scholarly journals Outcomes of Triple-Class (proteasome inhibitor, immunomodulator, CD38 monoclonal antibody) Exposed Relapsed or Refractory Multiple Myeloma (RRMM) in United States (US) Real-World Practice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3042-3042
Author(s):  
Christopher Kim ◽  
Megan Braunlin ◽  
Bhakti Mehta ◽  
Rebecca Payne
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Median Time ◽  
Real World ◽  
Overall Response Rate ◽  
Response Rate ◽  
Study Entry ◽  
Publicly Traded ◽  
Drug Classes ◽  
Younger Age

Abstract Background: As new therapeutics for multiple myeloma (MM) are approved in earlier lines of therapy, drug classes with demonstrated benefit may be exhausted after initial therapy, including proteasome inhibitors (PI), immunomodulatory imides (IMiD), and CD38 targeting monoclonal antibodies (MoAB). Clinical recommendations are to utilize unique drug classes at relapse. This study aims to describe relapsed or refractory multiple myeloma treatments and outcomes in clinical trial eligible patients with prior treatment of at least 1 PI, IMiD, and CD38 MoAB and their outcomes (real world overall response rate (rwORR), progression free survival (rwPFS), overall survival (rwOS)) in US community practice. Methods: This study used Flatiron Health electronic health record (EHR)-derived de-identified database (New York, NY). These data represent ~280 cancer clinics (mostly community-based practices). Inclusion criteria included ≥18 years old, 2+ clinic visits after 2015, measurable disease, prior PI/IMiD/CD38 MoAB exposure, ECOG ≤2, adequate hematologic/renal/hepatic function, and no stem cell transplant within six months of study entry. Study period was treatment initiation at ≥ second line from November 2015 through December 2019, follow-up through December 2020. Patients with multiple eligible lines of therapy, the last eligible line was evaluated. Real world overall response rate was adapted from Foster et al 2019, rwPFS was measured from treatment until death, progression, or start of new line of therapy, and rwOS was measured from treatment until death. Results: 120 patients were eligible for this study. Median time from diagnosis to study entry was 3.8 years. Half were 70 years or older (n=62, 52%), with 20% (n=24) ISS III, 35% (n=42) high-risk cytogenetics, and 64% (n=77) at ≥5L treatment. At study start, 38% (n=46) had a prior transplant, 73% (n=88) were triple-class refractory, and 21% (n=25) penta-refractory. The most common regimens were either daratumumab-based (n=35), carfilzomib-based (n=25), or elotuzumab-based (n=15). The most frequent regimens were daratumumab/pomalidomide/dexamethasone (n=8), carfilzomib/cyclophosphamide/dexamethasone (n=7), carfilzomib/pomalidomide/dexamethasone (n=7), carfilzomib/dexamethasone (n=5), elotuzumab/lenalidomide/dexamethasone (n=5), and elotuzumab/pomalidomide/dexamethasone (n=5). The rwORR in this population was 18.33% (95% CI: 11.41-25.26, n=22). The rwORR was lower in key subgroups: younger age (<65 years old: 13.79% [95% CI: 1.24-26.34], n=4/29), high risk cytogenetics (0%, n=0/10), ISS III (12.12% [95% CI: 0.99-23.26], n=4/33), triple-class refractory (15.91% [95% CI: 8.27-23.55], n=14/88), and penta-refractory (4.00% [95% CI: 0-11.68], n=1/25). The median rwPFS in this population was 3.5 months (95% CI: 2.3-4.8). The rwPFS were shorter in key subgroups: younger age (<65 years old: 2.1 months [95% CI: 1.8-3.5]), high risk cytogenetics (2.0 months, [95% CI: 0.7-5.0), ISS III (2.2 months [95% CI: 1.6-6.5]), triple-class refractory (3.2 months [95% CI: 2.1-4.8]), and penta-refractory (2.1 [95% CI: 0.9-3.6]). The median rwOS in this population was 15.8 months (95% CI: 9.9-26.0). The OS was shorter in key subgroups: younger age (10.8 months [95% CI: 4.9-.]), high risk cytogenetics (9.4 months [95% CI: 2.2-27.9]), ISS III (14.6 months [95% CI: 6.1-27.9]), triple class refractory (15.1 months [95% CI: 7.5-25.5]), and penta refractory (7.1 months [95% CI: 3.6-26.0]). Discussion: In this study of patients that were majority triple-class refractory (PI, IMiD, CD38 MoAbB), low rwORR and short rwPFS were observed. Most patients received re-treatment with at least one drug they had previously failed or were refractory to. Additionally, many patients had additional therapies including novel agents and combinations that could be effective at prolonging OS despite short rwPFS. Compared to academic center patients (Gandhi et al 2019), survival was longer (mOS 15.8 months versus 9.3 months), but in Gandhi 2019, the median time to study entry was 4.5 versus 3.8 years, patients were more penta-refractory (26%) and had prior transplant (72%). Patients who were penta-refractory (bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab) had particularly dismal outcome. Overall, these data suggest need for continued development of effective novel classes of therapies for late line myeloma patients. Figure 1 Figure 1. Disclosures Kim: Amgen: Current Employment, Current equity holder in publicly-traded company. Braunlin: Amgen: Current Employment, Current equity holder in publicly-traded company. Mehta: Amgen: Current Employment. Payne: Amgen: Consultancy.

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.

A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chemotherapeutic Agents ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2713-2713
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

FISH Analysis in Multiple Myeloma - a Retrospective Study from India

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5646-5646 ◽  
Author(s):  
Pratibha Dhiman ◽  
Shalini Goel ◽  
Priyanka Samal ◽  
Nitin Sood ◽  
Ritesh Sachdev ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Chromosomal Aberrations ◽  
Overall Response Rate ◽  
Response Rate ◽  
Indian Subcontinent ◽  
Fish Analysis ◽  
Interphase Fish

Abstract Introduction Multiple myeloma (MM) is a malignancy involving terminally differentiated plasma cells. It is characterized by a complex pattern of extensive genomic aberrations involving many chromosomes and it constitutes about 1% of all malignancies. Its exact incidence in India is not known. Based on data available from 6 population-based cancer registries in India (covering 0.3% of the population) its incidence varies from 0.3 to 1.9 per 100 000 for men and 0.4 to 1.3 per 100 000 for women. Among various prognostic markers in MM, cytogenetic abnormality detected by conventional cytogenetic and FISH studies are major factors deciding clinical outcome. Interphase FISH studies from various parts of the world have reported variable incidence (40 - 66%) of cytogenetic abberations. However, there is insufficient published data from Indian subcontinent addressing the frequency of chromosomal aberrations using interphase FISH in MM patients. Patients and Methods Sixty eight patients clinically diagnosed with multiple myeloma were studied. The retrospective period of recruitment was from Jan 2015 to June 2016. The diagnosis of MM was based on serum electrophoresis and immunofixation, bone marrow plasmacytosis, and end organ involvement. Interphase FISH analysis was performed on bone marrow samples using specific DNA probes- Del 13q14.3 (LSI D13S25) , t (4;14) ( Kreatech IgH/ FGFR3 DC-DF), t (11;14) (Zytovision directly labeled IgH/CCND1 DC-DF), t (14;16) (Kreatech IgH/ MAF DC-DF), Del 17p13.1( LSI TP53). A total of two hundred nuclei were enumerated for each FISH Panel probe and cut off for detection of deletion/ fusion signal in normal individuals was taken as 3%. An interim analysis of treatment protocols was also done. Results A total of 68 cases with MM were evaluated which included 55 males and 13 females. We report a median age of 58 years (37-86 years). Interphase FISH analysis was done in all patients. Out of sixty eight patients, 23 (33.82%) patients had one genetic abnormality. Results revealed that deletion 13q14.3 was the most frequent aberration. Out of 68 patients, 10 patients have 13q14 (14.7%) abnormality. This includes 70% males and 30% females. In addition absence of p53 at 17p13 was detected in 8/68 (11.8%) patients. Similarly 11q13 abnormality was observed in 3/68 (4.4%). IgH (14q32) aberrations were noted in 2/68 (2.94%) patients. Of which t(4;14) was detected in these patients, whereas none of them showed t(14;16). More than one chromosomal aberrations were present in 4 patients. Data for serum β2-microglobulin at the time of presentation could be evaluated in 52 patients only. Most of the patients 40(76.9%) belonged to ISS stage 3. From the available data, 4 patients with ISS stage 3 had high risk chromosomal abnormality whereas 3 patients with ISS stage 2 and none of the patient of ISS stage I disease had high risk chromosomal abnormality. A total of 40 patients received cyclophosphamide, bortezomib and dexamethasone as the primary treatment whereas 23 patients received Bortezomib, lenalidomide and dexamethasone based therapy. Post 2 cycles of cyclophosphamide based therapy showed an overall response rate (CR + VGPR) of 87.5% whereas in case of lenalidomide based therapy the overall response rate was 91%. Thirteen patients underwent autograft after durable response, out of which one had a clinical relapse within 3 months. Median survival can only be commented on further follow up. Conclusion In comparison to the west, the frequency of chromosomal aberrations are different and much less in India whereas the studies of median survival is comparable. An early age of presentation in Indian subcontinent is another issue to be addressed as we know that secondary mutations accumulate with increasing age, but a younger population presenting with same severity of disease needs exploration of additional abnormalities in India. Being a resource constraint country and non availability of molecular lab at every place, evaluation of each patient is difficult, however increasing awareness of the role of biology in the management of MM is inspiring the clinicians for detailed evaluation and close follow up of these patients. Certainly, larger trials are required to understand the biology of this disease in the country. Disclosures No relevant conflicts of interest to declare.

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.

Vorinostat in Combination with Lenalidomide (L) and Dexamethasone (d) in Multiple Myeloma Patients Refractory to Previous Lenalidomide-Containing Regimens: Results of a Phase IIb Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4264-4264 ◽  
Author(s):  
Larysa Sanchez ◽  
Yucai Wang ◽  
Laura McBride ◽  
Elizabeth Bilotti ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Hdac Inhibitor ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Study Entry ◽  
Significant Difference ◽  
Grade 3 ◽  
Line Of Therapy

Abstract Background: Despite improvements in the treatment of relapsed/refractory multiple myeloma (RRMM), the disease remains incurable and new approaches to treatment are necessary. Clinical trials of vorinostat (V), a Class I/II pan-histone deacetylase (HDAC) inhibitor, in combination with proteasome inhibitors (PI) and immunomodulatory agents (IMiDs) have shown activity in RRMM. We report a Phase IIb, open-label, single institution study of V in combination with Ld in MM pts refractory to previous L-containing regimens. Patients and Methods: Eligibility criteria included pts with RRMM who had received ≥1 prior anti-MM regimen, no prior HDAC inhibitor, and must have been refractory to L, defined as either progression of disease (PD) on L therapy or no clinical response (< minimal response (MR) to at least 2 cycles on a previous L-containing regimen. LVd was administered in a 28-day cycle with oral V 400mg d 1-7 and 15-21, L 25mg d 1-21 and dexamethasone 40mg d 1,8,15, and 22. The primary endpoint was overall response rate (ORR). Results: 25 pts were enrolled from March 2012 to January 2014. Median age was 65 years (48-82), 18 (72%) were male. The median time from diagnosis to study entry was 4.95 yrs, median number of prior regimens was 5 (3-10); 24 (96%) had undergone at least 1 prior autologous transplant, 20 (80%) had prior PI exposure, and 9 (36%) had prior thalidomide. The last line of therapy prior to study entry was Ld in 16 (64%) and a non-L regimen in 9 (36%). Of pts on Ld prior to study entry, 11 were refractory and 5 relapsed/refractory to treatment. The last line of therapy in all 9 pts on a non-L regimen prior to study entry was a PI-containing therapy and in these pts the median time since last treatment with a L-containing regimen was 13.31 months (mos) (1.87-58.38). The ORR (≥ partial response (PR) was 24% (n=6); in addition 1 MR and 13 SD (52%) was observed for an overall objective response rate (≥ SD) of 80%. The median time to best response was 1.90 mos (0.93-3.67); median duration of response of pts in PR was 3.25 mos (95% CI 1.17-5.33). Five pts (20%) had PD after the first cycle of therapy. Of the 5 pts who were relapsed/refractory to Ld therapy prior to study entry, 1 achieved PR, 1 MR, and 3 SD. The median PFS of the entire cohort was 5.4 mos (95% CI 1.58-9.15), with 6-month (mo) PFS rate 48% and 12-mo PFS rate 6% (Figure 1). There was no significant difference in ORR between pts whose last line of therapy prior to study entry was Ld vs. a non-L regimen: ORR 19% and 33%, respectively (p=0.42). Median PFS was 3.80 mos (95% CI 3.16-4.44) vs. 6.97 mos (95% CI 3.06-10.87) in pts whose last line of therapy prior to study entry was Ld vs. a non-L regimen, respectively (p = 0.084, log rank test). All 25 pts (100%) had at least 1 drug-related adverse event (AE). Common AEs (any grade, most of which were Grade 1/2) at least possibly attributable to the study drugs included diarrhea (72%), fatigue (72%), anorexia (28%), nausea (28%), dysgeusia (28%). Most grade 3/4 AEs were related to hematologic toxicities with Grade 3/4 anemia, neutropenia, and thrombocytopenia occurring in 20%, 48%, and 32%, respectively. Dose modifications for either V or L were necessary in 18 pts (72%) due to thrombocytopenia, neutropenia, and/or diarrhea. 8 pts (32%) experienced at least one serious AE, of which only 2 were considered possibly related to therapy. Only one patient was withdrawn from study due to toxicities (cytopenias), other reasons for study discontinuation included PD 20 pts (80%) and consent withdrawal in 3 (12%). Median OS was 23.4 mos (95% CI 16.42-30.45), with 12-mo and 24-mo OS 72% and 49%, respectively (Figure 2). Conclusions: The combination of V with Ld resulted in ORR 24% and overall objective response rate of 80%, an appreciable clinical benefit considering the study group was a heavily pre-treated population with RRMM. Notably, in pts progressing on Ld immediately prior to study entry, the addition of V to Ld appears to enhance the anti-myeloma effect of L and re-sensitize pts to Ld therapy. Further studies are warranted to better characterize the role of vorinostat and other novel HDAC inhibitors in combination with IMiDs and PIs in RR MM. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures McBride: Celgene: Speakers Bureau. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. Vesole:Idera Pharmaceuticals: Research Funding; Celgene Corporation: Speakers Bureau. Biran:Celgene: Speakers Bureau. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau.

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.

Patients with Newly Diagnosed Multiple Myeloma and a Gain of the Long Arms of Chromosome 1 Have Inferior Outcomes, Including Early Onset Extramedullary Disease, Despite the Use of Novel Triplet Regimens

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4996-4996
Author(s):  
Noa Biran ◽  
Vesna Najfeld ◽  
Emily Bagiella ◽  
Sundar Jagannath ◽  
Ajai Chari
Keyword(s):  
Spinal Cord ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chromosome 1 ◽  
Newly Diagnosed ◽  
Inclusion Criteria ◽  
Novel Agent

Abstract Abstract 4996 BACKGROUND: In patients with newly diagnosed multiple myeloma (MM), a gain of the long arms of chromosome 1 is found in approximately 20% of patients by cytogenetics and 40% by FISH. A few studies have not found these abnormalities to be predictive of inferior progression free survival (PFS) and overall survival (OS) on multivariate analysis. The many studies that have were prior to the use of novel therapies in induction. Currently, testing for a gain or amplification of 1q21 locus is not included in the high risk genetic abnormalities by the International Myeloma Working Group (IMWG). Recently, two groups have reported inferior outcomes with bortezomib based induction regimens followed by high dose melphalan consolidation and maintenance therapy. The gain of 1q21 was either detected by cytogenetics or gene expression profiling (GEP70) at the University of Arkansas (Waheed et al, Cancer 2011) or by FISH in CD138 selected cells by the HOVON group (Neben et al, JCO 2012). However, the outcomes of these patients when treated with a bortezomib, lenalidomide, and dexamethasone induction regimen, which is associated with an overall response rate (ORR) of 100% and VGPR or better rate of 74% is unknown (Richardson et al. Blood 2010). Here, we describe the poor outcomes of patients with newly diagnosed MM with gain of 1q21 by FISH in unselected bone marrow aspirates despite novel agent triplet therapy. METHODS: The inclusion criteria for this IRB approved retrospective study were patients with symptomatic MM starting in June of 2008 who had a gain of 1q21 by FISH in 200 bone marrow interphase cells at the time of diagnosis. Patients with 1q amplification had at least 3 or more copies. PFS and OS were calculated by Kaplan-Meier analyses. RESULTS: 23 patients met the inclusion criteria. The median age was 59. 7 (range 46–71) and twenty patients (87%) were DS III at diagnosis, 13/23(57%) were ISS Stage 3. 6/23 (26%) had hypercalcemia, 8/23 (35%) had renal insufficiency, and 19/23 (83%) had anemia. Lytic lesions were present in 17/23 (74%) of patients at diagnosis. Of note, while 4 patients had deletion 13 by cytogenetics only 2 patients had other high risk findings, one with t(4;14) and another with deletion 17. All patients were treated with novel agent induction therapy. 19/23 (83%) were treated with triplet regimens (bortezomib, dexamethasone, and either lenalidomide or cyclophosphamide i. e. VRD or VCD). Disappointingly, primary induction failure, defined by PD or SD after 3–4 cycles, was observed in 30% of all patients. Of the 17 patients who received upfront triplet VRD or VCD therapy (with or without HDM plus SCR) the overall response rate (ORR) was only 77% (13/17), and 47% (8/17) achieved VGPR or better. More specifically, 3/17 (18%) had CR, 5/17 (29%) had VGPR, 5/17 (29%) had PR, 1/17 (6%) had SD and 1/19 (6%) had PD. Of the 4 patients who received novel doublet therapy (VD or RD) upfront, only 1 had a VGPR, one had SD and 2 had PD. The responses noted were not very durable, with a median PFS of 14 months. Although 3 patients have died (after 11–13 months from diagnosis), the median OS has not been reached with a median follow up of 13 months. Plasmacytomas of the bone with soft tissue expansion were present in 48% of the patients and 3 of 23 (13%) had spinal cord compression. Extra-osseous MM within 3 months of diagnosis was observed in 5/23 (22%) patients and 4/5 did not have any other high risk cytogenetics. Three patients (13%) had CNS MM at median of 5. 3 months after diagnosis. One patient had concomitant parenchymal brain lesions, myleomatous meningitis, and intra spinal cord disease. CONCLUSIONS: Even in the era of novel agent induction therapies, in our series of newly diagnosed 23 patients with a gain of 1q21, the failure rate of induction was 30% with a median PFS of 14 months. Moreover, these patients had a particularly aggressive clinical course with both medullary and extramedullary plasmacytomas, suggesting that PET-CTs, rather than just skeletal surveys should be considered for initial staging and monitoring. Also, given an unusually high incidence (13%) of early onset CNS disease, prompt CSF evaluation and brain MRI should be performed on patients with neurologic symptoms or signs. We recommend that gain or amplification of q21 identified either by FISH (even without CD138 selection – as demonstrated here) or GEP be prospectively studied in patients with newly diagnosed MM with consideration of novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBORD) Is a Feasible and Active Regimen for Non-Transplant Eligible Multiple Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5751-5751 ◽  
Author(s):  
Victor H Jimenez Zepeda ◽  
Peter Duggan ◽  
Paola E. Neri ◽  
Nizar J Bahlis
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Time ◽  
Light Chain ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Novel Drugs ◽  
Good Partial Response

Abstract Introduction With the advent of novel drugs for the treatment of Multiple Myeloma (MM), the clinical outcomes have significantly improved over the last decade both in the setting of stem cell transplant eligible and non-eligible patients. Combinations of novel drugs have improved and deepened response and this is true for CyBORD, a regimen able to induce rapid and deep responses. Based on the above mentioned, we aimed to assess the role and feasibility of CyBORD as upfront therapy for non-transplant eligible patients with MM. Methods. All consecutive patients with documented symptomatic MM not eligible for transplant treated with CyBORD at our Institution were evaluated. Treatment consisted of a 28-day cycle of bortezomib 1.3 mg/m2 or 1.5 mg/m2 intravenously or subcutaneously on days 1, 8, and 15, cyclophosphamide 300 mg/m2 orally administered on days 1, 8, and 15 and dexamethasone 20-40 mg orally on weekly basis. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. The primary endpoint of the study was to assess the efficacy and feasibility of CyBORD in this group of patients. All analyses were performed using the SPSS 20.0 software and all p-values were 2-sided and statistically significant if <0.05. Results Between 07/11 and 07/14, 20 patients were identified for the study. Clinical and laboratory characteristics are listed in Table 1. The median age for this cohort of patients was 76 years (range 66-90). Sixty-five percent of patients had IgG isotype, 5% had IgA, and 30% had light chain only disease. After a median of 5 cycles, the overall response rate was 95% (19/20) with 70% of patients achieving VGPR or better response. (Table 2 ) The median time to first response was 6 weeks with majority of cases achieving at least PR after 2 cycles of therapy. At a median follow-up of 9.5 months, all patients are alive and 5 had already progressed at a median time of 12 months. With regards to toxicity, 6 patients experienced non-hematological grade 3/4 adverse events (20%), including muscle weakness, sepsis and pneumonia. Neutropenia and thrombocytopenia were seen in 2 patients (10%), both patients required dose reduction of cyclophosphamide with one patient being discontinued of cyclophosphamide after 2 cycles but still receiving bortezomib and dexamethasone. In conclusion, CyBORD is a highly active and viable option for the treatment of non-transplant eligible patients with MM. As suggested by other studies, elderly patients required dose adjustments and special considerations while receiving active therapy, balancing the efficacy and toxicity given by the different drug combinations. Table 1. Clinical and Laboratory characteristics of non-transplant eligible MM patients treated with CyBORD Characteristic N Median Range % Age (years) 20 76 66-90 Gender -Male -Female 11 9 55% 45% ISS Stage I II III 5 7 8 25% 35% 40% Heavy chain IgG IgA Free light chain only Light chainKappa Lambda 13 1 6 11 9 65% 5% 30% 55% 45% Hemoglobin (g/L) 20 106 73-158 Creatinine (µmol/L) 20 117 49-671 Calcium (µmol/L) 20 2.4 2.0-2.99 LDH (IU/L) 20 229 118-814 B2-microglobulin (mg/L) 20 4.1 1.41-19 Albumin (g/L) 20 32 22-37 FISH Cytogenetics Standard risk High risk 18 2 90% 10% Table 2. Response rates for non-transplant eligible MM patients treated with CyBORD Characteristic Median (Range) N % Number of cycles 5 (1-12) Overall Response rate 19/20 95% Near Complete Response Complete Response 1 2 5% 10% Very Good Partial Response 11 55% Partial Response 5 25% Less than PR 1 5% Progression 5/20 25% Time to progression (months) 12 (3-15) Alive 20 100% CyBORD: Cyclophosphamide, bortezomib and dexamethasone Disclosures Jimenez Zepeda: Janssen Ortho: Honoraria. Bahlis:Celgene: Honoraria, Research Funding.

Real-world experience of talimogene laherparepvec in patients receiving immunotherapy in metastatic melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22003-e22003
Author(s):  
Tapas Ranjan Behera ◽  
Jung Min Song ◽  
Jennifer S. Ko ◽  
Michael J. McNamara ◽  
Pauline Funchain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Metastatic Melanoma ◽  
Treatment Response ◽  
Median Time ◽  
Real World ◽  
Overall Response Rate ◽  
Response Rate ◽  
Talimogene Laherparepvec ◽  
Overall Response

e22003 Background: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus approved by the FDA for intralesional therapy in unresectable metastatic melanoma. However, little is known regarding the effectiveness of TVEC+checkpoint inhibition (CPI) outside of clinical trials. We present outcomes of the largest single institution experience with TVEC in the context of different immune checkpoint inhibitors. Methods: All patients with stage III-IV unresectable melanoma having received TVEC were evaluated. Patient demographics, clinicopathological characteristics, TVEC treatment response and outcomes were assessed. Final analysis included those who received TVEC adjacent to CPI with a minimum 6-month follow-up, excluding patients on clinical trials. Response was estimated by sequential measurement of injectable on-target lesions. Results: A total of 62 patients received TVEC from 2016 to 2019, of which 43 remained excluding Merkel cell carcinoma, patients on trials, and TVEC monotherapy. Of 30 patients with available treatment response data and at least 6-months follow-up, median age was 68.5 years (30-99 years), 40% were female, 16 (53.3%) stage IV. Median follow-up was 17.5 months (6-43 months). At 6 months, 20 (67.7%) patients were alive; at 1 year, 17 (56.7%) patients were alive. Eighteen patients received pembrolizumab, 7 nivolumab and 5 ipilimumab/nivolumab. Median number of TVEC doses received was 8 (3-31 doses). Median time on TVEC therapy was 4 months (1-26 months). Overall response rate for on-target lesions was 24 (80%), with complete local response (CR) in 15 (50%), partial response (PR) in 9 (30%), and progressive disease (PD) in 6 (20%). Median time to response was 6 weeks (2-17 weeks); 5 in CR, 6.5 in PR and 5.5 in PD groups. Adverse events were mostly mild and limited to constitutional symptoms. Conclusions: To our knowledge this is the largest real-world experience assessing TVEC in patients receiving CPI. Local overall response rate appears higher in comparison to historic numbers for TVEC monotherapy. The findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma and has robust outcomes in real-life clinical settings.

Sign in / Sign up

Export Citation Format

Share Document