The Prognosis of PR Patients after Induction Therapy Was Not Inferior to CR in ASCT-Eligible NDMM Patient.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5682-5682
Author(s):  
Anna Takahashi ◽  
Yuko Mishima ◽  
Norihito Inoue ◽  
Yoshiharu Kusano ◽  
Hirofumi Yamauchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
High Dose ◽  
Myeloma Cells ◽  
Ecog Ps ◽  
Cell Harvest

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for newly diagnosed multiple myeloma (NDMM) patients who are younger than 70 years old. In the IFM 90 trial, 5-year OS was 52% in the ASCT group compared to 12% in the initial chemotherapy group (p=0.03). 5-year EFS was 28% in the ASCT group compared to 10% in the chemotherapy only group (p=0.01). MRC Ⅳ trial also showed a higher rate of OS (p=0.04) and PFS (p<0.001) in the ASCT group. However, there was no result about the differences of the prognosis between CR and PR before ASCT. In this study, we studied the response level before ASCT to understand if it is related to the prognosis after ASCT. Methods: We studied 25 NDMM patients who received ASCT in our hospital from 2005 to 2015. Induction therapies were VRD, VCD, VAD, VD, Rd or VTD-PACE. Stem cells were collected using G-CSF or cyclophosphamide plus G-CSF. After stem cell harvest, all patients underwent high dose melpharan (200mg/m2) before ASCT. The responses according to the IMWG guidelines were performed at the point of 4-6 weeks after ASCT. Statistical analyses were performed using a software, EZR version 1. Results: The total number of NDMM patients was 25. The median age was 55 years (range 33-62), the median follow-up period was 1,375 days (range 340-3,763). Male were 16 (64%), 11 patients (44%) were ISS Ⅱor more and 20 (80%) were D&S stageⅡor more. ECOG PS 2 was 4 patients (8%) and one (4%) is ECOG PS 3. Before ASCT, 21 patients (84%) received 1 regimen and 4 (16%) received 2 regimens. In the 1 regimen group, 9 patients (43%) were treated by VCD with 2-4 cycles, 9 received VD with 4-5 cycles and 5 (24%) were received VAD with 3 cycles before ASCT. In the 2 regimens group, details of induction therapy were VD with BCD, VCD with Rd, VCD with VRD and VCD with VTD-PACE. In all patients, 3-year OS was 91.6% (95% CI, 70-98%) and 3-year PFS was 56% (95% CI, 34-74%). After induction therapy, CR was achieved in 11 (44%), VGPR was 2 (8%), PR was 11 (44%) and MR was 1 (4%). After ASCT, CR was achieved in 18 (72%), VGPR was 2 (8%), PR was 4 (16%) and PD was 1 (4%). 4 patients (16%) died for progression of multiple myeloma. There were no statistical differences in 3-year OS and PFS between CR group and VGPR + PR group after induction therapy (3-year OS; 100% vs 92%, p=0.11, 3-year PFS; 70% vs 50%, p=0.26). There were also no differences between the two groups CR group and PR without VGPR group (3-year OS; 100% vs 90%, p=0.18a, 3-year PFS; 70% vs 60%, p=0.4). As sub-analysis, the achievement time until normalization of FLC and disappearance of serum or urine M-protein in IFE did not affect 3-year OS and PFS. Discussion and Conclusions: When MM patients having residual disease did the stem-cell harvest, it has been possible to contaminate of myeloma cells in their collected stem cells. Several literatures described the contamination of myeloma cells in the stem cells induced inferior prognosis after ASCT. However our limited data suggested that the prognosis of patients who had residual disease after induction therapy, if they had achieved better than PR, were not inferior to CR group. This is reasonable data for recommendation of ASCT to MM patients getting PR after induction therapy. Disclosures Mishima: Chugai: Consultancy. Nishimura:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Chugai: Research Funding; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Meiji-Seika: Consultancy.

A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2258-2258
Author(s):  
Tomer M Mark ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
Morton Coleman ◽  
David Bernstein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Yield ◽  
High Dose ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

Light Chain Deposition Disease: Impact of Stem Cell Tranplant on Hematological Response Achievement.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4600-4600 ◽  
Author(s):  
Victor H Jimenez-Zepeda ◽  
Norman Franke ◽  
Andrew Winter ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Elevated Serum ◽  
High Dose ◽  
Light Chain Deposition Disease ◽  
Monoclonal Protein ◽  
Light Chain Deposition ◽  
High Dose Melphalan

Abstract Abstract 4600 Light chain deposition disease (LCDD) is a systemic disorder characterized by deposition of monoclonal light chains (LC) in different organs. A single clone of plasma cells is responsible for the overproduction of either kappa or rarely lambda LC. Renal dysfunction generally is the main feature but many organs could be affected. The treatment of LCDD has not been standardized and remains controversial because of the small number of patients reported in the literature. However, as LCDD is associated with plasma cell dyscrasias, patients have typically been treated with regimens used for multiple myeloma, most commonly melphalan (mel) and prednisone and VAD (Vincristine, Adriamycin and Dexamethasone). Here, we report our experience using High Dose Melphalan (HDM) with Autologous Stem Cell Transplant (ASCT) in five patients (pts) with LCDD. In addition, we report the use of Velcade (vel) as induction therapy in two patients before undergoing ASCT. Patients and Methods We retrospectively reviewed the records of all pts treated with HDM/ASCT at Princess Margaret Hospital between January 2004 and December 2009 and identified five pts with LCDD. Pretreatment evaluation included staging investigations: 1) complete blood cell counts, 2) complete biochemistry panel, 3) albumin and β2-microglobulin, 4) Blood and Urinary Monoclonal protein assessment including Free LC Assay; 5) skeletal survey. 6) Bone marrow aspirate and biopsy. Pts with LCDD and concurrent multiple myeloma were excluded. LCDD was diagnosed by renal biopsy in all pts with histology confirming characteristic linear monoclonal LC deposits along the tubular membrane staining for kappa and lambda chains on inmunofluorescence. All pts received induction therapy prior to consolidation with HDM/ASCT [dexamethasone (n=3) and vel plus dexamethasone (n=2)]. Assessment of hematologic response (HR) to treatment was based on modified EORTC consensus criteria. Results Pts characteristics are shown in Table 1. Two pts were male subjects; the median age was 55 (range 45–65). All five pts, had elevated serum FLC and an abnormal κ-to- λ ratio. All of the pts presented with kidney involvement. The monoclonal protein deposited in the kidney consisted of free κ-LC in four pts and free lambda LC in 1. Two pts received vel and dexamethasone (3 cycles) induction therapy achieving PR after 6 weeks of therapy and three received dexamethasone alone: 1 pt achieving a PR and 2 SD. All of them received a conditioning regimen of mel 200 mg/m2. Complete HR was seen in 3 pts and PR in 1 patient (ORR 80%, CR 60%). Transplanted pts had a median time to ANC ≥0.5 ×109/L of 12d (Range 12–13) and time to platelets ≥ 20 ×109/L was 14 days (Range 12–17). Median time to discharge was 17 days (range 13–30) and no pts exhibited engraftment syndrome. There was no mortality related to transplant. The most common grade 3/4 adverse events included: neutropenic fever (n=5); mucositis (n=2); and transient worsening in kidney function (n=1). All pts are alive and progression-free at a median follow-up of 20 months (range 7–37) from transplant. As kidney dysfunction represents the most prominent morbidity in LCDD, it is important to emphasize that the elevated serum creatinine was ameliorated in these pts after ASCT Conclusions LCDD is a rare condition and its management is controversial. In a few small series, investigators have reported that high-dose melphalan (HDM) followed by ASCT can be associated with beneficial results whereas toxicity remains acceptable in this group of pts. We report our experience using HDM and ASCT in pts with LCDD without concurrent myeloma, demonstrating feasibility and tolerability. Disclosures: Reece: Celgene: Honoraria, Research Funding. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

High Dose Intravenous Busulfan and Melphalan Followed By Bortezomib (BuMelVel) As Conditioning With Autologous Stem Cell Transplantation (ASCT) For Patients With Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3376-3376
Author(s):  
Danielle Sterrenberg ◽  
Patrick J Stiff ◽  
Mala Parthasarathy ◽  
Aileen Go ◽  
Scott E. Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Therapy ◽  
Research Funding ◽  
Fixed Dose ◽  
High Dose ◽  
Target Area ◽  
Preparative Regimen

Abstract Background Progression free and overall survival (PFS/OS) for Multiple Myeloma (MM) have improved over the past 20 years largely as a result of ASCT as well as novel conventional dose therapeutic agents. However, since the 1990s improvements in PFS and OS due to ASCT have improved minimally due to continued reliance on single agent melphalan (MEL). In order to improve PFS and OS, better transplant regimens should be investigated. The combination of Busulfan (BU) and MEL delivers better PFS compared to MEL alone (Lahuerta, et al) with similar toxicity rates to MEL alone. Furthermore, in vitro and in vivo studies indicate synergy between MEL and proteasome inhibitors such as Botezomib (BTZ). Superior response rates and PFS were seen when BTZ is combined with MEL when compared with historical controls using MEL in a recent IFM study. (Roussel et al. Blood 2010). We hypothesize that IV BU and MEL followed by BTZ (BuMelVel) could be an effective preparative regimen with acceptable toxicity for patients with MM. Methods Between July 2009 and June 2013 57 patients with Multiple Myeloma who had already undergone induction therapy and were eligible for ASCT were enrolled. Patients received IV BU administered as a daily intravenous infusion for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min. Pharmacokinetic (PK) analysis performed after the first dose of IV Bu was used to determine Bu AUC and individualized Bu PK-directed dosing for later doses (d-4 and -3). MEL was administered at 140 mg/ m2 IV over 15-30 minutes on D-2. BTZ 1.6 mg/m2 was administered IV push on D-1. Palifermin was given for mucoprotection at a dose of 6.25 mg IV for two consecutive days before the first busulfan dose (days -8 and -7). A third dose of 6.25 mg was give on day 0 after stem cell transplantation. Results Of the 57 patients enrolled 56 are evaluable for toxicity and 54 for response at D +100. Median age is 61 (31 - 72). 49 % of patients had received ≥ 2 induction regimens (range 1-4) and 69% were DS stage III. 38% of patients had achieved at least a VGPR after induction with 9% of those achieving a CR. After transplantation, 70% of patients had at least a VGPR including 37% CR or sCR. All but 4 patients had a PR or better to induction therapy (three had stable and one progressive disease). The most common grade ≥ 3 toxicities were neutropenic fever (n = 42) and mucositis (n=21). No VOD or treatment related deaths at D+100 were observed and all patients engrafted. Median time to engraftment was 10 days (range 10-12) and median hospital stay was 20 days ( 15-31). Median PFS at 2 years was 78%. Conclusion BuMelVel is an effective novel preparative regimen with ≥ VGPR and CR/sCR of 70% and 37% respectively which compare favorably to responses previously reported with MEL 200 alone (43% and 11%, respectively) by Roussel et al. At the time of reporting, 12 patients had relapsed; 2 and 3-year PFS rates were 78% and 60% respectively. The regimen of BuMelVel is well tolerated and may lead to improvements in PFS and OS in patients with multiple myeloma. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

scholarly journals Impact of Radiation Therapy on Stem Cell Harvest in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5822-5822 ◽  
Author(s):  
Sandra Sauer ◽  
Andreas Marco Fischer ◽  
Andrea Fraenzle ◽  
Christina Kunz ◽  
Maximilian Merz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Research Funding ◽  
Bone Lesions ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Cd34 Cells ◽  
Cell Harvest ◽  
Stem Cell Collection

Abstract Background: Bone disease is a hallmark of multiple myeloma (MM) and destructive osteolytic bone lesions affect more than 80 % of patients resulting in pain, spinal cord compression and a reduced quality of life. Local radiation therapy (RT) is generally used to achieve rapid improvement of bone pain, control of local tumor growth and recalcification of osseous lesions. However, patients with a high tumor burden, eligible for high dose therapy and autologous stem cell transplantation (ASCT) require systemic treatment with three to four cycles of induction therapy followed by stem cell harvest and high dose therapy. So far, it remains uncertain, if RT prior to mobilization influences stem cell harvest in newly diagnosed patients with MM. Methods: We retrospectively analyzed the impact of RT on stem cell harvest and outcome in 168 transplant-eligible patients with newly diagnosed symptomatic MM (median age 57 years, range 28-73 years). All patients received RT to symptomatic lytic bone lesions before (n=114) or after (n=54) stem cell harvest and high dose therapy. A median of three cycles induction therapy was applied followed by mobilization therapy before stem cell harvest and high dose therapy. We analyzed, whether RT before stem cell collection influenced the number of leukaphereses needed to achieve stem cell yield, the number of stem cells collected per leukapheresis and the total number of collected stem cells. Additionally, we investigated if timing of RT influenced progression-free (PFS) and overall survival (OS) after high-dose therapy and ASCT. Results: Patients receiving RT before stem cell harvest needed more than one leukapheresis to collect the planned number of stem cells (before: 68.8%; after: 44.2%; p=0.09). The median number of stem cells collected per leukapheresis was significantly lower in patients treated with RT before harvest (before: 2.6 x 106 CD34+ cells per kg / bodyweight, after: 3.8 x 106 CD34+ cells per kg / bodyweight; p<0.001). Also the total median number of collected stem cells was significantly lower in the group treated with RT before stem cell harvest (before: 9.0 x 106 CD34+ cells per kg/bodyweight, after: 10.3 x 106CD34+ cells per kg/bodyweight; p<0.02). Patients treated with RT after stem cell harvest showed a longer PFS (48.9 months) compared to the group receiving RT before harvest (36.3 months; p=0.09). No effect on OS was observed. Conclusion: We demonstrate that RT before stem cell harvest negatively influences stem cell collection in patients with symptomatic MM. Furthermore, we observed a negative trend towards shorter PFS in the group treated with RT before stem cell collection. Therefore, we suggest applying RT after stem cell mobilization in transplant-eligible patients with MM if clinically possible. Disclosures Wuchter: Sanofi: Honoraria; ETICHO: Consultancy, Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

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.

Combination High-Dose Cyclophosphamide and Bortezomib Is Safe and Effective for Stem Cell Harvesting in Chemotherapy Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5459-5459 ◽  
Author(s):  
Miriam Katzman ◽  
Theresa George ◽  
Heather Doell ◽  
Patricia Danyluk ◽  
Sheri Briggs ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Combination Chemotherapy ◽  
Plasma Cells ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Cell Harvesting ◽  
Cell Mobilization ◽  
Cell Harvest

Abstract Introduction: High-dose melphalan and autologous stem cell transplantation is the accepted therapy for most patients with multiple myeloma (MM) following steroid-based induction therapy. In a significant proportion of patients, however, the disease is refractory to standard induction. The use of dose-intense combination chemotherapy, such as D-PACE (dexamethasone, doxorubicin, cyclophosphamide, and cisplatin), may affect the ability to harvest an adequate number of hematopoeitic stem cells prior to transplantation. In addition, in those patients not achieving adequate cytoreduction despite combination chemotherapy, there is a theoretical risk of stem cell product contamination by malignant plasma cells. Bortezomib is a therapeutic agent with a novel mechanism of action, which in preliminary studies appears to be synergistic to alkylating agents and does not appear to affect stem cell yield. We piloted the addition of bortezomib to high-dose cyclophosphamide during stem cell harvesting in a series of patients failing to achieve an adequate response to D-PACE salvage. Patients and Methods: Between 2002 and 2006, fifteen MM patients refractory to standard dexamethasone-based induction therapy received ≥ 2 cycles of D-PACE prior to proceeding to autologous stem cell harvest and transplantation. 7/15 patients achieved adequate cytoreduction and proceeded to high-dose cyclophosphamide (3 g/m2) and filgrastim plus ancestim stimulation for stem cell mobilization. However, 8 patients in this cohort did not achieve adequate disease cytoreduction following D-PACE. Therefore, bortezomib was added to the mobilization regimen on days 1, 4, 8, and 11, in addition to high-dose cyclophosphamide given on day 11. Identical growth factor stimulation was provided. Response assessment included days to stem cell harvest, number of CD34 cells harvested, plasma cells in the product, disease response, and hematologic parameters. Results: Pre-treatment toxicities from D-PACE were similar in both groups. The addition of bortezomib to cyclophosphamide during stem cell mobilization did not lead to increased symptomatic toxicity. Grade 3/4 thrombocytopenia occurred in 5/8 patients receiving combination bortezomib/cyclophosphamide. No episodes of significant bleeding, peripheral neuropathy, or skin rash were noted. The average CD34-positive stem cell harvest in both groups was >5.0 × 106/kg. Time to stem cell harvesting was not significantly different between the groups. Flow cytometric examination of the harvested product from the bortezomib/cyclophosphamide group consistently demonstrated <2% cells bearing plasma cell markers. One patient in each group failed to mobilize sufficient stem cells. Bone marrow plasmacyte counts following combination therapy and harvesting decreased in all assessed patients. Time to engraftment was similar in both groups. Post-transplant disease control and survival remains to be assessed, as some patients in the combination group have only recently undergone transplantation. Conclusion: The addition of bortezomib to high-dose cyclophosphamide during stem cell mobilization does not increase toxicity or decrease stem cell harvest yield or quality, and appears to achieve adequate disease reduction in patients otherwise refractory to combination chemotherapy. This may result in improved relapse-free survival in patients with refractory MM.

Molecular Level of Minimal Residual Disease in Bone Marrow Before High-Dose Therapy and Autologous Stem Cell Transplantation Is a Prognostic Parameter in Patients with Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1496-1496 ◽  
Author(s):  
Roland Fenk ◽  
Mark Korthals ◽  
Nina Sehnke ◽  
Ingmar Bruns ◽  
Akos Czibere ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Induction Therapy ◽  
Residual Disease ◽  
High Dose ◽  
High Dose Therapy ◽  
Prognostic Group ◽  
Minimal Residual

Abstract Background: Using real-time quantitative (RQ) PCR we recently (Haematologica89,2004) identified a prognostic cut-off level of residual clonotypic cells in the bone marrow of patients with multiple myeloma before high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (PBSCT). In this study we validate this report with a larger number of patients. Patients and Methods: Bone marrow samples of 68 patients with stage II/III multiple myeloma and heavy chain disease were obtained at the time of diagnosis and after induction therapy and stem cell collection but before single HDT and autologous PBSCT. Sequencing of the patient specific immunoglobulin heavy chain (IgH) locus was successful in 51 patients (75%). For 49 patients (72%) RQ-PCR using allele-specific oligonucleotide (ASO) Taqman probes together with LightCycler technology could be established with a sensitivity of 10−4 to 10−6 and linear amplification conditions. The proportion of clonotypic cells was assessed as IgH / 2 beta-actin ratio in percent. Patients were divided in two prognostic groups by a threshold level of 0.03% clonotypic cells. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.05% (range: 0–21%). Time to progression (TTP) from the time of diagnosis of patients in the ¨good¨ prognostic group (n = 21) was 51 months and significantly (p = 0.002) longer in comparison to 20 months of patients with a pre-transplantation minimal residual disease level of more than 0.03% in BM (n = 28). Overall survival (OS) of patients within the ¨good¨ prognostic group was also significantly prolonged (median OS: not reached versus 46 months, p = 0.03). Univariate analysis also revealed kind of maintenance / consolidation therapy (thalidomide, interferon, reduced intensity conditioning (RIC) allogeneic transplant) and cytogenetic banding analysis as prognostic markers for TTP. For OS kind of maintenance therapy, cytogenetic abnormalities, ISS stage, CRP and LDH levels were of prognostic relevance. In multivariat analysis grouping by pre-transplantation MRD level was an independent prognostic factor for either TTP and OS. Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for TTP and OS of patients with multiple myeloma. This finding has two controversial implications. One conclusion could be, that induction therapy should be continued and intensified e.g. with novel agents until a low MRD level is achieved. An alternative conclusion is, that a low tumor burden after induction therapy may be a surrogate parameter for chemosensitive disease, which makes patients more susceptible for high-dose chemotherapy. Therefore, further MRD studies are needed to answer this important question.

Bortezomib Does Not Impair Cytokine Induced Mobilization of Stem Cells Prior to Autologous Transplantation in Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2926-2926 ◽  
Author(s):  
Geoffrey L. Uy ◽  
Nicholas M. Fisher ◽  
Steven M. Devine ◽  
Michael H. Tomasson ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
High Dose ◽  
Front Line ◽  
Post Transplant ◽  
Autologous Transplant ◽  
Cd34 Cells ◽  
Stem Cell Collection

Abstract Bortezomib (VELCADE®) is a selective inhibitor of the proteasome approved for the treatment of relapsed or refractory multiple myeloma (MM). Emerging evidence indicates that bortezomib is also effective alone or in combination with cytotoxic agents in the front-line treatment of myeloma. Given the superiority of high dose therapy with autologous transplant compared to conventional therapy in myeloma, the application of bortezomib to novel front-line therapies depends in part on its effects on subsequent stem cell mobilization and engraftment. Previous reports have demonstrated successful chemotherapy induced mobilization of stem cells following bortezomib. To determine the effects of bortezomib on cytokine mobilization and engraftment of stem cells, we conducted a study of bortezomib administered prior to high-dose melphalan with autologous stem cell transplant. Following induction therapy, two cycles of bortezomib 1.3 mg/m2 were administered on days 1, 4, 8, and 11 of a 21-day treatment cycle. One week after the last dose of bortezomib, stem cells were mobilized with G-CSF 10 mcg/kg/day for 5 days and harvested by large volume apheresis (20 L/day) until a minimum of 2.5 x 106 CD34+ cells/kg were collected. Melphalan 100 mg/m2/day x 2 days was administered followed by reinfusion of peripheral blood stem cells 48 hours later. GM-CSF 250 mcg/m2/day was given post-transplant until the ANC ≥ 1,500/mm3 for 2 consecutive days. Forty patients were enrolled in this study with 37 continuing on to autologous transplant. Study population consists of 24 male and 16 female patients with the median age at enrollment of 56 years (range 38–69). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (29), IgA (10), light chain only (1), with stage I (1), II (12), or stage III (27) disease. Prior to receiving bortezomib, 20 patients had been previously treated with an anthracycline containing regimen and 22 with thalidomide for induction therapy. Two patients did not receive any prior chemotherapy. Two patients did not proceed to stem cell harvest, one secondary to disease progression on bortezomib and the other because of a stroke suffered during G-CSF mobilization. Stem cell collection was successful in 37 of 38 patients with the first collection containing a median of 4.24 x 106 CD34+ cells/kg. The majority of patients (29) required a single pheresis session, 7 required two sessions, and 1 patient required 5 sessions. The only patient failing stem cell collection had received extensive radiation to the pelvis in addition to a prior history of breast cancer for which she received adjuvant chemotherapy. All transplanted patients successfully engrafted with a median time to neutrophil engraftment (ANC ≥ 500/mm3) of 11 days (range 9–14 days). Platelet engraftment (platelet count ≥ 20,000/mm3 sustained for 7 days without transfusion) occurred at a median of 11 days (range 9–31 days). In an intention-to-treat analysis at 100 days post-transplant, we observed a compete response (CR) in 6 patients (15%), a near CR in 10 patients (25%) with an additional 19 partial responses (48%) for an overall response rate of 88%. We conclude that pre-transplant treatment with 2 cycles of bortezomib following anthracycline or thalidomide containing chemotherapy does not adversely affect stem cell yield or time to engraftment and results in high CR / near CR rates.

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