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.

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 >500/μL) at a median of +13 days (range, +6 to +21 days), and platelet engraftment (platelets >20,000/μL unsupported by transfusion) at a median of 14 days (range, +11 to +24). Using a transfusion threshold of hemoglobin <8.0 g/dL and platelets <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.

High-dose melphalan is not associated with extramedullary relapses in high-risk multiple myeloma.

1993 ◽  
Vol 11 (9) ◽  
pp. 1832-1832 ◽  
Author(s):  
P Moreau ◽  
R Bataille ◽  
B Mahé ◽  
N Milpied ◽  
J L Harousseau
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
High Dose ◽  
High Dose Melphalan

scholarly journals A Phase 1/2 Trial of Carfilzomib + High Dose Melphalan Conditioning for Auto-HCT Followed by Carfilzomib Maintenance for Patients with Relapsed Multiple Myeloma

2017 ◽  
Vol 23 (3) ◽  
pp. S81-S82
Author(s):  
Luciano J. Costa ◽  
Heather Landau ◽  
Saurabh Chhabra ◽  
Parameswaran Hari ◽  
Racquel Innis-Shelton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
High Dose ◽  
High Dose Melphalan

Second Autologous Peripheral Blood Stem Cell Transplantation with High Dose Melphalan (HDM/SCT) in Patients Relapsing After An Initial Course of HDM/SCT for the Treatment of AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2318-2318
Author(s):  
Karen Quillen ◽  
David C. Seldin ◽  
Kathleen T. Finn ◽  
Vaishali Sanchorawala
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Time Interval ◽  
Al Amyloidosis ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Organ Function ◽  
High Dose Melphalan

Abstract Abstract 2318 Poster Board II-295 High-dose melphalan and autologous stem cell transplant (HDM/SCT) can induce complete hematologic responses (CR), defined as disappearance of the underlying monoclonal gammopathy from serum and urine by immunofixation electrophoresis, and of the clonal plasma cell dyscrasia by bone marrow immunohistochemistry, and extend survival in patients with AL amyloidosis. HDM/SCT results in a CR in 40% of patients, and leads to clinical improvements in organ function in >70% of those who achieve a CR. However, hematologic and clinical relapses occur in ∼8% of patients who initially achieve a CR. Tandem cycles of HDM/SCT, which are typically performed within 12 months of each other, have been shown to achieve a higher ultimate CR rate of >60%. Among patients who do not achieve a CR following a single cycle of HDM/SCT, 30% nonetheless experience improvement in organ function. However, in this latter group, clinical improvement is not durable. We designed a study to explore the feasibility, and efficacy, of a second cycle of HDM/SCT in patients who relapse after initially responding to a first cycle of HDM/SCT. Results: Eleven patients, median age 55 (range 39-62), M:F 7:4, who had achieved hematologic and clinical responses after an initial cycle of HDM/SCT, were treated with a second cycle of HDM/SCT when a hematologic and/or clinical relapse occurred after a median time interval of 34 months (range 12-63). Five patients underwent a second course of G-CSF mobilization and a mean of 5.1 million (range 3.4-7.6 million) CD34 cells/kg was collected in a median of 2 days; the other patients had cells saved from the first mobilization. Six patients received 200 mg/m2 HDM; 5 patients received modified high-dose HDM at 140 mg/m2. Engraftment occurred at a median of 10 days for neutrophils, and 12 days for platelets (two days without platelet transfusion support); this engraftment timing is similar to that following the initial transplants (10 days for neutrophils, 13 days for platelets). There was no treatment-related mortality, but toxicity was moderate; almost all patients (except one) experienced grade III/IV non-hematologic toxicities. Of the 11 patients, 3 achieved hematologic CR at one year; these patients are alive and in continuous remission at 2-6 yr after the second transplant, including one patient who received a subsequent renal transplant. Three patients died of progressive disease at 1-2 years after the second transplant. Five patients are alive at 1-3 years post second transplant, in partial remission. Conclusion: 27% (3/11) of patients with AL amyloidosis who experience a hematologic or clinical relapse after responding to initial HDM/SCT can achieve a hematologic CR with a second course of HDM/SCT. Disclosures: No relevant conflicts of interest to declare.

Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1970-1970
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin Obryant ◽  
Lisa l Wood ◽  
Nicole Porter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Treatment Protocol ◽  
Sensory Neuropathy ◽  
Hematological Toxicity ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Post Transplant

Abstract Abstract 1970 Background: An effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains challenging. We report the efficacy and side effect profile of an all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide (Revlimid®) given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d (RCP). Responses were assessed on intent-to-treat basis based on the International Uniform Response Criteria. Treatment was planned for 6 cycles. Responding patients proceeded to observation, or transplantation, based on patient's preferred choices. All patients received, unless contraindicated, aspirin prophylaxis (81 or 325 mg daily) for prevention of deep-vein thrombosis, acyclovir for herpes zoster prevention, and bisphosphonates. Results: Forty six patients were enrolled from October 2007 to August 2010. Median follow up duration was 5.6 months. At this time, 38 of 46 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). The median age was 63 years (range, 41–76). 16 patients had ISS stage II (42%) and 8 (21%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). Among the 38 evaluable patients, the overall response rate was 95%, consisting of CR: 1 (3%), VGPR: 9 (24%) and PR: 26 (68%). One patient had stable disease (1%) after the first cycle and treatment is ongoing. One patient had progression (3%). Thirty twoof 38 patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (24), disease progression (3), adverse event (2), non compliance (1), alternate treatment (1) and withdrawal of consent unrelated to toxicity (1). The most common toxicity was sensory neuropathy (24%): 8 (21%) grade I and 1 (3%) grade II. Other common toxicity included constipation (21%), pruritus (21%) and edema of limbs (18%). The most common hematologic toxicity was neutropenia (18%); 4 grade III and 2 grade IV. Infections were seen in 4 patients (2 febrile neutropenia and 2 with normal ANC). Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Thirteen patients had dose adjustments or interruption, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Twenty-five patients had stem cell collection. In all, sufficient numbers of stem cells (CD34+ cells ≥ 4.0 × 106 cells/kg) were collected for the transplantation use. To date, fifteen have undergone high dose chemotherapy and stem cell transplantation. Of eight patients with PR on RCP, seven achieved VGPR and one achieved CR post transplant. Of four patients with VGPR on RCP, 2 achieved CR and 2 remained in VGPR post transplant. Post-transplant response is not yet evaluable in the 3 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: No relevant conflicts of interest to declare.

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