scholarly journals Randomized Comparison of Rituximab Versus Bortezomib Plus Cyclophosphamide and Dexamethasone in Newly Diagnosed Waldenstrom Macroglobulinemia Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4003-4003
Author(s):  
Shuhua Yi ◽  
Wenjie Xiong ◽  
Yi Wang ◽  
Rui Lv ◽  
Li Zengjun ◽  
...  
Keyword(s):  
Adverse Event ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Response Rate ◽  
Routine Practice ◽  
Newly Diagnosed ◽  
Minor Response ◽  
Overall Response ◽  
Good Response Rate ◽  
Grade 3

Background:Waldenstrom's macroglobulinemia (WM) is one type of lymphoma that had the characteristic of both lymphocytes and plasma cells. Rituximab-based or bortezomib-based regiments are commonly used treatment approaches in routine practice in previously untreated patients with LPL/WM. However, which regiment is better still unknown. The purpose of this study is to compare the efficacy of RCD (Rituximab,cyclophosphamide and dexamethasone) and BCD (Bortezomib, cyclophosphamide and dexamethasone)in newly diagnosed WM patients. Methods:30 newly diagnosed WM patients were randomly assigned to BCD or RCD group for introduction chemotherapy. Chemotherapeutic response was evaluated after 3 cycles. If a minor response (MR) or better response achieves, addition 3 cycles will be given. If not, patients will be crossed to control group for another 3 cycles. If a MR or better response comes out, addition 3 cycles will be given, otherwise, the patients will quit this study. Results: Finally, 15 patients were assigned to each treatment group. The basic characteristics of the two groups were similar. The median time to response in RCD and BCD group were 4 months and 3 months, respectively. The CR rate in RCD and BCD group was 20% and 26.7% respectively, with VGPR rate 26.7% and 6.7%, PR rate 46.7% and 40% in each group respectively. Additional 20% minor response was observed in BCD group. The overall response was 86.7% in both groups. However, RCD group had higher good response rate (≥VGPR) compared to BCD ( 46.7% vs 33.4%, p=0.05). The rate of major response (≥PR) in RCD group was higher than that in BCD group (86.7% vs 66.7%, p=0.195). The median follow-up time was 29 months. The median duration of response in RCD and BCD group was 35 months and 30 months, respectively. The 3-year progression-free rate of RCD group was significantly higher than that of the BCD group (87.5% vs 39.2%,p=0.045). The 3-year overall survival rate was 100% with RCD group versus 70% with BCD group (100% vs 70%, p=0.127)The most common adverse events of any grade with RCD and BCD were hematological toxicity. 3 patients in the RCD group had grade 3 or higher granulocytopenia.4 patients in the BCD group occurred grade 3 or higher hypocytosis. Other adverse event in the RCD group included pneumonia (40%), non-infectious fever (26.7%), hyperglycemia (13.3%) and rash (6.7%).The most common non-hematological adverse event in BCD group were peripheral neuropathy (40%), pneumonia (26.7%), herpes zoster (13.3%) and ventosity(6.7%). Events of non-infectious fever occurred more frequently in the RCD group (26.7% vs 0%, p=0.032). However, peripheral neuropathy was more common in the BCD group (40% vs 6.7%, p=0.031). There was no serious non-hematological grade 3 or higher adverse events occurred in the both groups. Conclusion: The RCD and BCD regimens have similar overall response in newly diagnosed WM. RCD regimen has higher good response rate and longer PFS time compared to BCD regimen. Both regimens have good tolerance. Disclosures No relevant conflicts of interest to declare.

Single Agent Bortezomib Is Associated with a High Response Rate in Patients with High Risk Myeloma. A Phase II Study from the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3527-3527 ◽  
Author(s):  
Angela Dispenzieri ◽  
Lijung Zhang ◽  
Rafael Fonseca ◽  
David H. Vesole ◽  
Philip R. Greipp
Keyword(s):  
Peripheral Neuropathy ◽  
High Risk ◽  
Adverse Events ◽  
Response Rate ◽  
Single Agent ◽  
Novel Therapies ◽  
Newly Diagnosed ◽  
Monoclonal Protein ◽  
Grade 3

Abstract Background: MM is an incurable disease with an anticipated overall survival ranging from months to decades. Novel therapies like bortezomib have activity in both the relapsed/refractory and up front settings. There are sparse data on whether novel therapies may overcome high risk features. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients received bortezomib 1.3 mg/m2 every other week indefinitely. Patients relapsing on maintenance schedule resumed full induction schedule. Responses were defined by the EBMT criteria. The primary end-point was the response rate (90% power to detect a response rate of >=50% ). Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled. Among the 43 eligible patients, median age was 63; 51% were male. All had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Response data are available for 37 of the 43 eligible patients. The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patients with CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable). The median progression free survival is 9.4 months. Thirty-three percent of patients completed the 8 cycles of planned induction therapy and moved to maintenance. Reasons for discontinuing therapy have included progression or death (n=18), adverse events (n=6), and other (n=14). Only 12% of patients remain on active therapy: 0% of deletion 13q patients; 25% of t(4:14) and 12% each of high B2M and high PCLI patients. Of the 14 patients who entered the maintenance phase of treatment, 3 have progressed. Of these 3, 2 took re-induction, and neither responded. Median time to progression for those entering maintenance was12.4 months from the time of starting maintenance. The most common adverse events of grade 3 or higher included neutropenia (33%), diarrhea (31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%), fatigue (14%). Grade 1–2 sensory peripheral neuropathy occurred in 53% of patients, with only 2% having grade 3 sensory neuropathy. One patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses of protocol treatment due to heart block and asystole. Updated results on the full study population will be presented at the meeting. Conclusions: In high risk patients, upfront bortezomib appears to result in comparable response rates to those reported for unselected cohorts of newly diagnosed myeloma patients. Continued follow-up of these patients will provide information about whether this will translate into better overall outcomes. Figure Figure

A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
Author(s):  
Angela Dispenzieri ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Partial Response ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Labeling ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

Bortezomib in Combination with Dexamethasone and Subsequent Thalidomide for Newly-Diagnosed Multiple Myeloma in Chinese Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4827-4827
Author(s):  
Zhen Cai ◽  
Weiyan Zheng ◽  
Guoqing Wei ◽  
Xiujin Ye ◽  
Jingsong He ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Staging System ◽  
Primary Treatment ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Overall Response ◽  
International Staging System ◽  
Grade 3

Abstract Background: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology12(3):235–239, 2007), but this regimen has not been reported in Chinese patients. We now report our experience with this combination. Objectives: To investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. Patients and Method: Between June 2006 and August 2007, 11 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m2 IV on days 1, 4, 8 and 11, dexamethasone at 20 mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Seven of 11 patients were male and 4 were female. Median age was 57 years (range 47–86). Seven of 11 patients were stage 2 according to the International Staging System, 4 out of 11 patients were stage 3. Eleven patients received a median of 2 cycles of therapy (range 1–6). The Blade criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. Results: Nine out of 11 patients (82%) achieved PR and 2 (18%) achieved CR; therefore the overall response rate was 100%. With a median follow-up duration of 5 months (1– 14 months), no patients died. Grade 3–4 toxicities included fatigue (3/11), thrombocytopenia (3/11), diarrhea (3/11) and orthostatic hypotension (2/11). Grade 2 neuropathy occurred in 3 out of 11 patients, herpes zoster occurred in 3 out of 11 patients. Routine anticoagulation or anti-thrombosis was not used. There was no DVT/PE in 11 patients. Conclusion: Our preliminary experience indicated that bortezomib-dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade 3 and 4 toxicities were rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in this report with Chinese MM patients are being cautiously observed.

A phase II study of combination of bortezomib, liposomal doxorubin, and dexamethasone (VDD) as first line therapy for multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17504-17504 ◽  
Author(s):  
A. J. Jakubowiak ◽  
J. Friedman ◽  
T. Kendall ◽  
A. Al-Zoubi ◽  
M. S. Kaminski
Keyword(s):  
Peripheral Neuropathy ◽  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Cell Transplant ◽  
First Line ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

17504 Background: We have recently reported that a combination of bortezomib (Velcade), liposomal doxorubicin (Doxil), and dexamethasone (VDD) is very active and well tolerated in relapsed/refractory myeloma (MM) producing 83% overall response rate and 33% of complete (CR) or near complete (nCR) response rate. In the current study, we evaluated the activity of VDD as first line therapy in newly diagnosed patients with MM. The primary objective of this study was to determine the efficacy of this regimen. Methods: This is a phase II, single institution trial which opened in July 2005 with target accrual of 30 patients. EBMT criteria were used for evaluation of responses. The regimen was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone for a total of 160 mg per cycle, initially at 40 mg on days 1–4 and then 20 mg on days of Velcade and the day after. VDD was repeated every 3 weeks for a total of 6 cycles. Results: To date, 19 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 4.7 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 58 (range 39–83), chromosome 13 deletion in 4 patients, beta2-microglobulin 4.4 (61% > 4.0). CR + nCR have been observed in 2 patients (11%), very good partial response (VGPR) in 5 patients (28%), partial response (PR) in 9 patients (50%) and minor response (MR) in 1 patients (5%) for an overall response (≥ MR) of 94%, ≥ PR of 89% and ≥ VGPR of 39%. All patients who proceeded to stem cell transplant collected without any problems. The regimen was very well tolerated. Most surprisingly, only 1 patient developed peripheral neuropathy grade 1. One patient developed pneumonia and PE and one patient grade 3 diarrhea, which was found to be secondary to cryptosporidium. Grade 3 or 4 neutropenia was observed in 6 patients and grade 3 thrombocytopenia in 1 patient. The most common grade 1 and 2 toxicities were thrombocytopenia and fatigue, both significantly less common than in relapsed patients treated with the same regimen. One patient developed grade 2 DVT and 1 grade 2 PPE. Conclusions: VDD combination shows high overall activity of 94% and ≥ 90% disease reduction of 39%. The regimen is very well tolerated and has a surprisingly low incidence of peripheral neuropathy. [Table: see text]

A phase II trial of low-dose nab-paclitaxel for patients with previously treated or recurrent advanced gastric cancer (OGSG1302).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 350-350
Author(s):  
Masashi Hirota ◽  
Shigeyuki Tamura ◽  
Hirokazu Taniguchi ◽  
Atsushi Takeno ◽  
Hiroshi Imamura ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Dose Intensity ◽  
Relative Dose Intensity ◽  
Grade 3

350 Background: Paclitaxel is a key drug in second-line chemotherapy for advanced or recurrent gastric cancer (AGC) and nanoparticle albumin-bound paclitaxel (nab-PTX) is also widely used in Japan. A previous phase II trial in Japan showed the effectiveness of nab-PTX (260 mg/m2) administered every 3 weeks (q3w) in patients with AGC with a response rate (RR) of 27.8%; however, toxicity was major concern with grade ≥3 neutropenia (49.1%) and peripheral neuropathy (23.6%). To solve this problem, we investigated the efficacy and safety of low-dose q3w nab-PTX regimen in AGC. Methods: Eligibility requirements included: aged ≥20 years, HER2-negative, histologically confirmed, unresectable or recurrent gastric adenocarcinoma, one or more prior chemotherapy containing fluoropyrimidine regimens, presence of measurable lesion(s) according to RECIST ver. 1.1, ECOG PS of 0–2, and adequate organ function. Nab-PTX was administered at a dose of 220 mg/m2 every 3 weeks. The primary endpoint was the RR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity and proportion of patients who received subsequent chemotherapy. Results: Thirty-three patients were enrolled from 10 institutions in Japan. Of the 32 patients treated with protocol therapy, RR (CR, PR) was 3.1% (95% CI, 0–16.2%), which was not reached the protocol-specified threshold (p = 0.966). DCR (CR, PR, SD) was 37.5% (95% CI, 21.1–56.3%), median OS and PFS were 6.3 months (95% CI, 4.4–14.2) and 2.2 months (95% CI, 1.8-3.1). Relative dose intensity was 97.8% (215 mg/m2). 62.5% of patients received subsequent chemotherapy. Most common grade ≥3 adverse events were neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Conclusions: Low-dose regimen of q3w nab-PTX was slightly less toxic, although it did not demonstrate the same effect as the original regimen in response rate. Therefore, it is not recommended for AGC in second or later line setting. Clinical trial information: UMIN 000012701.

scholarly journals Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study

2020 ◽  
Vol 99 (11) ◽  
pp. 2589-2598
Author(s):  
Jing Li ◽  
Li Bao ◽  
Zhongjun Xia ◽  
Sili Wang ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Response Rate ◽  
Real Life ◽  
Comparable Efficacy ◽  
Routine Practice ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Frontline Therapy ◽  
Grade 3

Abstract The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients’ preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1–20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

scholarly journals Retrospective Analysis of the Efficacy and Safety of Modified Bortezomib-Lenalidomide-Dexamethasonelite (modified RVD-lite) Therapy for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1961-1961
Author(s):  
Kiyoshi Okazuka ◽  
Tadao Ishida ◽  
Junichiro Nashimoto ◽  
Takao Yogo ◽  
Kanji Miyazaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Staging System ◽  
Median Number ◽  
Al Amyloidosis ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract [Background] Thecombination therapy consisting of bortezomib, lenalidomide and dexamethasone (RVD) for newly diagnosed multiple myeloma has been one of the standard induction therapies in recent years. However, 9-23 % of patients discontinued treatments because of severe adverse events in the previous reports (SWOG S077, IFM2009). Thus, it has not been clarified ifthe dosing schedule of RVD is appropriate. Here, we investigated the efficacy and safety of modified RVD-lite for 45 transplant eligible patients with newly diagnosed multiple myeloma (NDMM). [Patients and methods] We retrospectively analyzed 45 transplant eligible patients with NDMM who received modified RVD-lite for induction therapy between February 2016 and March 2018. The median age was 58 years old (range 36~66), and 6 (13.3%) patients were AL amyloidosisassociated with multiple myeloma. Patients received bortezomib 1.3 mg/m2once weekly subcutaneous (SC) on days 1, 8, 15, 22, lenalidomide 15 mg/day on days 2-7, 9-14, 16-21 and dexamethasone 40mg on days 1, 8, 15, 22. The Revised International Staging System (R-ISS) wereI in 13 (28.9%), II in 30 (66.7%) and III in 2 (4.4%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 5 (11.1%) patients. After 4 cycles of modifiedVRd-lite, we evaluated the efficacy and adverse events. [Results] The overall response rate (ORR) after four 28-day cycles of modifiedRVD-lite was obtained in 41 (91.1%), including sCR in 6 (13.3%) and CR in 5 (11.1%). SD and PD were observed in 2 patients (4.4%) and 1 patient (2.2%), respectively. One patient was not evaluated efficacy, because a patient changed modifiedRVD-lite to ixazomib, lenalidomideand dexamethasone therapy for grade 3 peripheral neuropathy. Thirty-eight of 45 patients (84.4%) received autologous stem cell transplantation (ASCT) after at least 4 courses of modifiedVRd-lite. The median number of CD34+cells/kg collected was 4.83 x 106(range, 1.1-11.9). All patients received melphalan at doses of 200 mg/m2. In these patients, response after ASCT were sCR in 15(41.7%), CR in 2 (5.6%), VGPR in 8 (22.2%) and PR in 8 (22.2%). Three of seven patients who did not received ASCT will receive ASCT ina few months. Among other 4 patients who did not receive ASCT, 2 patients chose other therapies without ASCT, and 2 patients could not receiveASCT because they showed no improvement in cardiac AL amyloidosis. Grade 3 or higher adverse events (AEs) were observed in 17 (37.8%). Most frequent grade 3 or higher AE was neutropenia (grade 3:17.8%, grade 4:6.7%). Only one patient (2.2 %) discontinued modifiedRVD-lite because of grade 3 peripheral neuropathy. [Conclusions] The ORR after 4 cycles ofmodifiedRVD-lite was high (91.1%). These results might be related to low rate of discontinuation of treatment. Also, the ORR after ASCT was comparable to the results previously published (N Engl J Med .2017 Apr 6:376(14):1311). AEs in modified RVD-lite were feasible and manageable in most patients. Our results suggest that modifiedRVD-lite is very feasible and effective treatment for patients with transplant eligible NDMM. Disclosures Suzuki: Sanofi Aventis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment.

scholarly journals Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

2021 ◽  
pp. JCO.20.03433 ◽  
Author(s):  
Nathan H. Fowler ◽  
Felipe Samaniego ◽  
Wojciech Jurczak ◽  
Nilanjan Ghosh ◽  
Enrico Derenzini ◽  
...  
Keyword(s):  
Adverse Event ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Dual Inhibitor ◽  
Free Survival ◽  
Pi3k Inhibitors ◽  
Overall Response ◽  
Duration Of Response ◽  
Grade 3

PURPOSE Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20–based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.

Response-Adapted Therapy for Newly Diagnosed Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3606-3606
Author(s):  
Frederic J. Reu ◽  
Tomas Radivoyevitch ◽  
Jason Valent ◽  
Chad Cummings ◽  
Katherine Tullio ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Research Funding ◽  
Response Rate ◽  
Response Assessment ◽  
Second Primary ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Minor Response ◽  
High Dose Melphalan

Abstract Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints. Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed. Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin. Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. Disclosures Reu: Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.

scholarly journals Peripheral Neuropathy in the Cassiopeia Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-48
Author(s):  
Cathelijne Fokkema ◽  
Bronno Van Der Holt ◽  
Mark van Duin ◽  
Ruth Wester ◽  
Tom Cupedo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Older Age ◽  
Newly Diagnosed ◽  
Dose Modification ◽  
Grade 3

Introduction Peripheral neuropathy (PNP) remains one of the most common adverse events during multiple myeloma (MM) treatment. The immunomodulatory agent thalidomide and proteasome inhibitor bortezomib are particularly prone to induce PNP (Dimopoulos MA et al., Leukemia., 2010). Both agents are part of standard treatment regimens for newly diagnosed transplant-eligible MM patients. PNP varies from mild symptoms to severe disability, depending on timely dose reduction or discontinuation of treatment. Currently, incidence or severity of PNP cannot be predicted. Therefore, it is of utmost importance to monitor incidence of PNP in different treatment combinations, and in order to identify risk factors for developing PNP. Aims To investigate the incidence of PNP in patients treated in the Cassiopeia trial, to evaluate the role of CD38 antibody (daratumumab) treatment in development of PNP, and to identify risk factors for the development of PNP. Methods We retrospectively analysed incidence of PNP grade 2 to 4, scored according to common terminology criteria for adverse events version 4 (CTCAE) in the Cassiopeia study, a phase III trial conducted by IFM/HOVON, investigating the efficacy of adding daratumumab to bortezomib, thalidomide and dexamethasone (VTD). 1074 newly diagnosed MM patients were randomised. Patients received 4 induction cycles and 2 post transplantation consolidation cycles of 28 days each. Cycles included subcutaneous bortezomib (1.3 mg/m2 days 1,4,8,11), oral thalidomide (100 mg daily), dexamethasone (20-40 mg) and daratumumab intravenously (16 mg/kg and weekly during induction cycles 1 and 2 and once every two weeks during induction cycles 3,4 and consolidation). This trial was registered as ClinicalTrials.gov NCT02541383 and was supported by the French IFM and Dutch HOVON groups (Moreau et al., Lancet, 2019). Multivariate analysis was performed including sex, age, arm, body mass index (BMI), cytogenetics, ISS stage, country, diabetes mellitus (DM), creatinine clearance, liver function, ECOG, baseline PNP and disease characteristics. Results Baseline characteristics in dara-VTD and VTD arms were similar. Overall, 380/1074 (35%) patients developed grade ≥2 PNP and 102/1074 (9%) patients developed grade ≥3 PNP. Multivariate analysis indicated that the cumulative incidence of PNP grade ≥2 was significantly lower in the dara-VTD arm (33%) when compared to the VTD arm (38%) (hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.59-0.91, P=0.004). Furthermore, risk factors associated with a higher cumulative incidence of PNP grade ≥2 included older age (HR=1.03; P=0.020), grade 1 PNP at baseline (HR= 2.75; P= 0.002) and higher BMI (HR=1.46, P=0.003 for BMI 25-30 to HR=2.02, P=0.004 for BMI > 35). Progression free survival (PFS) from the end of induction was similar (86% vs 80% at 2 years, HR = 0.74, 95% CI 0.41-1.33, P=0.32) for patients developing grade ≥2 PNP during induction (179 pts, 17%). An unexpected finding was the difference in cumulative incidence between countries participating in this trial: in the Netherlands 68/141 (49%) of patients developed grade ≥2 PNP, while in France this was 280/846 (33%) and in Belgium 31/87 (36%) (p<0.001). The protocol of the Cassiopeia trial included instructions of discontinuation and dose modification, when PNP grade ≥2 was observed. However, in a subset of patients reaching PNP grade ≥ 2 the (temporary) discontinuation or adjustment of dose as described in the treatment protocol had not been applied (respectively in 148/352 (42%) with PNP ≥ 2 and in 39/97 (40%) with PNP ≥3). Conclusions Despite bortezomib being administered subcutaneously and clear instructions on discontinuation and dose modification, we observed a clinically relevant incidence of grade ≥2 PNP (35%) and grade ≥3 PNP (9%) in patients treated in the Cassiopeia trial. Patients in the dara-VTD arm showed less grade ≥2 PNP, suggesting a possible positive effect of daratumumab. Risk factors for the development of grade ≥2 PNP included older age, PNP at baseline and BMI > 25. Differences in incidence between countries were observed, however no clear explanation was found. Furthermore, standard measures for grading PNP, such as CTCAE criteria, are subject to interpretation bias of both the patient and the treating physician. Continuous screening and correct grading of PNP and strict compliance with guidelines is warranted. Disclosures Moreau: Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Sonneveld:Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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