

AbstractThis analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.

Efficacy of bevacizumab and temozolomide therapy in locally advanced, recurrent, and metastatic malignant solitary fibrous tumour: A population-based analysis

2018 ◽  
Vol 25 (6) ◽  
pp. 1301-1304 ◽  
Author(s):  
Mário L de Lemos ◽  
Isabell Kang ◽  
Kimberly Schaff
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Locally Advanced ◽  
Case Series ◽  
Progression Free Survival ◽  
Population Based ◽  
Solitary Fibrous Tumour ◽  
Free Survival ◽  
Overall Response

Background Patients with locally advanced, recurrent or metastatic solitary fibrous tumour are often treated with bevacizumab and temozolomide based on the clinical efficacy reported in a case series of 14 patients. Given the rarity of solitary fibrous tumour, large trials are not feasible. We report the efficacy of this regimen based on a population-based analysis. Methods This was a population-based retrospective, multi-centre analysis using patient data from a provincial cancer registry and treatment database. Cases from June 2006 through October 2016 were identified for patients receiving bevacizumab and temozolomide for locally advanced, recurrent or metastatic solitary fibrous tumour or hemangiopericytoma, which is sometimes used to describe tumours arising from the meninges. The primary outcome was overall response rate. Secondary outcomes included time to response, progression free survival and overall survival estimated using the Kaplan–Meier method. Results Fourteen patients were identified: median age 59 (range 44–70), male 78.6%. Diagnoses were solitary fibrous tumour in 10 (71.4%) and hemangiopericytoma in four (28.6%), with metastatic disease in 10 (72.7%) patients. The most common primary sites were meninges in four (28.6%) and pelvis in three (21.4%) patients. The median follow-up was 15.5 months, with median treatment of four months. Overall response rate was 21.4% (no complete response, 3 partial response), with median time to response of four months. Median progression free survival, six-month progression free survival and overall survival were 17 months, 65.0%, and 45 months, respectively. Conclusions Efficacy of bevacizumab and temozolomide in solitary fibrous tumour appeared to be similar to that previously reported. Our findings confirmed that bevacizumab and temozolomide is an effective and tolerated treatment for this patient population.

scholarly journals Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma

2019 ◽  
Vol 37 (18) ◽  
pp. 1529-1537 ◽  
Author(s):  
Vatche Tchekmedyian ◽  
Eric J. Sherman ◽  
Lara Dunn ◽  
Crystal Tran ◽  
Shrujal Baxi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Adenoid Cystic Carcinoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Overall Response ◽  
End Point ◽  
Adenoid Cystic

PURPOSE Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC. PATIENTS AND METHODS This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted. RESULTS Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician’s discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1). CONCLUSION This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

scholarly journals Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab

2018 ◽  
Vol 36 (20) ◽  
pp. 2052-2060 ◽  
Author(s):  
Erik van Dijk ◽  
Hedde D. Biesma ◽  
Martijn Cordes ◽  
Dominiek Smeets ◽  
Maarten Neerincx ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Multicenter Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Tumor Biopsy ◽  
Overall Response ◽  
European Multicenter Study

Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.

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