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.

T-Bird (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], Dexamethasone) Therapy in Newly Diagnosed Symptomatic Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2937-2937
Author(s):  
Tomer M Mark ◽  
Manan Shah ◽  
Melissa Rodriguez ◽  
Ryann Quinn ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival ◽  
Line Therapy ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Abstract 2937 Background: The addition of thalidomide to BiRD therapy (clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) may enhance anti-myeloma activity of the combination while not adding to overall regimen toxicity, given the different side effect profiles of thalidomide and lenalidomide. We now report an update of the phase 2 trial of T-BiRD (thalidomide/Thalomid®, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) in up-front treatment of symptomatic multiple myeloma (MM). Methods: Twenty-six patients with newly diagnosed symptomatic MM received T-BiRD. T-BiRD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1, 8, 15, 22; and lenalidomide 25mg for days 1–21 of a 28-day cycle. Thalidomide was given at a dose of 50mg daily for the first week and thereafter at 100mg daily. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patients until disease progression. Results: Twenty-six patients were enrolled. The median number of T-BiRD cycles delivered was 6.5 (range 0–17). The overall response rate (ORR) to T-BiRD (audited at time of autologous stem cell transplant [ASCT] or other planned change in therapy) was 77% (4% progressive disease (PD), 19% stable disease (SD), 42% partial response (PR), 31% very good partial response (VGPR), 4% CR). Eight patients (31%) withdrew from study, including 4 (15%) early withdrawals prior to completion of cycle 2 (1 due to Grade 4 rash, 2 due to Grade 3 rash, and 1 due to renal failure secondary to MM). Excluding these early withdrawals, ORR was 86% (5% PD, 10% SD, 45% PR, 36% VGPR, 5% CR). In these patients, median time to PR was 1 cycle [range 1–5]; the median time to max response was 4 cycles [range 1–7]. All eighteen patients who electively underwent autologous stem cell collection were successful, with median 16.317 CD34+ cells/kg collected [range 5.8–43.9] over a median of 1.5 apheresis sessions [range 1–5]. Eleven subjects underwent ASCT as part of a first line of therapy with T-BiRD induction; ORR to first line therapy in these subjects was 100%, with 18% PR, 46% VGPR, and 36% CR. At 4 years of study follow-up for 1st line therapy, median progression free survival (PFS) and event free survival (EFS) was 135.6 and 65.3 weeks respectively. Median overall survival (OS) was not reached; at 4-year follow-up, 4 patients had died of progressive myeloma, giving an overall survival rate of 84.5%. Twelve patients experienced grade 3 non-hematologic toxicity (weakness: 4; rash: 3; popliteal vein thrombosis: 2; respiratory infection: 1; hyperglycemia: 1; anorexia/dysgeusia: 1; renal insufficiency: 1; dizziness: 1; psychomotor agitation: 1; myocardial infarction: 1). One subject had grade 4 rash during cycle 1. 1 subject died of progressive myeloma prior to completion of 10 days of cycle 1. Conclusions: T-BiRD is a highly active regimen in treatment-naïve multiple myeloma, with prolonged responses achieved; however, early treatment toxicity precluded extended use in up to a third of patients. Responding patients achieved PR within 1 cycle, indicating that this regimen may be useful when a swift drop in paraprotein is desired. T-BiRD allows for successful autologous stem cell collection and transplant outcomes. These data support the use of immunomodulatory-based regimens in the upfront treatment of MM and highlight the potential additive toxicities of the simultaneous administration of thalidomide and lenalidomide. Disclosures: Mark: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The combination of thalidomide and lenalidomide was tested in relapsed myeloma; the combination is not FDA-approved. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Gemcitabine, Vinorelbine and Dexamethasone (GVDexa) As Second-Line Salvage Regimen in Relapsed and Refractory Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3948-3948
Author(s):  
Anjana Joel ◽  
Prasanth Ganesan ◽  
Tenali Gnana Sagar ◽  
Krishnarathnam Kannan ◽  
Trivadi Ganesan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Second Line ◽  
First Line ◽  
Line Therapy ◽  
Baseline Characteristics ◽  
Third Line ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract INTRODUCTION: Traditional platinum-based salvage regimens like DHAP, ICE are effective in relapsed Hodgkin's lymphoma (HL), but are more toxic. Gemcitabine based regimens are equally effective in salvage of lymphomas, but are less toxic and allow better stem cell collection for subsequent high dose therapy (HDT). There is limited data on the usefulness of gemcitabine based salvage regimens after the failure of salvage therapies like DHAP and ICE. At our center, we used a combination of gemcitabine, vinorelbine and dexamethasone (GVDexa), a non-platinum containing regimen in those patients who failed DHAP/ ICE based salvage treatment. METHODS: The records of patients with relapsed and refractory Hodgkin's lymphoma, who were treated with GVDexa, were reviewed. The regimen consisted of Gemcitabine 1000mg/m2 IV (D1,8), Vinorelbine 25mg/m2 IV (D1,8) Dexamethasone 40mg oral (D1-4) given as outpatient. It was given for 2-3 cycles until best response or till the patient underwent HDT. RESULTS: Between July 2010 to Jun 2015, 25 patients received GVDexa. The median age was 23 years (Range: 11 to 45 yrs) and 64% were males. Baseline characteristics are summarised in Table 1. Twenty-one patients (84%) had previous exposure to salvage therapy with DHAP/ ICE and GVDexa was given as third line treatment. The overall response rate was 48% (12/25) with complete response in 20% (5/25) and partial response in 28% (7/25). Toxicity: A total of 61 cycles [Median: 2 (Range: 1-6)] were delivered among 25 patients. Grade 3/4 haematological toxicities (neutropenia and thrombocytopenia) occurred in 9/61 (14.7%) cycles and febrile neutropenia occurred in 2 (3.2%) cycles. Grade 3/4 non-haematological toxicities were rare (paralytic ileus in 1 patient). There were no toxic deaths. Stem cell collection: Stem cell harvesting for HDT was attempted in 12 patients and was successful (> 2 million CD34 positive cells/kg) in 8 (67%) patients. Seven of these patients successfully completed HDT. Two patients who failed stem cell collection underwent reduced intensity conditioning allogeneic transplant. CONCLUSIONS: GVDexa, when used as third line therapy in relapsed and refractory HL shows promising response rates, with minimal toxicity. The high response rates achieved despite failure of first line platinum based salvage, points to the potential usefulness of this regimen as first line salvage therapy in refractory HL. GVDexa could emerge as a safe and effective non-platinum containing alternative regimen for second-line therapy in HL. Table 1. Baseline characteristics (N=25) PARAMETER Number (Range/Percentage) Age (median, range) 23 yrs (10 to 45 yrs) Male sex 16 (64%) Prior exposure to DHAP/ICE chemotherapy 21 (84%) Previous lines of chemotherapy (median, range) 2 (1 to 4) Time from 1st diagnosis to relapse (median, range) 31.5 months (4.3 to 153.7 months) Primary progressivea/refractory 13 (52) Stage III/IV at relapse 20 (80) Haemoglobin < 10g/dL at relapse 12 (48) a. Progressed within 3 months of completion of first line chemotherapy Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcomes in Advanced-Stage Plasmablastic Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2519-2519
Author(s):  
Sophia Lee ◽  
Christen Dillard ◽  
Raphael E Steiner ◽  
Babak Soltanalizadeh ◽  
Lei Feng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Progression Free Survival ◽  
Plasmablastic Lymphoma ◽  
Advanced Stage ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

Abstract Introduction: Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin B-cell lymphoma (NHL), often characterized by immunoblastic morphology and plasmacytic immunophenotype. PBL was initially described in HIV-positive patients (pts) and is now often diagnosed in post-transplant and HIV-negative pts with other immunodeficiency. Pts with limited stage disease treated with induction chemotherapy and consolidative radiotherapy have a good prognosis; however, pts with advanced stage have poor outcome. Previously studied treatment regimens vary and include CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone), HyperCVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine), and DA-EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) with or without radiation and autologous stem cell transplant, with no current standard therapy, largely due to the rarity of PBL. Methods: We conducted a retrospective analysis of pts diagnosed with PBL between April 2003 and August 2020 to describe outcomes for pts treated at our center over the past 2 decades. We hope to use this to improve outcomes with novel therapies in the future. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). We used descriptive statistics including mean, standard deviation, median, and range for continuous variables, and frequency counts and percentages for categorical variables. Best response and its 95% exact confidence interval were calculated. Kaplan-Meier method was used to estimate the time-to-event endpoints including progression free survival, and overall survival. Results: 39 pts with PBL were identified, with a median age of 51 years (range 27-91). 16 were HIV+, and 5 were on immunosuppression for autoimmune disease (2), infectious hepatitis (2), or liver transplant (1); the other 18 had no apparent immunosuppression other than advanced age (defined as 70 years and older) in 13. Among those with HIV, 14 were on antiretroviral therapy at time of diagnosis of PBL. The median CD4 count was 140 (range 15-391) and 5 patients had an active viral load. 24 pts were EBV/EBER positive. 6 pts had stage III disease and 33 had stage IV disease. The primary sites of disease included head and neck (13), lymph node (7), gastrointestinal tract (6), other soft tissue (3), abdomen (3), breast (2), gynecologic (2), skin (2), and bone (1). The median LDH was 629 IU/L (313-618). A serum protein electrophoresis was checked in 21 pts and the median was 1.4 g/dL (range 0.2-2.6 g/dL, normal = 0). A beta 2 microglobulin was checked in 28 pts and the median was 3.95 (range 2.55-10.4, normal =0.8 to 2.3 mg/L). The median Ki-67 proliferation index was 85%, and the PBL cells were invariably CD20 negative. 12 cases showed MYC overexpression; 2 had MYC rearrangement by FISH. 32 pts received systemic therapy and were evaluable with 2 median lines of treatment (range 1-6). First line therapy included Hyper-CVAD (n=7), CHOP (n=3), EPOCH (n=19), and other (n=3). The antimyeloma therapy, bortezomib, a proteasome inhibitor, was added to EPOCH for 4 patients or used with dexamethasone in one pt, while the CD38 antibody daratumumab was added to hypercytoxan for the first cycle of an elderly pt with poor performance status (PS). He responded well with improvement in his PS, and subsequently completed 5 cycles of DA-EPOCH and remains in CR. After first line therapy, 59% pts achieved complete response, 13% partial response, and 9% stable disease. 20 pts received intrathecal chemotherapy, 9 pts received radiation, and 8 pts underwent autologous stem cell transplantation (7 as consolidation and 1 at relapse). Please see figure for PFS and OS based on different treatment modalities. Median PFS and OS were 21 and 35.2 months, respectively. Median follow up time was 25.85 months. Conclusions: The majority of our pts (87%) with advanced stage PBL were immunocompromised with HIV (16), requiring immunosuppression (5), or elderly (13). Despite a 56% CR rate with induction, 69% of patients relapsed. Median PFS was less than 2 years and OS was less than 3 years. The dismal outcomes of pts with PBL suggests that this rare and aggressive subtype of NHL with plasmacytic differentiation requires further evaluation with therapies against plasma cell directed antigens such as CD38, BCMA or SLAMF7. *S Lee & C Dillard contributed equally. Figure 1 Figure 1. Disclosures Steiner: BMS: Research Funding; Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy.

The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1945-1945
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Albrecht Reichle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Current Phase ◽  
Newly Diagnosed ◽  
First Line ◽  
Peripheral Blood Stem Cells ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.

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.

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.

Implementing Cybord As First-Line Therapy For Transplant-Eligible Multiple Myeloma Patients : A Single-Center Preliminary Comparaison

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5403-5403
Author(s):  
Dominic Duquette ◽  
Vincent Laroche
Keyword(s):  
Multiple Myeloma ◽  
Response Rates ◽  
Median Number ◽  
Cell Transplant ◽  
First Line ◽  
Historical Cohort ◽  
First Line Therapy ◽  
Line Therapy ◽  
Induction Regimen ◽  
Grade 3

Abstract Introduction The best induction regimen for first-line therapy in multiple myeloma patients who are eliglible for autologous stem cell transplant (ASCT) is still unknown. In 2009, we started to use CyBorD and gradually changed our first-line therapy from Vel-Dex to CyBorD based on published work from Princess Margaret Hospital in Toronto. Here, we describe the first 10 patients to have received CyBorD and compare them to an historical cohort from the same institution. Methods We conducted a retrospective review of patient’s charts and transplant database from 2009/10/02 to 2013/04/19. We collected information on blood labs, cytogenetics, immunofixation, response rates, adverse events and graft collection. Patients not receiving the anticipated protocol or less than 3 cycles of treatment arm were excluded from this review. Results All patients (100%) in both cohorts received an ASCT (CyBorD, n=10 and Vel-Dex, n=11). The 2 groups were comparable and there was 1 patient in each arm with unfavorable cytogenetics. The response rates pre ASCT were CR = 20%, >VGPR = 90% compared to CR = 0%, >VGPR = 81,8% in CyBorD and Vel-Dex patients respectively. Response rates at 100 days post-ASCT was CR = 60%, >VGPR = 100% compared to CR = 36.4%, >VGPR = 90.9% in CyBorD and Vel-Dex patients respectively. Patients in CyBorD had a median of 1 (1-2) day for graft collection and a median number of graft cells of 5,01 x 109(2,06-6,48) compared to 1 (1-2) and 4,46 x 109 (3-6,82) in the Vel-Dex group. The rate of grade 3/4 thrombocytopenia was 0%(n=0) vs 9%(n=1) in CyborD and Vel-Dex patients respectively. No case of neuropathy grade 3 or 4 was observed in the CyBorD arm. Conclusion CyBorD is an effective and safe induction regimen for first-line therapy in ASCT eligible multiple myeloma patients. It produces less neuropathy and has an easier schedule to administer. It is now our standard protocol for these patients but dexamethasone has been reduced to once weekly for every cycle since then. NB: CyBorD (Cyclophosphamide 300 mg/m2 PO days 1,8,15,22; Bortezomib 1,5 mg/m2 SC days 1,8,15,22, Dexamethasone 20 mg PO bid days 1-4, 9-12, 17-20 for cycles 1-2, 20 mg PO bid once weekly for cycles 3-4.) Disclosures: Duquette: Janssen: Consultancy, Honoraria. Off Label Use: CyborD is a widely accepted regimen but has not been accepted by the FDA.

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.

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