A Phase 2 Study of Bortezomib as First-Line Therapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 333-333 ◽  
Author(s):  
Sundar Jagannath ◽  
Durie Brian ◽  
Jeffrey L. Wolf ◽  
Elber Camacho ◽  
David Irwin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Neuropathic Pain ◽  
Stem Cell ◽  
Adverse Events ◽  
Karnofsky Performance Status ◽  
Phase 2 ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Cell Harvest

Abstract Introduction: The proteasome is an important therapeutic target in multiple myeloma (MM). Bortezomib, a first-in-class proteasome inhibitor that inhibits proliferation and induces apoptosis, is approved for the treatment of relapsed and refractory MM. We present results in patients (pts) who have completed a phase 2 trial evaluating bortezomib as first-line therapy for MM. Methods: Newly diagnosed adult pts with measurable disease and a Karnofsky performance status (KPS) ≥50% were included. Eligible pts received bortezomib 1.3 mg/m2 twice weekly for the first 2 weeks of a 3-week cycle for a maximum of 6 cycles. Pts achieving < partial response (PR) after 2 cycles or < complete response (CR) after 4 cycles received oral dexamethasone 40 mg on the day of and day after each bortezomib dose. Response evaluation criteria were based on modified EBMT criteria, with the addition of a near CR (nCR) category (nondetectable M-protein by electrophoresis but positive immunofixation with normal marrow). The primary endpoint was response rate. Neurologic assessments, including nerve conduction tests, were performed, and stem cells for transplantation-eligible candidates were harvested at the discretion of the physician. Results: As of August 2004, 38 pts were accrued. The first 23 pts (44% males, median age 63 yrs) who have now completed the study presented at baseline with IgG (61%), IgA (26%), Freelite (9%), or kappa light chain (4%) disease, with a median KPS of 90 (range, 50–100). The majority of pts were Durie-Salmon stage II (36%) or IIIA (36%). 19 (83%) pts achieved major responses (CR+nCR+PR): CR in 3 pts (13%), nCR in 4 (17%), and PR in 12 pts (53%). A minimal response (MR) was observed in 3 (13%) pts. 43% of pts reached their best response after cycle 2, 39% after cycle 4, and 13% after cycle 6. 14 pts (61%) received dexamethasone combination therapy (8 pts after cycle 2 and 6 pts after cycle 4), and the combination resulted in improved response in 9 pts: 6 pts improved from MR to PR, and 3 pts from stable disease to PR. Five of 5 pts had successful stem cell harvest, and 2 pts who underwent transplantation had complete hematologic recovery. Ten pts discontinued early: 7 due to adverse events, 1 due to progressive disease, and 2 pts withdrew. One pt with relapsing disease died of sepsis shortly after coming off study. The most common adverse events (grades 1–3) were neuropathy (56%), fatigue (56%), diarrhea (44%), constipation (38%), and neuropathic pain (12%). Neuropathic pain abbreviated therapy for 2 pts, with subsequent resolution of symptoms. One grade 4 neutropenia and one episode of each of the following grade 3 events occurred: abdominal pain, diarrhea, dizziness, dyspnea, fever, neuropathic pain, neutropenia, syncope, and vomiting. Conclusion: Bortezomib is a promising addition to the treatment armamentarium of initial therapies for previously untreated pts with MM. Major responses were seen in 83% of the pts at the time of this analysis, and combination bortezomib + dexamethasone provided additional benefit. Toxicities, including peripheral neuropathy, were manageable and reversible. Stem cell harvest and engraftment were feasible. Study accrual is ongoing, and final results of the full complement of 42 pts will be available in November 2004.

A Phase II Study of Bortezomib (Velcade ®), Cyclophosphamide (Cytoxan®), Thalidomide (Thalomid®) and Dexamethasone as First-Line Therapy for Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 94-94 ◽  
Author(s):  
William Bensinger ◽  
Sundar Jagannath ◽  
Robert Vescio ◽  
Elber S. Camacho ◽  
Jeffrey Lee Wolf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Induction Therapy ◽  
Response Rate ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Cell Harvest

Abstract Background: This phase II trial evaluated the response rate of sequential bortezomib (VELCADE®), cyclophosphamide (Cytoxan®), and dexamethasone ([VCD]; 3 cycles) followed by bortezomib, thalidomide (Thalomid®), and dexamethasone ([VTD]; 3 cycles) as first-line therapy for patients with multiple myeloma. The primary endpoints were overall response, achievement of „d very good partial response (VGPR), as well as assessment of safety and tolerability. Methods: Patients with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of bortezomib 1.3mg/m2 days 1, 4, 8, and 11, cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg p.o. or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of bortezomib 1.0mg/m2 days 1, 4, 8, and 11; thalidomide 100 mg p.o. daily and dexamethasone same as cycles 1–3. Patients received thrombosis prophylaxis with ASA 325mg daily during cycles 4–6. Upon completion of the 6 cycles, patients proceeded to autologous stem cell harvest, transplant and/or maintenance therapy. Responses were defined as a decrease in serum and/or urine monoclonal (M) protein by 50% or greater. VGPR and other responses were as per the International Response Criteria. Results: This report provides results for all 44 eligible patients: median age 59 years; 68% male; 61% Stage III (D/S); documented ISS Stage II/III 59%; IgG 66%, IgA 17%; 17% light chain only. To date the first 30 patients are fully evaluable for response with 28-day post therapy follow up. The overall response rate (ORR; ≥PR) is 90% with 18/30 (60%) achieving CR + VGPR (CR 33%); 9/30 (30%) PR and 3/30 (10%) stable disease or not evaluable. Overall, both components of the sequential regimen were very well tolerated. One patient had a ruptured colonic diverticulum possibly related to dexamethasone, but recovered well and achieved VGPR on trial. There have been 49 therapy attributed toxicity events which have required drug/schedule adjustments. Of these, 9 events were Gd 3/4: 3 attributed to cyclophosphamide, 3 to dexamethasone, 2 attributed to bortezomib and 1 to thalidomide. DVT occurred in one patient who was at high risk because of prior bilateral hip surgery. Fourteen patients have proceeded to successful stem cell harvest and autologous transplant. Post transplant follow up as well as response information for all 44 patients will be presented. Conclusion: This bortezomib/cyclophosphamide/dexamethasone (VCD) based combination induction therapy followed by VTD is a promising addition to the treatment armamentarium for previously untreated patients. The response rates: ORR 90%; □ VGPR (60%) and CR (33%) are extremely encouraging and improve over our bortezomib/dexamethasone 2-drug experience which produced 90% □ PR and 38% □ VGPR. This very well tolerated new regimen is potentially an important step forward in induction therapy with presentation of more mature data. Supported by the Aptium Oncology Research Network and a research grant from Millennium Pharmaceuticals, Inc.

High-Dose Carfilzomib and Dexamethasone As First-Line Treatment in Symptomatic Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4258-4258 ◽  
Author(s):  
Tomer M Mark ◽  
Sujitha Yadlapati ◽  
Lyubov Neglyad ◽  
Jennifer Bourke ◽  
David Jayabalan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Research Funding ◽  
Maximum Response ◽  
First Line ◽  
Disease Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Background: Carfilzomib (Cfz) is approved for use in relapsed and refractory multiple myeloma (RRMM) at a dose of 27mg/m2 after escalation from 20mg/m2. The response rate for Cfz and dexamethasone (dex) as first-line therapy in multiple myeloma (MM) is unknown. Higher doses of Cfz have been shown to enhance overall response in RRMM (Lendvai 2014); the presence of a dose-response relationship of Cfz for first-line therapy in untreated MM has not been evaluated. A protocol of Cfz-Dex induction at two dosing levels, followed by BiRd (Clarithromycin 500mg PO BID, Lenalidomide (Len) 25mg for 21/28 days, Dex 40mg weekly) consolidation, and thereafter Len (10mg 12/28 days) maintenance, evaluated response and safety by Cfz dose level in patients (pts) with newly diagnosed symptomatic MM. The ORR and safety data for Cfz-Dex induction stratified by Cfz dose is reported. Methods: 70 patients with untreated MM were enrolled in a phase 2 study of Cfz-dex. Cfz-dex is: Cfz IV on D1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of cycle 1 and 45mg/m2 thereafter and Dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Screening echocardiogram and pulmonary function testing were performed. Brain natriuretic peptide (BNP) was measured with each cycle. Cfz-dex was continued until plateau in disease response (unchanged M-protein for 2 cycles). Elective stem cell collection was then performed in transplant eligible pts. This was followed by BiRd until 2nd response plateau, and then by LEN maintenance. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Results: 25 pts received Cfz-Dex at 45 mg/m2 and 44 (out of 45 enrolled) pts at 56 mg/m2 for at least 1 cycle and were evaluable for response. 56% of pts were ISS II/III and 64% had high-risk cytogenetics as per IMWG definition. Pts received a median of 5 cycles of Cfz-dex in both the 45 mg/m2 (range 1-10) and 56 mg/m2 groups (range 1-14). Maximum response to Cfz-dex is shown in Table 1. There was no difference in response between the 45 and 56mg/m2 groups (P = 0.20). Median time to PR and maximum response for the 45 and 56 mg/m2 cohorts were both 2 and 3 cycles, respectively. 42 pts had stem cell harvest. All collected stem cells to support at least two transplants (> 5 x 10^6 CD34/kg) in one mobilization attempt using G-CSF, with mean yield of 13.74x10^6 CD34/kg (range 5.94-32.14). 79% collected in 1 apheresis session. Adverse events (AEs) were notable for renal failure in 3 pts (2 Grade 2, 1 grade 3) and congestive heart failure in 1 pt (grade 3). Two of the 3 cases of renal failure occurred in the 56 mg/m2 cohort, all other AEs occurred in the 45mg/m2 cohort. All AEs resolved after stopping Cfz. There was no correlation with TTE, PFTs or serial BNPs and development of cardiac or pulmonary toxicity. Discussion: This is the first prospective study evaluating induction responses to Cfz-dex in MM. Cfz-dex is safe and active in induction at both 45 and 56 mg/m2, with an ORR of 93% and rate of >= VGPR of 68% despite a primarily high risk population. Specific dose did not correlate with response. Higher dose of Cfz did not lead to more toxicity. Cfz-dex induction led to successful stem cell collection in all attempts. Cfz-dex is a highly active and well-tolerated induction regimen. Transitioning to IMiD-based therapy after maximum response led to deeper responses with a remarkable 97% rate of VGPR or better. Table 1. Maximum Response with Cfz-Dex, followed by BiRD consolidation and lenalidomide maintenance: Response Category Cfz-Dex 45 mg/m2 Cfz-Dex 56 mg/m2 Overall Cfz-Dex phase BiRD phase Lenalidomide maintenance phase N = 25 (%) N = 44 (%) N = 69 (%) N = 44 (%) N = 33 (%) >= PR 22 (88) 42 (95) 65 (93) 44 (100) 33 (100) >= VGPR 16 (72) 31 (70) 45 (68) 42 (95) 32 (97) >= CR 3 (12) 2 (5) 5 (7) 12 (27) 15 (45) SCR 3 (12) 2 (5) 5 (7) 9 (20) 13 (39) CR 0 (0) 0 (0) 0 (0) 3 (7) 2 (6) VGPR 13 (52) 29 (66) 42 (61) 30 (68) 17 (52) PR 6 (24) 11 (25) 17 (25) 2 (5) 1 (3) SD 3 (12) 2 (5) 5 (7) 0 0 Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib as first line therapy in myeloma.. Rossi:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pearse:Celegen: Consultancy. Perry:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.

Bortezomib with HIG-Dose Dexamethasone as First Line Therapy in Patients with Multiple Myeloma Candidates to High-Dose Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3595-3595 ◽  
Author(s):  
Alessandro Corso ◽  
Luciana Barbarano ◽  
Silvia Mangiacavalli ◽  
Luigi Montalbetti ◽  
Paola Brasca ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
Light Chain ◽  
High Dose ◽  
First Line ◽  
High Dose Therapy ◽  
First Line Therapy ◽  
Line Therapy

Abstract Introduction: A phase II multi-center study was performed to investigate the efficacy of Bortezomib with high-dose dexamethasone (Vel-Dex) as induction therapy in multiple myeloma (MM) patients (pts) candidates to high-dose therapy. Methods: Patients were planned to receive 4 courses of Vel-Dex (Bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, 11; oral Dexamethasone 40 mg on days 1–4 and 8–11 every 3 weeks), followed by 2 courses of DCEP 4 weeks apart with stem cell collection, and a single autologous transplant with melphalan 200 mg/m2. Patients were untreated, aged ≤65 years, with Durie-Salmon stage III, II, or I in progression. Criteria of response were: CR: negative serum/urine immunofixation with &lt;5% bone marrow plasmacytosis (BMPC); nCR: positive serum/urine immunofixation with &lt;5% BMPC; VGPR/PR: reduction of at least 90%/50% of serum/urine monoclonal component (MC), and of BMPC. Adverse events (AE) were graded by the NCI-CTC version 3.0. Mann-Whitney U test was used to correlate response and main prognostic parameters. Results: From March 2006 to June 2007, 52 out of the 54 planned pts entered the protocol. Patient characteristics at enrolment were: male/female 33/19; median age 57 years (37–65); IgG/IgA/light-chain 33/9/10 pts; stage III/II/I in progression 44/5/3 pts; ISS I/II/III 21/14/17 pts; cytogenetic analysis showed del 13 in 54%, t (4;14) in 15%. Thirty-nine of 52 enrolled pts are evaluable for efficacy and toxicity after 4 Vel-Dex courses. Six pts were withdrawn (3 for progression, 2 for toxicity, 1 patient withdrew informed consent). Overall response rate (ORR) was 85%, with 67% major responses (CR 33%, nCR 26%, VGPR 8%), PR 18%, stable disease 7%, progression 8%. No statistically significant correlation was found between response and either age, stage, ISS, or unfavorable cytogenetics. Friedman ANOVA (p=0.00001) and Wilcoxon Matched Pairs (p&lt;.05) tests showed a statistically significant progressive decrease of serum MC after each Vel-Dex cycle. Urine MC and serum free light chain ratio showed a strikingly rapid reduction after the first course with no further statistically significant decrease during the following courses. Regarding toxicity, NCI grade 1 or 2 AE were: infection (19), constipation (16), peripheral neuropathy (13), diarrhea (9), gastritis (6), nausea (5). NCI grade 3 AE were: infection (9) with 5 varicella-zoster, peripheral neuropathy (4), cardiac arrhythmia (2). A single grade 4 AE (fatal sepsis) occurred. At the time of this analysis, 25 pts completed the stem cell mobilization phase. All pts collected adequate number of stem cells (median CD34+ cells 6.2x106/kg, range 3.5–18.0x106/kg, median number of collection procedures 1). Discussion: This study shows that Vel-Dex as first line therapy produces high response rates in MM pts (ORR 85%, major response 67%). Toxicity was generally predictable and manageable. Stem cells were successful harvested in all patients. Vel-Dex appears an effective and safe pre-transplant treatment for younger MM patients.

scholarly journals Real-Life Experience With First-Line Therapy Bortezomib Plus Melphalan and Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma Ineligible for High Dose Chemotherapy With Autologous Stem-Cell Transplantation

2021 ◽  
Vol 8 ◽  
Author(s):  
Gabriele Buda ◽  
Maria Livia Del Giudice ◽  
Elisabetta Antonioli ◽  
Francesco Ghio ◽  
Enrico Orciuolo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Elderly Patients ◽  
Autologous Stem Cell Transplantation ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Introduction: Currently, the regimen with bortezomib plus melphalan and prednisone (VMP) is a standard treatment for multiple myeloma and it is recommended as the first-line therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy with autologous stem-cell transplantation.Objectives: Participants of the clinical trial are highly selected populations; therefore, the aim of this study was to present observations from real practice that can provide important information for practitioners and to investigate clinical outcomes of VMP regimen in elderly patients with newly diagnosed MM.Patients and Methods: We retrospectively analyzed the data on the efficacy and survival parameters, such as overall survival (OS) and event-free survival (EFS), with attention to the effect of gender, age and International Staging System (ISS) stage, of VMP regimen in 164 patients with newly diagnosed MM not eligible for high-dose chemotherapy with autologous stem-cell transplantation (median age, 75 years; range, 60–86 years).Results: Patients aged 75 years or older constituted 50.6% of the study cohort. Frail patients were 10.36%, according to the clinical frailty scale of geriatric assessment (GA). A total of 1203 courses of VMP regimen (mainly VMP 1–29, 99.16 %) were administered. The median cumulative delivered dose of bortezomib was 46.8 mg/m2. The overall response rate (ORR), including all patients with a partial response or better, was 81.7% and the complete response rate (CRR) was 10.36 %. After a median 38.51 months of follow-up, the median overall survival (OS) was 34.33 months; the median event-free survival (EFS) after VMP and second-line therapy (mainly Rd, 56.31%) were 18.51 and 10.75 months, respectively. In the subgroup of patients with 75 years or older the median OS was 29.76 months; the median EFS after first and second-line therapy were 17.76 and 8.93 months, respectively. The hazard ratio for OS was 2.276 (p-value 0.046) and for EFS was 1.507 (p-value 0.055) for the ISS stage II and III group. Age and gender were not negative predictors of survival.Conclusions: VMP treatment is highly effective in the first-line therapy of elderly patients with multiple myeloma ineligible for HDT with auto-SCT.

191 Association of immune related adverse events with the efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A205-A206
Author(s):  
Vasilii Bushunow ◽  
Leonard Appleman ◽  
Roby Thomas
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Kaplan Meier

BackgroundImmune checkpoint inhibitors (ICI) are first-line therapy for tumors including metastatic renal cell carcinoma (mRCC). Use of ICI is complicated by diverse immune-related adverse events (irAEs), which can add significant morbidity but are also associated with improved efficacy of therapy.1 2 Risk factors for development of irAE are still poorly understood. We hypothesized that patients with mRCC treated with ICI as first-line therapy have higher rates of developing irAE’s than patients previously treated with other therapies.MethodsWe conducted a single-institution, retrospective medical record review of patients with mRCC treated with immune-checkpoint inhibitors from March 2011 through April 15, 2020. We identified therapy duration, and presence, severity, and treatment of adverse events. We defined overall survival as time elapsed from date of diagnosis until death or until completion of study. We classified severity of adverse events according to CTCAE guidelines. Statistical methods included univariate Cox proportional hazards and logistic regression models, and Kaplan-Meier curves were plotted for subgroups.ResultsA total of 64 unique charts were reviewed. 18 patients (28%) of patients were treated with ICI as first-line therapy. 28 patients (44%) experienced immune-related adverse events with a total of 40 irAE’s identified. Most irAE were grade I-II (78%), with 7 (17%) grade III and 1 (2.4%) grade IV irAE’s. Most common sites were skin (29%), thyroid (20%) and gastrointestinal (15%). Patients with irAE had increased survival compared to those who did not have irAE (median survival not reached, vs 139 weeks, p=0.0004) (figure 1). This finding remained after excluding patients who had only experienced dermatologic irAE (median survival not reached in non-derm irAE subgroup, vs 144 weeks for dermatologic or no irAE, p=0.01) (figure 2). Patients treated with ICI as first line therapy had greater rates of developing irAE (72%) than those who had prior therapies (32%) (OR 5.4; p = 0.006). There was no association between histology type and rate of irAE.Abstract 191 Figure 1Kaplan-Meier survival plot of OS between patients with any irAE and those without any irAEAbstract 191 Figure 2Kaplan-Meier survival plot of OS between patients with non-dermatologic irAE and those without any irAE or only dermatologic irAEConclusionsThe development of irAE’s in patients with mRCC treated with ICI is associated with longer survival. This study joins the growing body of evidence showing that presence of irAE’s is associated with increased treatment efficacy. Use of ICI as first-line therapy is associated with higher risk of irAE. Given growing use of ICI as first-line therapy, further study to predict onset and severity of irAE’s is required.AcknowledgementsHong Wang, PhD, for statistical support.Ethics ApprovalThis study was approved by the University of Pittsburgh Institutional Review Board. Approval number STUDY19100386.ReferencesElias R, Yan N, Singla N, Levonyack N, Formella J, Christie A, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. J Clin Oncol 2019;37(7):S645.Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer 2019;7(1):99.

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