scholarly journals High-Dose Carfilzomib Recaptures Response in Relapsed/Refractory Multiple Myeloma Resistant to Low-Dose Carfilzomib By Co-Inhibiting β2 Subunit of Proteasome Complex: The First in Human Evidence

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 818-818
Author(s):  
Xiang Zhou ◽  
Andrej Besse ◽  
Jessica Peter ◽  
Max Mendez Lopez ◽  
Larissa Haertle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Remission ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Significant Difference ◽  
Proteasome Subunits

Abstract Background Proteasome, a complex involved in the intracellular protein degradation, consists of multiple subunits, but only three subunits have enzymatic activity to cleave and degrade proteins, namely β1, β2 and β5. Carfilzomib (CFZ), a second-generation proteasome inhibitor (PI), can induce cell death by selective and irreversible inhibition of β5 subunit of proteasome. Preclinical data suggested that high-dose CFZ could co-inhibit predominantly β2 proteasome activity, followed by β1 inhibition (Besse et al, Cell Chem Biol. 2019). Over the past few years, CFZ has become a corner stone for multiple myeloma (MM) therapy. Currently, CFZ is approved by the FDA in different dosing schedules in combination with lenalidomide or daratumumab and dexamethasone. However, the optimal CFZ dosing is still a matter of debate, with the approved dosage ranging from 20to 70mg/m 2 in different regimens. In addition, if response can be recaptured by escalating CFZ dose in patients progressing from low-dose CFZ has yet to be determined. The aim of our current study was to analyse the profile of proteasome inhibition in the respective dose cohorts and to elucidate if high-dose CFZ could recapture response in patients resistant to low-dose CFZ. Methods We prospectively collected clinical data and peripheral blood mononuclear cells (PBMC) of 32 patients with relapsed/refractory (RR) MM before and 1-8 hours after CFZ administration. PBMC were lysed and labelled for the activity of individual proteasome subunits using activity based proteasome probes and the proteasome subunits were separated using SDS-PAGE. The activity of constitutive and immunoproteasome β1, β2 and β5 subunits was evaluated by densitometry analysis and combination of the activity of constitutive and immunoproteasome individual subunit was used for further analysis. Results Overall, six, nine, twelve and five patients received CFZ at a dose of 20, 27, 36 and 56 mg/m 2, respectively. As expected, the total activity of proteasome decreased with higher doses of CFZ. Significant inhibition (median inhibition > 50%) of β5 subunit was observed already at 20 mg/m 2 dose, while β2 subunit started to be co-inhibited only at a dose of ≥27 mg/m 2. Significant co-inhibition of β2 activity was seen at 36 mg/m 2 dose, at which also β1 subunit started to be co-inhibited. Finally, at 56 mg/m 2, the activity of all active subunits was inhibited with a median inhibition of > 50%, with the strongest inhibition of the β5 subunit, followed by β2 and then β1. When we compared the patient groups low-dose CFZ (20 or 27 mg/m 2) versus high-dose CFZ (36 or 56 mg/m 2), we observed a significant difference in β2 (P=0.002) and β5 (P=0.02) subunit inhibition between the both groups. In terms of total proteasome activity, high-dose CFZ demonstrated a significantly higher proteasome inhibition in comparison with patients receiving low-dose CFZ (P=0.01). In brief, our results suggested that high-dose CFZ, in contrast to low-dose CFZ, could obtain superior proteasome inhibition by co-inhibiting β2 subunit of proteasome complex. In light of this finding, we successfully treated six RRMM patients who were resistant to low-dose CFZ with CFZ dose escalation. All six patients were heavily pretreated with 3-12 lines of therapy including daratumumab, two PIs, two immunomodulatory drugs and autologous stem cell transplant. Additionally, one and two patients received prior treatment with B-cell maturation antigen targeted bi-specific antibody and chimeric antigen receptor modified T-cell, respectively. In the last line of treatment, these six patients showed progression during CFZ based regimens with low-dose CFZ, namely 20 or 27 mg/m 2. We therefore increased the CFZ dose to 36 or 56 mg/m 2 and the doses of agents other than CFZ in the combination regimens remained the same. High-dose CFZ dose recaptured response in all six patients with four and two patients that achieved partial remission and very good partial remission, respectively, and the progression free survival ranged from 1-13 months. Conclusion In summary, high-dose CFZ, namely ≥ 36mg/m 2, showed more effective proteasome inhibition via blocking β5 and β2 subunits, while low-dose CFZ could not achieve a sufficient inhibition of β2 subunit. We provided the first in human evidence that high-dose CFZ could recapture response in RRMM patients resistant to low-dose CFZ by co-inhibiting the β2 subunit activity of proteasome complex. Figure 1 Figure 1. Disclosures Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.

scholarly journals 20 Years of Transplant Program in Multiple Myeloma - a Single Centre Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5749-5749
Author(s):  
Jiri Minarik ◽  
Edgar Faber ◽  
Ludek Raida ◽  
Tomas Szotkowski ◽  
Jaroslav Bacovsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Remission ◽  
Response Rates ◽  
Individual Treatment ◽  
Cell Transplant ◽  
Conventional Chemotherapy ◽  
Post Transplant ◽  
Treatment Line ◽  
Novel Drugs ◽  
Significant Difference

Abstract Aims: The aim is to present the results of 20 years of autologous stem cell transplant (ASCT) program in multiple myeloma (MM) at our site. Patients and methods: Since 1997 till 2017, a cohort of 348 patients underwent ASCT at the Department of Hemato-Oncology of the University Hospital Olomouc. Altogether 274 were 1st ASCT, 62 were 2nd transplants, the rest were tandem or third ASCT. The patients had standard baseline characteristics, including age, gender, immunoglobulin and light chain type, Durie-Salmon (DS) and International Staging System (ISS). The induction regimens for 1st ASCT included VAD (vincristin, adriamycine, dexamethasone) in 34%, THAL in 15%, BTZ based regimens in 34%, the rest (17%) were combined polychemotherapeutic regimens. The re-induction regimens before 2nd ASCT included CAD (cyclophosphamide, adriamycine, dexamethasone) in 27%, BTZ in 31% and THAL based regimens in 18%, other patients (24%) had LEN based regimens, polychemotherapy or no re-induction. 163 patients (47%) had maintenance, mostly interferon based (25%), conventional chemotherapy based (9%) or THAL based (7%), and 53% of patients had no maintenance. We assessed response rates, ie the rate of complete remission (CR), very good partial remission (VGPR), partial remission (PR), minimal response (MR), stable disease (SD), progressive disease (PG) and overall response rate (ORR) based on International Myeloma Working Group (IMWG) criteria. The survival measures of individual treatment lines were assessed by means of progression free survival (PFS). We assessed the efficacy of ASCT with respect to treatment line, pre-transplant and post transplant response achieved (day+100), and with respect to DS and ISS as well as to treatment modality used for induction and maintenance. For statistical estimation we used Kaplan-Meier curves, Log rank test (Mantel-Cox), Post-hoc tests according to Dunn, Pearson ChiSquare test, Fisher´s Exact Test, Kruskal-Wallis test, and McNemar-Bowker Test. Results: The response rates after 1st ASCT were following: CR 32,1%, VGPR 26,5%. PR 34,8%, MR and SD 3% and PG 3,4%. Median PFS after 1st ASCT was 35 months and it corresponded to the depth of treatment response: CR 48 months, VGPR 36 months, PR 33 months, MR and SD 13 months, PG 9 months, p<0,0001. Pre-transplant responses showed a trend towards better outcomes with deeper responses but beyond statistical significance (p = 0,077). Advanced DS stage correlated with worse PFS (stage I 58 months, stage II 42 months, stage III 31 months). Patients under age 59 years tended to have slightly better PFS (37 vs 34 months, p = 0,078). Both pre and posttransplant responses were significantly better after novel drugs than conventional chemotherapy, still, there was no statistically significant difference in PFS. None of the maintenance (chemotherapy, interferon, THAL-based) lead to a better PFS. There were very few patients treated with BTZ, LEN or ixazomib maintenance precluding valid statistical analysis. There were no differences in either responses or PFS with regard to treatment line but there were only 19 patients not having ASCT as their first regimen. The response rates after 2nd ASCT were as follows: CR 26,7%, VGPR 13,3%, PR 38,3%, MR+SD 8,3% and PG 13,3%. Median PFS after 2nd ASCT was 20 months, decreasing with inferior responses (CR 34,8 months, VGPR 22,5 months, PR 33,1 months, MR and SD 18,8 months, PG 6,6 months p<0,0001). There were no differences in PFS with respect to either ISS, DS stage or re-induction regimen. Patients transplanted in their first relapse tended to have better PFS than in later relapses. Conclusion: The use of ASCT is still the gold standard in MM. Regardless of treatment line, it achieves significant outcomes. Novel drugs induce deeper pre-transplant responses, still, the major advantage against conventional chemotherapy is in the speed of response and absence of severe adverse events, enabling more patients to reach ASCT. Maintenance therapy accounts for better survival, however, this is true only for novel drugs (such as bortezomib, lenalidomide) whereas older modalities including interferone, post-transplant chemotherapy, steroids or thalidomide do not possess such activity. The second ASCT is comparable to to current treatment modalities in relapsed MM with fair post-transplant outcomes as well as PFS, with high rate of complete responses. Supported by the grant IGA-LF-2018-004 andMH CR - RVO (FNOl, 00098892). Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of Two Post-Transplant Predictive Indexes: Day 100 is a Better Time-Point for Response Evaluation after Autologous Stem Cell Transplantation in Multiple Myeloma: Ass Retrospective Study

2020 ◽  
Vol 7 (8) ◽  
Author(s):  
Ma’koseh M ◽  
◽  
Sa’deh S ◽  
Halahleh K ◽  
Abu-Jazar H ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Response Evaluation ◽  
Therapeutic Implications ◽  
Significant Difference

In Multiple Myeloma (MM), response to High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT) has important prognostic and therapeutic implications. Best timing for response evaluation after ASCT is not well studied. Our study evaluated the correlation between response on day 30 and day 100 after ASCT with Progression Free Survival (PFS) and Overall Survival (OS) in 119 MM patients. Median follow-up was 39.8 months. Complete Response (CR) was achieved in 53.8% and 55.5% of patients on D 30 and D 100, respectively. On D30, there was no significant difference in PFS or OS in CR vs. no CR group (35.4 vs. 22.1 months, p: 0.058) and (92.6 months vs. not reached p: 0.96) respectively nor in responders (R) vs. Non-Responders (NR) group (97.8 vs. 47.1 months p: 0.08) and (30.2 vs. 18.9 months, p: 0.09) respectively. While on D100, PFS was significantly better in CR vs. no CR group (33.8 vs. 18.1 months, p: 0.0047) as well as in R vs. NR (30.6 vs. 16.9 months p: 0.015). However, OS was not better in either (92.6 vs. 52.1 months p: 0.46) and (92.6 months vs. not reached p: 0, 88) respectively. In conclusion, after HDC and ASCT for MM, we recommend doing response evaluation on D100 rather than D30 as it better correlates with PFS. Further studies are required to confirm this finding in the era of consolidation and maintenance treatment.

Single Autologous Stem Cell Transplant Using Busulfan and Cyclophosphamide as Conditioning Regimen in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4436-4436
Author(s):  
Giampaolo Talamo ◽  
David F. Claxton ◽  
Joseph Drabick ◽  
David W. Dougherty ◽  
Jeff Sivik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Single Agent ◽  
Conditioning Regimen ◽  
High Dose ◽  
Cell Transplant ◽  
Transfusion Threshold ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract Autologous peripheral blood stem cell transplantation (ASCT) has been shown to improve survival in patients with multiple myeloma (MM). High-dose melphalan is considered the current standard of care among the preparative regimens used in ASCT for MM patients. We report the results of ASCT in 79 consecutive MM patients using a conditioning regimen with busulfan and cyclophosphamide (Bu/Cy), given as single ASCT and without maintenance therapy. Peripheral blood stem cells were mobilized with cyclophosphamide 5,000 mg/m2 IV + etoposide 1,000 mg/m2 IV, followed by granulocyte colony stimulating factor (G-CSF) 5 mg/Kg/day until the end of stem cell collection. A median of 41.1 × 106 CD34+ cells/Kg (range, 2.1–139.7 × 106) of ideal body weight were mobilized. The conditioning regimen consisted of busulfan 1 mg/Kg PO or 0.8 mg/Kg IV every 6 hours x 16 doses (days -7 to -3), and cyclophosphamide 60 mg/Kg/day IV for 2 days (days -3 to -2). Patients achieved neutrophil engraftment (absolute neutrophil count &gt;500/μL) at a median of +13 days (range, +6 to +21 days), and platelet engraftment (platelets &gt;20,000/μL unsupported by transfusion) at a median of 14 days (range, +11 to +24). Using a transfusion threshold of hemoglobin &lt;8.0 g/dL and platelets &lt;10,000/μL, patients required a median of 2 units of RBC transfusions (range, 0–8), and 1 platelet transfusion (range, 0–15) until hematologic engraftment. Forty-eight and 20 patients reached PR and CR, respectively, for an overall RR of 86%. At a median followup of 41 months (range 2–132 months), the estimated median overall survival (OS) and progression-free survival (PFS) were 45 months [95% confidence interval (CI) = 38–92] and 20 months (95% CI = 15–25), respectively. Veno-occlusive disease developed in 4 pts, and it was lethal in 1 of them. The Bu/Cy regimen was overall well tolerated, and transplant-related mortality was 4%. No statistically significant difference in terms of OS and EFS were observed between the group of patients receiving oral (n=13) vs IV busulfan (n=66). OS was not statistically different between the group receiving ASCT in first remission (n=62) and the group receiving ASCT as salvage therapy, i.e., upon MM progression (n=17), either calculating OS from the day of ASCT or from the day of MM diagnosis. We conclude that our reported clinical outcomes of the Bu/Cy regimen are equivalent to those obtained in historical controls with high-dose melphalan followed by a single ASCT. Thus, given the equivalent effectiveness but greater complexity of administration of the Bu/Cy regimen compared with that of single agent melphalan, we believe the latter should remain the agent of choice for ASCT in MM.

scholarly journals An Increased Number of Cybord Induction Cycles Does Not Increase Peri-Transplant Morbidity in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2312-2312
Author(s):  
Mahmood Al-Abri ◽  
Jonathan How
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Hospital Stay ◽  
High Dose ◽  
Cell Transplant ◽  
Number Of Patients ◽  
Co Morbidity ◽  
Significant Difference ◽  
Post Infusion ◽  
Icu Transfer

Abstract Introduction: Despite a plethora of novel therapies, autologous stem cell transplant (ASCT) continues to offer a progression free survival benefit to multiple myeloma patients. At our institution, standard of care for transplant-eligible patients remains induction with cyclophosphamide, bortezomib, and decadron (CyBorD) for 4 cycles, followed by ASCT. However, limited resources for collection and the logistics of receiving late referrals from outside centers often result in patients receiving additional cycles of treatment prior to transplant. We sought to determine whether the administration of additional induction chemo led to increased peri-transplant morbidity. Methods: With REB approval, chart review was done for myeloma patients receiving an ASCT between 2007 and 2017. Only patients receiving induction with CyBorD or bortezomib-decadron on a like schedule were included in analysis. Patients received pre-ASCT conditioning of high-dose melphalan (93.5%) or busulfan-melphalan (6.5%). Data collected included patient's age, gender, myeloma subtype, ISS score, and cytogenetics, as well as the number of induction cycles received and hematopoietic cell transplantation-specific co-morbidity index (HCT-CI). The primary endpoint assessed was median length of hospital stay (LOS) post-infusion. Secondary end-points included time to engraftment, ICU transfer rate, infection rate, organ-specific toxicity, 100-day mortality, and response as measured by VGPR rate at 100 days. Patients were grouped into those who received 2-4 cycles vs. 5-9 cycles of induction. Results: Fifty-three patients received 2-4 cycles of induction and 54 received 5-9. Median age was 61 for both groups, gender was well-matched (53% vs. 57% male), and HCT-CI ≥ 3 was similar (26% vs. 31%).The only significant difference between groups was the subtype of myeloma, with the 2-4 group having 30.1% light chain disease (vs. 14.8%) and 39.6% IgG subtype (vs. 61.1%) (p = 0.026). Median LOS post-infusion was 20 days in the 2-4 group and 17 days in the 5-9 group. Median time to engraftment was 12 days in both (range 9-21 in 2-4 group, 10-20 in 5-9 group). ICU transfer was needed in 4 (7.5%) and 6 (11.1%) patients in the respective groups, and there were two deaths in the 5-9 group (one of sepsis at d+16 and one of multi-organ failure at d+46). Both patients had HCT-CI scores of 5, and the differences in ICU and mortality rates were not statistically significant. There were no significant differences in measurable toxicity. Documented infection or febrile neutropenia occurred in 92.5% vs. 88.9% (p = 0.53); acute kidney injury in 20.8% vs. 11.1% (p= 0.17); and acute liver injury in 24.5% vs. 14.8% (p = 0.21). Among evaluable patients, 84.6% achieved VGPR or better in the 2-4 group and 78.4% in the 5-9 group, although the latter had a higher number of patients with high-risk cytogenetics by FISH (6 vs. 10 with t(4;14) or 17p-). Discussion: Evidence for a precise number of cycles of induction prior to ASCT is scarce. A recent study by Charaborty et. al.(BJHJul 2018) showed that median PFS and OS were similar between patients who received ≤ 4 months vs. > 4 months of induction. 39% of their patients received bortezomib-based induction without lenalidomide, akin to our regimen. Likewise, our study showed no significant difference in VGPR rates at 100 days, an endpoint used at our center as one criterion for determining the need for tandem transplant and potential increased chemotherapy exposure for the patient. Our overall VGPR rate for the group of 81.6% is comparable to previously published results, suggesting our population is representative of a typical myeloma cohort. Most importantly, our data suggests no increase in peri-transplant toxicity as a result of the additional induction chemotherapy burden. In fact, there was a surprising trend towards decreased organ toxicity and shorter hospital stay, and the only two early deaths occurred in high-risk patients. Among the 17 patients who received the heaviest induction burden (7-9 cycles), there were no deaths and only 1 ICU transfer. While there did not appear to be any long-term benefit to greater induction length, our study provides reassurance that it is safe to continue CyBorD induction past the intended 4 cycles without compromising patient safety at the time of transplant. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

A Phase 1 Study of Total Marrow Irradiation Combined with High-Dose Melphalan for Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4646-4646
Author(s):  
Pritesh R. Patel ◽  
Annie L. Oh ◽  
Matthew Koshy ◽  
Bulent Aydogan ◽  
Karen Sweiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Significant Difference ◽  
Total Marrow Irradiation ◽  
High Dose Melphalan

Abstract High dose melphalan at 200mg/m2(Mel200) followed by autologous stem cell transplant (ASCT) prolongs the survival of patients with multiple myeloma (MM) although it does not prevent relapse. Enhancing the anti-myeloma effect of pre-transplant conditioning without increasing toxicity is an important goal. To this purpose, intensity modulated radiation therapy (IMRT) can be used to deliver radiation to the marrow (total marrow irradiation, TMI) while sparing other organs. Here we tested the safety of combining linear accelerator based TMI to Mel200 in a phase 1, 3+3 trial. Twelve patients with MM who relapsed after at least one line of therapy were enrolled in 3 dose cohorts (3Gy, 6Gy and 9Gy). Prior ASCT was permitted. All patients received Mel200 over 2 days. In addition, 1.5Gy TMI was administered twice daily for 1, 2 or 3 days depending on dose cohort. Dose-limiting toxicity was defined as the occurrence of any NCI-CTCAE grade 4/5 non-hematologic toxicity or failure to engraft prior to day 30 after ASCT. Quality of life (QoL) was assessed using the FACT-BMT scale at baseline and 90-100 days after ASCT. Three groups of patients were enrolled and received 3Gy (n=3), 6Gy (n=3) or 9Gy (n=6). Median age at time of transplant was 66 years (range 40-71). Three patients had high risk FISH/ karyotype as defined by IMWG criteria. Median lines of prior therapy was 2 (range 1-4). Five patients (42%) had undergone prior autologous transplant. Of eleven patients (92%) who received prior lenalidomide, 7 (58%) were considered lenalidomide refractory. Similarly, of 11 (92%) patients previously treated with bortezomib, 6 (50%) were considered refractory. Eleven patients had a pre-transplant PET scan performed with 8 (73%) having skeletal PET avidity. All patients received TMI as scheduled. The mean reduction in dose to organs at risk (lens, oral cavity, kidneys, liver, bowels, lung) ranged from 25-63%. Median time to neutrophil (greater than 0.5x109/L) and platelet (greater than 20x109/L) engraftment were 10 (range 9-15) and 13 (range 9-17) days respectively. There were no dose limiting toxicities. Five patients experienced a total of 7 NCI CTCAE grade 3 toxicities including: diarrhea, n=2; mucositis, n=3; and nausea, n=2. Four of 6 patients who received 9Gy did not experience any toxicity greater than grade 2. Using the FACT-BMT scale, we observed that there was no significant difference in QoL between baseline and day 90 assessments. At day 100 overall response rate was 82% with 5 patients (45%) achieving a complete response. Four of 6 patients in the 9Gy cohort achieved at least a very good partial response. With a median follow up of 314 days, all patients were alive and only 4 patients (33%) relapsed. In this phase 1 trial we showed that TMI at 9Gy can be safely added to Mel200 without an increase in transplant related toxicities. Initial promising clinical results, even in high risk MM patients, will be further tested in a phase 2 study. Disclosures No relevant conflicts of interest to declare.

Pegylated Liposomal Doxorubicin (Doxil®), Dexamethasone and Low Dose Thalidomide (DDt) as Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5164-5164 ◽  
Author(s):  
Delva Deauna-Limayo ◽  
Omar S. Aljitawi ◽  
Mathew Mayo ◽  
David C. Bodensteiner ◽  
Siddhartha Ganguly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Pulmonary Embolism ◽  
Stem Cell ◽  
Induction Therapy ◽  
Low Dose ◽  
High Dose ◽  
Combination Regimen ◽  
Cell Transplant ◽  
Full Dose ◽  
Cell Harvest

Abstract Background: Thalidomide with dexamethasone is considered the current standard induction therapy for multiple myeloma. Previously, treatment consisted mainly of infusional vincristine, adrimaycin and dexamethasone (VAD). High dose thalidomide is associated with significant toxicity. We conducted a study to evaluate efficacy and toxicity of adding liposomal adriamycin (Doxil®) to dexamethasone and low dose thalidomide. Stem cell harvest yield was also assessed. Methods: Patients were treated with Doxil® 40mg/m2 IV d1, thalidomide 100 mg PO Q HS, and dexamethasone 40 mg PO d1–4 and 15–18 Q 28 days for 4 cycles. After 4 cycles, eligible patients underwent autologous stem cell transplant. Patients received prophylactic Amoxicillin 250 mg PO Q day and Acyclovir 200 mg PO BID. Erythropoietin and biphosphonates were administered. Aspirin was changed to full dose coumadin anticoagulation after one death from pulmonary embolism. Results: Between 3/03 and 5/05, 11 out of planned 25 patients were enrolled on the study; 1 patient excluded for wrong diagnosis. Median age 61.5 (51–81yrs); 7 males; 7 IgG, 2 IgA and 1λ-light chain subtypes; Stage IB-1, Stage IIA-4, Stage IIIA-5; median albumin 3.75 (range:1.6–5.1 g/dL), creatinine 0.95 (range: 0.7 – 2.7 mg/dL) and B2M 1.95 (range: 1.1–10.1 mg/L). Four patients completed 4 cycles; one is undergoing treatment; three patients taken off study-one after 2 cycles per patient’s request, one secondary to grade 4 toxicity after cycle 1, and another after greater than 3 weeks treatment delay after cycle 3 secondary to pneumonia. Three patients (30%) developed grade 3–4 toxicities- two due to pneumonia (after cycles 2 and 3, respectively); and one with dehydration and renal failure after cycle 1. There were 2 deaths-one secondary to pulmonary embolism after cycle 1; another due to myocardial infarction after cycle 2. Two patients developed VTE- one after cycle 1 while on low dose coumadin; another died of pulmonary embolism after cycle 1, while on aspirin, requiring amendment to full dose coumadin anticoagulation. No further thrombotic episodes were encountered. Five patients underwent stem cell harvest with cyclophosphamide mobilization. The median harvest yield was 9.76 x106 CD34/kg (range: 5.27 – 31.94) with a median of 1 day (range: 1–7) to achieve at least 5 x 106 CD34/kg. Of the ten patients who received at least one cycle and assessable for response, the ORR was 80% (near complete remission(nCR)-10%; PR-70%), 1 MR, 1 SD. The M-spike response after first cycle of therapy ranged from 8% to 71%, with six patients (60%) having greater than 50% reduction in M-protein level. One patient achieved nCR after 2 cycles. Responses after the 3rd and 4th cycles were minimal. Conclusions: Doxil®, dexamethasone and low dose thalidomide represents an active induction therapy for patients with untreated multiple myeloma. Major responses were achieved rapidly, arguing for early stem cell harvest and autologous transplant after two cycles of therapy. Treatment related complications occurred early in the course of treatment. Full dose anticoagulation to prevent deep venous thromboembolism is essential when using this combination regimen. No adverse impact on stem cell harvest is associated with this therapy.

A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone Versus Lenalidomide Plus Low-Dose Dexamethasone in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 799-799 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Susanna Jacobus ◽  
Natalie Callander ◽  
Rafael Fonseca ◽  
David Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
M Protein ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
High Dose Dexamethasone

Abstract Background: Lenalidomide has shown efficacy in patients with relapsed myeloma in phase II and III clinical trials, and is currently being investigated as initial therapy for the disease. We report results of a phase III trial comparing lenalidomide plus high-dose dexamethasone (Dex) versus lenalidomide plus low-dose Dex as first line therapy in newly diagnosed multiple myeloma (MM). Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO on days 1–21 every 28 days. In addition, patients in the high-dose Dex arm (Arm A) received Dex 40 mg on days 1–4, 9–12, and 17–20 PO every 28 days, while pts in the low-dose Dex arm (Arm B) received Dex 40 mg on days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy until progression. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If the serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses need to be confirmed at least 4 weeks apart. Patients with disease progression or not responding to lenalidomide within 4 months switched to thalidomide with the same dose of dexamethasone they were receiving (Arms C and D, respectively). An independent Data Monitoring Committee approved release of these results. Results: 445 pts were enrolled: 223 randomized to Arm A and 222 to Arm B. Median age was 65 yrs. Serious adverse event data based on expedited reporting (AdEERS) is available on all pts (see table). Common adverse events of Grade 3 or higher were thromboembolism (18.4% in arm A vs 5.4% in Arm B), infection/pneumonia (18.8% vs 9.0%) and hyperglycemia (5.8% vs 1.8%). Incidence of any grade 4 or higher toxicity was 22.0% in Arm A vs 12.6% in Arm B. Response data is being analyzed. Conclusions: Lenalidomide plus two different schedules of Dex was investigated in this phase III trial. Preliminary results suggest that toxicity rates are higher in the high-dose Dex arm. The differences in the response rates between the two arms will dictate future trials and clinical practice. Major Toxicties (AdEERS) Toxicity Arm A (n=223) Arm B (n=222) Cardiac ischemia (Grade &gt;=3) 2.7% 0.5% Hyperglycemia (Grade &gt;=3) 5.8% 1.8% Infection/Pneumonitis (Grade &gt;=3) 18.8% 9.0% Neuropathy (Grade &gt;=3) 0.9% 0.9% Thromboembolism (Grade &gt;=3) 18.4% 5.4% Any non-Hem toxicity (Grade &gt;=3) 53.4% 36.0% Any toxicity (Grade &gt;=4) 22.0% 12.6% Death (Grade 5) 4.5% 1.4%

Favorable Responses to Novel Agents for Multiple Myeloma in African American Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4213-4213
Author(s):  
Santosh Saraf ◽  
Pritesh R. Patel ◽  
Howard Ozer ◽  
David Peace ◽  
Sangeetha Nimmagadda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African Americans ◽  
Induction Therapy ◽  
Partial Remission ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
High Dose Chemotherapy ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant

Abstract Abstract 4213 Multiple myeloma (MM) accounts for 10% of hematologic malignancies in the U.S. African Americans (AA) have twice the risk of developing multiple myeloma and, in previous studies, a higher mortality rate when compared to non-African Americans (non-AA). In recent years, clinical outcomes for patients with MM have improved as a result of new agents, such as immunomodulatory drugs (IMiDs) and bortezomib. However, the therapeutic impact of these new therapies in AA vs. non-AA patients has not been evaluated. In this study, 53 consecutive patients (23 AA, 30 non-AA) with newly diagnosed MM were retrospectively analyzed after induction treatment with thalidomide/dexamethasone (n=22), lenalidomide/dexamethasone (n=8), bortezomib/dexamethasone (n=5), bortezomib/thalidomide/dexamethasone (n=3), lenalidomide/bortezomib/dexamethasone (n=12), or an IMiD plus melphalan (n=3). AA and non-AA patients were comparable for age, immunoglobulin isotype, MM stage of disease, serum β2microglobulin and albumin levels, and cytogenetic abnormalities including del13 (27% vs. 38%, respectively, p=NS). When measured according to international uniform criteria, the response rate to induction therapy was not statistically different between AA and non-AA patients: complete remission (CR, 22% vs. 21.4%), very good partial remission (VGPR, 26% vs. 21.4%), or partial remission (PR, 43.4% vs. 32.1%). However, the rate of stable/progressive disease following induction therapy was significantly higher in non-AA patients (p = 0.03). Of 53 patients, 34 received high-dose chemotherapy followed by autologous stem cell transplant (ASCT). In this group, the CR + VGPR rate following ASCT was significantly higher in AA compared with non-AA patients (59% vs. 35%, p=0.0007). At a median follow up of 47 months, the relapse rate was 59% in AA and 46% in non-AA patients (p=NS) and the median time to progression (TTP) was 9.1 months in both groups. Five patients (9%) died. All deaths occurred in the non-AA cohort and in 4/5 cases death was due to disease progression. In conclusion, our findings demonstrate that despite their increased disease risk, AA patients with MM have a favorable outcome that is equivalent to that of non-AA patients when treated with IMiDs and/or bortezomib. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SUBCHRONIC TOXICITY TEST OF COMBINATION ETHANOL EXTRACT OF DETAM 1 SOYBEAN (GLYCINE MAX L. MERR) AND JATI BELANDA (GUAZUMA ULMIFOLIA LAMK) TOWARD FUNCTION, WEIGHT, AND HISTOPATHOLOGICAL OF WISTAR RAT LIVER

2016 ◽  
Vol 9 (5) ◽  
pp. 197
Author(s):  
Meilinah Hidayat ◽  
Sijani Prahastuti ◽  
Estherolita Dewi ◽  
Dewi Safitri ◽  
Siti Farah Rahmawati ◽  
...  
Keyword(s):  
Liver Function ◽  
Toxicity Test ◽  
Low Dose ◽  
Ethanol Extract ◽  
Good Effect ◽  
Control Group ◽  
High Dose ◽  
Subchronic Toxicity ◽  
Treatment Groups ◽  
Significant Difference

ABSTRACTObjective: As an antiobesity therapy, combination extracts of Detam 1 soybean and Jati Belanda will be consumed for a long time; therefore, theirtoxicities to the liver need to be investigated. To determine the effect of subchronic toxicity test of combination of ethanol extract of Detam 1 soybean(EEDS) and ethanol extract of Jati Belanda (EEJB) on liver function with parameters: Alanine transaminase (ALT), macroscopic, and histopathologicalof liver.Methods: This study was conducted on 120 Wistar rats (60 males and 60 females), 90 days (treatment group) and 120 days (satellite group). Ratswere divided into six treatment groups (3 test materials, 1 control, and 2 satellites); each group included 10 males and 10 females.Results: ALT levels of treatment groups (low dose, medium, and high), both males and females were lower than the control group (p<0.05). Thetreatment groups demonstrated a good effects effect on liver function. Liver weight of all groups showed no significant difference compared with thecontrol group (p>0.05). Results of histopathological score interpretation of male and female liver rats of low dose groups were not disturbed; middledose groups were slightly disturbed and high dose groups were damaged. Satellite high doses of male groups were disrupted, while female groupswere not.Conclusion: The combination of EEDS and EEJB has a good effect on liver function, did not lead to change organ weight and at low doses did not causerenal histopathology damage in rats after 90 days administration.Keywords: Combination of soybean Jati Belanda, Toxicity subchronic test, Function, Weight, Histopathology, Liver.

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