Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients with Multiple Myeloma Who Are Not Candidates for High Dose Chemotherapy: Toxicity Comparison of Two Dose Schedules

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Michael R. Savona ◽  
James Essell ◽  
Patrick Murphy ◽  
Luis Chu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Herpes Zoster ◽  
Research Funding ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
First Line ◽  
Off Label ◽  
Grade 3

Abstract Abstract 4047 Background: Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for patients with MM. Methods: Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema (schema A) consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Patients had the option to continue on maintenance bortezomib. An interim analysis found this combination to be efficacious but relatively toxic. As a result the treatment schema was amended to the following (schema B): bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Again, patients had the option to continue maintenance bortezamib. Acyclovir or equivalent viral prophylaxis was recommended on schema A and became required on schema B. Responses were assessed using the IMWG criteria. AEs were assessed using the CTCAE Version 4.0. We report the results of an interim safety assessment of the amended BBD combination and compare the results to those seen with the original regimen. Results: Treatment schema A accrued 18 patients between 5/2010 and 2/2011. Ten patients were accrued from 10/2011 and 4/2012 and treated on treatment schema B. The median ages of treatment schemas A and B were 75 and 72.5 respectively, with all other characteristics within expected distributions and no major differences between the groups. No grades 4 hematologic Adverse Events (AEs) were seen. Grade 3 hematologic AEs were similar in both arms seen in 33% of patients on treatment schema A and 40% of patients on treatment schema B. Grade 3/4 non-hematologic AEs were seen in 72% of patients on treatment schema A and 60% of patients on treatment schema B. Although the preliminary Serious Adverse Events (SAEs) were similar with 39% of patients on treatment schema A compared to 30% of patients on treatment schema B, a large proportion of patients on treatment schema A (39%) were unable to complete the study due to toxicity or related issues. The incidence and severity of neuropathy and herpes zoster infections were significantly different between the two schemas. Schema A had 72% of patients with any grade neuropathy, with 56% being grade 2 or worse while schema B had 40% of the patients with any grade neuropathy, all but one grade 1. Likewise, 44% of patients on the original treatment reported herpes zoster while there were no cases of herpes zoster reported for patients on the revised treatment schema. Thus far, the early response rates appear similar. Schema A had an ORR of 78% (56% >vgPR) while schema B had an ORR of 90% (40% >vgPR). Conclusions: The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in an elderly patient population. Using the revised schema, we were able to lower treatment toxicity without adversely impacting initial efficacy. Updated results will be presented at the meeting. Disclosures: Off Label Use: Off-label use of Bendamustine in the treatment of Multiple Myeloma. Chu:Millennium: Research Funding; Cephalon: Research Funding.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment Of Patients (Pts) With Multiple Myeloma Who Are Not Candidates For High Dose Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3193-3193 ◽  
Author(s):  
Jesus Berdeja ◽  
Michael Savona ◽  
Luis Chu ◽  
James Essell ◽  
Patrick Murphy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
First Line ◽  
Off Label ◽  
Grade 3 ◽  
Original Treatment

Abstract Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial. Methods Pts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m2 IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results As of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95). Conclusion The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing. Disclosures: Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.

Influence of First-Line Regimens on the Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 931-931 ◽  
Author(s):  
Bimalangshu R. Dey ◽  
Benjamin Cox ◽  
A. Jo Chien ◽  
Martin Caron ◽  
Steven L. McAfee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem ◽  
Group 2 ◽  
Group 1

Abstract Randomized trials that incorporated high-dose chemotherapy (HDC) plus autologous hematopoietic stem-cell transplantation (Au-HSCT) into the early treatment of patients with newly diagnosed multiple myeloma demonstrated superior overall and event-free survival (EFS) in patients 65 years of age or younger, who received Au-HSCT, as compared with patients who received conventional chemotherapy. Based on these encouraging results, Au-HSCT is recommended for patients with myeloma as part of their initial treatment, and today, myeloma is the most common indication for HSCT in the world. All patients in these trials received four to six months of conventional chemotherapy prior to HDC and Au-HSCT. In practice, however, both in the community as well as in academic hospitals, patients are undergoing Au-HSCT after being treated with various first-line regimens, including chemotherapeutics, high-dose dexamethasone (HDex), immunomodulatory drugs such as thalidomide and recently, proteasome inhibitors. In this retrospective study, we examined the impact of first-line therapy on the outcomes following Au-HSCT. Our objective was to compare two treatment groups - chemotherapy versus non-chemotherapy, prior to Au-HSCT - with respect to survival after Au-HSCT. Between 1997 and 2004, 37 previously untreated evaluable patients with myeloma, received either chemotherapy (group 1, n=25; vincristine, adriamycin and dexamethasone (VAD), n=24; melphalan and prednisone (MP), n=1) or non-chemotherapy regimens (group 2, n=12; HDex, n=9; thalidomide plus HDex, n=3), then received HDC followed by cyclophosphamide plus granulocyte colony stimulating factor-mobilized HSCT. The median age of patients in group 1 was 58 (range, 44–73) years and in group 2 was 55 (range, 41–67) years; 22 patients in group 1 (88%) and 10 patients in group 2 (83%) had stage III disease; the median times from diagnosis to HSCT were 6 (range, 5–16) and 8 (range, 5–25) months, respectively, in groups 1 and 2. The rates of complete and near-complete response were 44% in group 1 and 42% in group 2; the rates of partial responses were also similar: 48% and 42% respectively. The median duration of EFS was 31 (range, 7–89) months, and the median overall survival (OS) was 55 (range, 12–98) months in group 1, as compared with group 2 where EFS and OS were 21 (range, 12–40) and 31 (range, 16–76) months, respectively. The EFS at 3 years was 44% in group 1 and 25% in group 2, and OS at 5 years was 32% in group 1 and 8% in group 2 (statistically not significant). In conclusion, patients with newly diagnosed myeloma, when treated with chemotherapy prior to Au-HSCT, may have long-term overall and EFS advantages, as compared with patients who are treated with first-line non-chemotherapy regimens. The reasons for the longer duration of response in the chemotherapy group despite similar response rates in the two groups are unknown, but may be due to more effective suppression of residual disease or non-specific damage to the marrow microenvironment, which is necessary for the growth of myeloma cells. Although, the difference in survival outcomes following Au-HSCT between the two groups did not achieve statistical significance, our results raise an important question regarding the “adequacy” of different first-line regimens prior to Au-HSCT, and therefore, justify the need for prospective randomized studies to evaluate optimal pre-AuHSCT induction therapy.

A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2943-2943 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Daniel R. Couriel ◽  
Patrick Murphy ◽  
Ralph V. Boccia ◽  
Victor Priego ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Sensory Neuropathy ◽  
Response Rates ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract Abstract 2943 Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as single agent and in combination with steroids, thalidomide and bortezomib for the treatment of MM. Pönisch et al reported an overall response of 61% and CR of 15% in pts with relapsed/refractory MM using the combination of bendamustine, bortezomib and prednisone. In this study, the combination of bendamustine, bortezomib and dexamethasone (BVD) was tested for efficacy and safety in newly diagnosed pts with active MM who are not candidates for high-dose chemotherapy. Methods Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. Pts were treated with bendamustine 80 mg/m2 on days 1, 4, bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1, 2, 3, 4 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Responses were assessed using the IMWG criteria. We report on the preliminary efficacy and safety results of a planned interim analysis of the BVD combination. Results Between May 2010 and February 2011, 18 pts were enrolled, all evaluable for toxicity. The median age was 75 (range 56–82); nine (50%) pts were DS stage III; seven (39%) pts had a B2M ≥ 5mg/L. Cytogenetics and FISH analysis for 13 del, t4;14, t14;16, and 17p del were available for all but 1 pt; 8 (44%) pts had at least 1 chromosomal abnormality, while 9 (50%) pts had none. At the time of data cut off, pts completed a median of 5.5 cycles (range 1–8); with 11 (61 %) receiving at least 4 cycles; and 5 (28%) receiving 8 cycles. Seven (39%) pts remain on study and 10 have discontinued therapy (1 disease progression and 3 deaths on study [2 cardiac arrest, 1 pulmonary emboli; all 3 determined to be unrelated to treatment], 1 MD discretion, 1 non-compliance, 1 pt request, 2 poor tolerance, 1 intercurrent illness) and 1 completed treatment. The most common grade 3/4 adverse events, occurring in more than 10% of pts, were leucopenia (17%), neutropenia (11%), myalgia (17%) and sensory neuropathy (11%). Twelve pts had treatment emergent sensory neuropathy: 5 (28%) grade 1, 5 (28%) grade 2 and 2 (11%) grade 3. Of the 17 patients evaluable for response, 15 had at least a PR for an ORR of 88% (9 (53%) VGPR, 6 (35%) PR, 2 (12%) SD). The presence of cytogenetic abnormalities did not seem to have a strong impact on response rates, with 88% of pts with 1 or more abnormalities responding compared to 88% with none. The median time to best response was 9 weeks. Conclusions In this planned interim analysis, the combination of BVD produced a high ORR, however the current schedule is relatively toxic in this pt population. The majority of the non-hematological toxicities appear to be related to bortezomib and dexamethasone. For this reason, the protocol was amended where bortezomib and dexamethasone are now dosed weekly (days 1, 8, and 15). The amended trial is currently accruing. Disclosures: Off Label Use: Bendamustine in myeloma. Flinn:Cephalon and Millenium: Research Funding.

Pulse High-Dose Vorinostat Can Be Delivered with Rituximab, Ifosphamide, Carboplatin, and Etoposide In Patients with Relapsed Lymphoma: Final Results of a Phase I Trial.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2790-2790
Author(s):  
Lihua E Budde ◽  
Andrei Shustov ◽  
John M. Pagel ◽  
Ted Gooley ◽  
George Oliviera ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
High Dose ◽  
Off Label Use ◽  
Off Label ◽  
Relapsed Lymphoma ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 2790 Background: The development of more effective front-line regimens for lymphoma (e.g. R-CHOP, BEACOPP) has resulted in lower response rates to salvage regimens such as Ifosphamide, Carboplatin, Etoposide +/− Rituximab (RICE/ICE) and improved strategies are needed. Vorinostat (V) is a well-tolerated, oral pan-HDAC inhibitor approved for the treatment of cutaneous T cell lymphoma. In vitro data indicate that combinations of V at >2-5μM plus etoposide or platinum analogs yield synergistic anti-tumor activity, but these concentrations are not typically attained with standard dose regimens. We hypothesized that pulse high-dose V could safely augment the anti-tumor activity of ICE/RICE for patients with relapsed lymphoma. Here we present the final results of a multi-center Phase I trial defining the maximally tolerated dose (MTD) and pharmacokinetics of V that can be given with RICE or ICE. Methods: Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or mantle cell lymphoma [MCL] allowed), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC ≥ 1,500/μL, plts ≥ 100,000/μL, adequate hepatic/renal function, no known HIV. The primary objective was to define a maximally tolerated dose associated with a dose limiting toxicity (DLT) rate of ≤ 25%. DLT = gastrointestinal grade 3 NCI-CTCAE adverse event (AE) >7 days, any related non-hematologic grade ≥4 AE, inability to complete one full cycle of therapy due to toxicity, or any significant medical event at the discretion of the PI. Interpatient dose escalation was implemented using a “two stage” design (Storer et al) with single patient cohorts until a DLT was observed, followed by cohorts of 4 patients. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard ICE or RICE (CD20+ only) delivered on days 3 to 5 every 21 days for up to 2 cycles using G-CSF support. Results: Twenty-nine patients were treated, 9 in stage 1, 20 in stage 2. Baseline features: median age = 56 (range 23 to 69), median prior therapies 2 (range 0 – 7), refractory to last regimen = 14 (of 27 evaluable, 52%), and prior transplant 2 (7%). Histologies: Hodgkin Lymphoma (8), Diffuse large B-cell (7), MCL (5), T-NHL (4), Follicular (3), Marginal Zone (1), and Small Lymphocytic lymphoma (1). Fifteen patients received 2 cycles and 14 received 1 cycle due to a DLT (8), patient/MD choice (4), insurance denial (1), or progressive disease (1). Non-hematologic AEs ≥ grade 3 were observed in 25 patients with 14 experiencing grade 3 nausea, vomiting, diarrhea, and/or anorexia. The most common DLTs were infection (n=2), hypokalemia (n=2), transaminitis (n=2) (Table). The MTD was estimated to be 500mg BID × 5 days with full dose ICE/RICE. Responses were observed in 19 of 27 evaluable patients (70%) including 8 CR/CRU and 11 PR. Mobilization of peripheral blood stem cells was successful in 4 of 9 patients immediately following VICE/VRICE (median 5.52×106 CD34/kg), in all 4 attempting after prior unsuccessful VICE/VRICE mobilization (median 4.4 × 106 CD34/kg), and in all 12 others attempting after a subsequent regimen (median 7.5 × 106 CD34/kg). 25 (86%) patients are alive and 15 (52%) are progression-free with a median follow up of 5 months (range 1 – 23 months). Pharmacokinetic data indicated that the median peak V concentration day 3 was 4.5μM (range 4.2–6.0μM). Studies are underway evaluating the impact of high-dose V on histone acetylation patterns, BCL-2 family proteins, and gene expression profiles of patient-derived normal and tumor cells and will be reported. Conclusions: High-dose V can safely be delivered with ICE/RICE, achieves potentially synergistic drug levels, and responses are encouraging, though adequate prophylaxis and treatment of GI toxicity is required. The Phase II dose of V with ICE/RICE is defined as 500mg BID × 5 days and warrants further study. Disclosures: Budde: Merck: Research Funding. Off Label Use: Off label use of vorinostat. Shustov:Merck: Research Funding. Pagel:Merck: Research Funding. Gopal:Merck: Research Funding.

RAD (Lenalidomide, Adriamycin and Dexamethasone) Is a Novel and Very Effective Induction Regimen in Newly Diagnosed Multiple Myeloma Preceding a Risk-Adjusted Transplant Strategy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3967-3967
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Christoph Röllig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Research Funding ◽  
Current Phase ◽  
Induction Treatment ◽  
High Dose ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Abstract 3967 Background Triple combinations utilizing dexamethasone, at least one of the “novel drugs” and either an alkylating agent or an anthracycline are currently considered standard induction regimens in newly diagnosed multiple myeloma (MM). In patients (pts) deemed medically fit, subsequent autologous (auto) stem cell transplantation (SCT) yet is a mainstay of care. Whether allogeneic (allo) SCT in first line treatment of MM further improves prognosis remains, however, a matter of debate. We have shown the RAD regimen to be highly effective and well tolerated in relapsed and refractory MM. Therefore, we decided to integrate this combination as a means of induction into the up-front management. Patients and methods The current phase-II trial (DSMM XII) was designed to include pts up to the age of 65 years with newly diagnosed, symptomatic MM. We chose four cycles of RAD induction (lenalidomide 25 mg/day d 1–21; infusional adriamycin 9 mg/m2 and day d1-4; dex 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks followed by chemomobilization (cyclophosphamide, etoposide) of peripheral blood stem cells. Thromboprophylaxis by low molecular weight heparin is mandatory. All pts are scheduled to receive two transplants, the first of which being an auto SCT following standard high-dose melphalan (200 mg/m2). A subsequent allo SCT after preparation with treosulfan/fludarabin is scheduled for pts featuring at least one cytogenetic or serologic risk factor (RF). Those without any RF (“very favourable risk”) are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance. The primary end point of this trial is response to risk-adapted transplant as assessed after second SCT. This is the first planned efficacy interim analysis after 50 pts having terminated induction treatment. Results 148 pts with a median age of 55.5 (range, 30–66) years have been enrolled by 16 German centers between 9/2009 and 7/2011. In addition to the intended sample size, 2 pts had progressive disease for a total of 52 pts being evaluable for post-induction response according to the IMWG criteria. 32 pts (62%) had ISS stage II and III disease and all except three were evaluable for cytogenetic analysis based on fluorescence in situ hybridization (FISH). Incidences of chromosomal abnormalities were as follows: deletion of 13q, 31%; translocation (4;14), 15%; and deletion of 17p, 12%. Overall response rate was 79% including a 52% rate of at least very good partial response (VGPR). Seven pts (13%) achieved confirmed complete response (CR) and stringent CR. 18/52 pts (35%) experienced severe treatment-emergent adverse events (t-SAEs) with an incidence of hematologic events of 4%. Incidences of infections and venous thromboembolism were 8% and 6%, respectively. Conclusions Results from this interim analysis indicate RAD to be a very effective and well tolerated induction protocol in newly diagnosed MM. High-quality response (VGPR or better) to induction is known to be a major prognosticator for long-term prognosis in a given patient. Thus, combination of RAD with risk-adjusted SCT may contribute to enhanced disease control in a substantial proportion of pts. Disclosures: Knop: Celgene Germany GmbH: Consultancy. Off Label Use: Lenalidomide in combination with dexamethasone and adriamycine in first line treatment of multiple myeloma. Langer:Celgene Germany GmbH: Consultancy. Gramatzki:Novartis, Celgene: Consultancy, Research Funding. Einsele:Celgene Germany GmbH: Consultancy, Honoraria. Bargou:Celgene Germany GmbH: Consultancy, Honoraria, Research Funding.

Limited Efficacy of Ponatinib in Myeloproliferative Neoplasms Associated with FGFR1 Fusion Genes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2812-2812 ◽  
Author(s):  
Sebastian Kreil ◽  
Lionel Adès ◽  
Martin Bommer ◽  
Frank Stegelmann ◽  
Mark E Ethell ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Progressive Disease ◽  
Cytogenetic Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Fusion Genes ◽  
Off Label Use ◽  
Blast Phase ◽  
Off Label

Abstract The WHO classification (2008) defines "myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1" as a rare subtype of myeloid neoplasms. Whilst patients with PDGFRA or PDGFRB rearrangements respond very well to imatinib, the optimal therapy for patients with FGFR1 rearrangements, which we refer to as FGFR1 fusion gene positive MLN-eo (FGFR1+ MLN-eo), remains to be defined. Encouraging in-vitro data using inhibitors of the FGFR1 tyrosine kinase prompted the implementation of ponatinib, which inhibits FGFR1, into therapeutical strategies. In a recent report, the clinical activity of ponatinib was reported in a single patient who concomitantly received high-dose chemotherapy and allogeneic stem cell transplantation (ASCT, Khodadoust et al, Leukemia 2015). We sought to evaluate efficacy of ponatinib in seven consecutive FGFR1+ MLN-eo patients. Median age was 52 years (range, 48-74) with a male predominance (n=5). Median observation time after diagnosis was 10 months (range, 5-36). All patients presented with left-shifted leukocytosis but only three patients [all with t(8;13)] had eosinophilia of >0.5 x 109/l. Bone marrow biopsy revealed a hypercellular marrow consistent with myeloproliferative neoplasm in all patients. Five patients presented with concomitantly diagnosed lymphoid neoplasms, i.e. T-lymphoblastic lymphoma (T-LBL, n=3), biclonal accelerated phase (n=1) or lymphoid blast phase of MPN/B-cell acute lymphoblastic leukemia (B-ALL, n=1). Cytogenetic analysis revealed a reciprocal translocation with involvement of chromosome band 8p11 in all patients [t(8;13)(p11;q12), n=3; t(8;22)(p11;q11), n=2; t(1;8;22)(?;p11;q11), n=1; t(6;8)(q27;p11), n=1]. On molecular level, RT-PCR identified the associated fusion genes ZMYM2-FGFR1 (n=3), BCR-FGFR1 (n=3), and FGFR1OP-FGFR1 (n=1), respectively. In one patient with T-LBL, the FGFR1 rearrangement was revealed by FISH analysis in 80% of lymph node cells indicating an origin of both MPN and T-LBL from the same progenitor/stem cell (myeloid/lymphoid stem cell neoplasm) and T-LBL as a feature of extramedullary lymphoid blast phase. All patients were initially treated with chemotherapy-based regimens including hydroxyurea (n=4) and/or high-dose chemotherapy (n=3), the latter exclusively in patients with concomitant aggressive lymphoid neoplasms. Lack of complete response, e.g. persisting features of MPN, relapse or progression led to the off-label use of ponatinib at a dose of 30mg/day (n=2) or 45mg/day (n=5). Median duration of treatment was 8 weeks (range, 2-52). A temporary partial hematologic response (control of peripheral blood cell count) was observed in 6 of 7 patients. One patient did not respond at all and died within a few weeks while on ponatinib due to progressive disease. Three of the 6 responders had cytogenetic analysis at a median of 3 months after the start of ponatinib. One patient with t(8;13) achieved a partial cytogenetic response (50% of metaphases positive after 3 months of treatment); in all other patients no cytogenetic response was observed. Four patients underwent ASCT and are in complete molecular remission and alive after a median time of 19 months (range, 8-36) after diagnosis and 13 months (range, 4-29) after ASCT. For one patient with BCR-FGFR1-positive MLN-eo without concomitant lymphoid disease ASCT is planned. One patient is on supportive care. Conclusion: Unexpectedly, response to standard dose ponatinib in FGFR1+ MLN-eo has been poor. There was either progressive disease or no evidence for sustained hematologic or cytogenetic response. However, there was also no evidence for a sustained complete remission on intensive chemotherapy in patients with full myeloid/lymphoid phenotype. Hence, ASCT currently remains the only option to achieve long-term remission and possibly cure in FGFR1+ MLN-eo. Disclosures Off Label Use: ponatinib, used as FGFR1 inhibitor. Bommer:Alexion Pharmaceuticals: Honoraria. Cross:Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

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.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

Double Autologous Transplant Versus Tandem Autologus - Non Myeloablative Allogeneic Transplant for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 46-46 ◽  
Author(s):  
B. Bruno ◽  
M. Rotta ◽  
F. Patriarca ◽  
N. Mordini ◽  
B. Allione ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Allogeneic Hct ◽  
Autologous Transplant ◽  
Autologous Hct ◽  
Beta 2 Microglobulin

Abstract Allogeneic approaches employing low dose TBI nonmyeloablative conditionings reported a dramatic reduction of transplant-related mortality (TRM) compared to conventional high dose regimens in newly diagnosed multiple myeloma (MM) (Maloney et al, Blood, 2003). The role of allografting, however, compared to autologous HCT remains to be determined. From September 1999 to July 2004, 241 consecutive MM patients, up to the age of 65, were diagnosed at five academic Italian Institutions. Overall, 194/241 had natural siblings (Table 1): 158/194 (81%) were HLA typed, while 36/194 (19%) were not typed for the following reasons: patients not eligible for high dose chemotherapy (n. 14); siblings not eligible for peripheral hematopoietic cell (PHC) donation (n.11); patient refusal to high dose chemotherapy (n. 9), unknown (n.2). Seventy-six/158 (48%) with a matched donor were offered a tandem autologous- nonmyeloablative allogeneic HCT approach. Eventually, 56/76 (73%), the “auto-allo group”, were enrolled while 20 did not enter the tandem program as 5 siblings (5/76, 7%) were not eligible for PHC donation, 5 patients refused an allogeneic HCT, and 10 patients preferred allografting as a possible salvage treatment. Of 102 patients without matched donors or after refusal to allografting, 73, “double-auto group”, underwent a standard double autologous transplant while 29 received less intense treatments because of clinical conditions or patient preference. Table 1 Newly diagnosed pts 241 With sibs/without sibs 194 /47 (total 241) HLA typed /not HLA typed 158 /36 (total 194) Matched sibs /No matched sibs 76 /82 (total 158) Auto-Allo”/“Double Auto”/Other”“ 56 /73 /29 (total 158) After induction chemotherapy, patients of both groups underwent G-CSF mobilised autografting with high dose melphalan (200 mg/m2). In the “auto-allo” group, the autologous HCT was followed, 2-4 months later, by low dose (2.0 Gy) TBI, allogeneic PHC infusion, and post transplant mycophenolate mofetil and cyclosporin. In the “double-auto group”, patients received a second autologous HCT. Patients characteristics were as follows: age: 54 (range 34–65) vs 53 (range 33–64) (p=ns); stage III myeloma: 77% vs 64% (p=0.03); beta 2 microglobulin > 2,5 mg/dl: 75% vs 59% (p=0.005), for the “auto-allo group” and for “the double-auto group”, respectively. At the time of this analysis, 56/56 of the “auto-allo group” and 55/73 of “the double-auto group” had completed the transplant programs. After median follow up of 3 years (range 11–80 months), TRM was 11% vs 4% (p=0.09); complete remission rates, defined as the disappearance of the monoclonal paraprotein by immunofixation, were 46% vs 16% (p=0.0001); overall survivals were 84% versus 62% (p=0.003); progression free survivals were 75% vs 41% (p=0.00008); event free survivals were 61% (34/56)% vs 38% (30/73) (p=0.006) in the “auto-allo group” and in the “double-auto” group, respectively. Longer follow up is needed, however data suggest that the “auto- non myeloablative allo” approach is not inferior to “double autologous” HCT in newly diagnosed MM.

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