Modified-CVAD Or Modified-Cbad Compared To High Dose Cyclophosphamide For Peripheral Blood Stem Cell Mobilization In Patients With Multiple Myeloma

Abstract Background Peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (auto-HCT) is commonly carried out using growth factors alone. Approximately 10-15% of patients receive chemomobilization, which assists with cytoreduction and improving the cell yield; however, an optimal regimen has not been established. Here we report our experience with three chemomobilization regimens that have been used at our center: i) cyclophosphamide alone (Cy) ii) modified cyclophosphamide, vincristine, doxorubicin, dexamethasone (mCVAD) and iii) modified cyclophosphamide, bortezomib, doxorubicin, dexamethasone (mCBAD). Methods This is a single-center, retrospective chart review of patients with multiple myeloma undergoing mobilization for an auto-HCT with Cy, mCVAD, or mCBAD between January 1, 2006 and September 30, 2012. A total of 120 patients were identified as initiating stem cell mobilization with Cy (n=39), mCVAD (n=66) or mCBAD (n=15) for multiple myeloma within the defined time period. For the purpose of this study, we combined mCVAD and mCBAD into one group (n=81). The primary objective of this study is to compare successful mobilization and collection (≥ 2 x 106 CD34+ cells/kg collected) between high dose Cy (2-4 g/m2 x1) and mCVAD (cyclophosphamide 350 mg/m2 q12h x 4 days, vincristine 0.4mg continuous infusion daily x 4 days, doxorubicin 10 mg/ m2 continuous infusion daily x 4 days, dexamethasone 40 mg IV daily x 4 days) + mCBAD (same as previous, except using bortezomib 1.3 mg/m2 bolus x 4 days instead of vincristine). Secondary objectives include optimal mobilization (≥ 4 x 106 CD34+ cells/kg), median number of leukapheresis sessions required, use of plerixafor, post-transplant time to neutrophil engraftment, disease status at day 100, time to progression, and incidence of febrile neutropenia, hospitalization, and ICU admissions with each mobilization regimen. Results The groups were well-matched with regard to demographic characteristics. [Table] All 120 achieved a successful mobilization (≥ 2 x 106 CD34+ cells/kg collected) and 118 achieved an optimal mobilization (≥ 4 x 106 CD34+ cells/kg collected). There was no significant difference in the number of leukapheresis sessions (median 2, range 1-7) or plerixafor use (20.5% Cy vs. 8.6% mCVAD or mCBAD, p=0.08). There was no significant difference in the incidence of febrile neutropenia (10.3% Cy vs. 12.4% mCVAD or mCBAD, p=1.00), hospital admissions (18% Cy vs. 21% mCVAD or mCBAD, p=0.81), or ICU admissions (0% Cy vs. 1.2% mCVAD or mCBAD, p=1.00) between the groups. All 14 patients who had an episode of febrile neutropenia were hospitalized. One patient in the mCVAD or mCBAD group was admitted to the ICU with sepsis and renal failure, but was eventually discharged. There were no mobilization-related deaths in either study group. There was no significant difference in the time to neutrophil engraftment for the two groups (median 11 days, range 9-13). The median time to progression was 11.8 months in the Cy group and 9.1 months in the mCVAD or mCBAD group. Conclusion Cy, mCVAD or mCBAD can be used for successful PBSC mobilization in patients with multiple myeloma undergoing an auto-HCT without any unexpected toxicity. These approaches may be further evaluated in a randomized, prospective trial. Disclosures: Off Label Use: Cyclophosphamide, mCVAD, and mCBAD will be discussed as mobilization regimens used for patients with multiple myeloma. Vincristine and doxorubicin do not have specific indications for use in multiple myeloma. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees.

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Fractionated High-Dose Cyclophosphamide and G-CSF: An Extremely Effective Chemo-Mobilization Modality In Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.4521.4521 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4521-4521

Author(s):

Ahmad Antar ◽

Zaher K. Otrock ◽

Nadim El Majzoub ◽

Nabila Kreidieh ◽

Muhammad Muhammad ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Febrile Neutropenia ◽

Median Time ◽

Stem Cell Mobilization ◽

Fixed Dose ◽

High Dose ◽

Cd34 Cells ◽

Cell Mobilization ◽

Stem Cell Collection

Background The optimal stem cell mobilization regimen for multiple myeloma (MM) is undefined. Most centers use either granulocyte-colony stimulating factor (G-CSF) alone (steady state strategy) or cyclophosphamide (CY) followed by G-CSF (chemo-mobilizing strategy). However, the impact of CY dose on stem cell yield and subsequent engraftment, and toxicity is unknown. We retrospectively analyzed our experience using fractionated high-dose CY and G-CSF as our preferred chemo-mobilization strategy in MM patients (pts) and its impact on the mobilization outcomes, engraftment and the observed toxicity. Methods Between 01/2000 and 12/2012, 220 chemo-mobilization attempts were undertaken. Among these, 62 pts (M=37, F=25) had MM (1st-line=54, relapsed=8) and all received high-dose CY and G-CSF. Median age was 56 (37-75) yrs. ISS stage was I (n=34), II (n=16), and III (n=12). Pre-transplant induction consisted of VAD or VAD-like chemotherapy (n=26), bortezomib(bor)/dexamethasone (dex) (n=15), thalidomide (thal) /dex (n=10), bor/thal/dex (n=10), and 1 received bor/lenalidomide/dex. Fifty-six received fractionated high-dose CY (5g/m2 divided in 5 doses of 1g/m2 q 3 hrs) whereas 6 received CY 50 mg/kg for 2 doses. G-CSF was given at a fixed dose of 300 µg SQ q 12 hrs. Results All 62 (100%) pts achieved a circulating CD34 count ≥20/µl which is the cut-off level at our center to proceed with apheresis. The median peak peripheral blood CD34+ cell count was 111.5 (21-575) cells/μL. Success rate of stem-cell mobilization defined as collection of more than 2x106 CD34+ cells/kg was 100%. Median stem cell collection yield was 15.9x106 CD34+ cells/kg. Moreover, 61 (98.4%) pts and 46 (74%) pts collected >5x106 and >10x106 CD34+ cells/kg, respectively. Only 4 (6.4%) pts required 2 apheresis sessions. Conversely, 40 (64.5%) pts required hospitalization for febrile neutropenia (n=38) or transfusion support (n=2) for a median of 4 (1-8) days. No one required intensive level of care and all recovered. Also, 17 (27.4%) pts required blood transfusions and 16 (25.8%) required platelets transfusion. Autografting was successfully performed in all pts using high-dose melphalan with a median time from mobilization to the first transplant of 31 (16-156) days and median infused CD34+ cells of 7x106/kg (3.1-15.3). All pts achieved successful hematologic engraftment with a median time for neutrophil engraftment (ANC ≥500/µL) of 11 days and platelet engraftment (platelet ≥20000/microliter) of 12 days. Conclusion Fractionated high-dose CY and G-CSF is a highly effective chemo-mobilization strategy in MM in terms of successful rate of mobilization (100%), efficiency of stem cell collection (high yield), and timely hematologic engraftment (100%). However, the relatively high-rate of hospitalizations for febrile neutropenia requires an assessment of its cost-efficiency as compared to new mobilization strategies using G-CSF and preemptive plerixafor. Disclosures: No relevant conflicts of interest to declare.

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The Impact of Different Mobilization Strategies in the Setting of Multiple Myeloma

Blood ◽

10.1182/blood-2019-126118 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3254-3254

Author(s):

Francesco Mazziotta ◽

Gabriele Buda ◽

Nadia Cecconi ◽

Giulia Cervetti ◽

Lorenzo Iovino ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Peripheral Blood ◽

High Dose ◽

Roc Curve Analysis ◽

Cd34 Cells ◽

Significant Difference ◽

The Impact

INTRODUCTION Multiple myeloma (MM) is considered an incurable disease. Despite the introduction of novel agents allowed deeper response, high-dose chemotherapy and autologous stem cell transplantation (ASCT) remain the standard of care for patients (pts) in good clinical conditions. The most used strategies to mobilize stem cells from bone marrow (BM) into peripheral blood are high-dose cyclophosphamide (HD-CTX) plus G-CSF and G-CSF plus plerixafor (G-CSF+P). The goal of this retrospective study is to investigate whether the two different mobilization strategies have an impact on the clearance of monoclonal PCs in the apheresis products and on pts' outcome. PATIENTS AND METHODS We analyzed 62 pts (median age 61, range 41-75, 37 males and 25 women) diagnosed with MM and treated with ASCT between Mar 2014 and Mar 2018 at our Hematology Division (Pisa, Italy). All pts received induction therapy with at least 4 cycles of bortezomib, thalidomide and dexamethasone (VTD). 9/62 pts obtained a less than partial response (PR) and received lenalidomide-based regimens. After induction, 8 (12,9%) pts achieved complete remission (CR), 26 (41,9%) were in PR, 28 (45,2%) obtained a very good partial response (VGPR). 43/62 fit pts received HD-CTX (2-3 g/sqm) on day 1 followed by G-CSF (30 MU/day) started on day 4 until day 7, increased to 60 MU/day from day 8 until the end of apheresis. In 19/62 pts, after 4 days of G-CSF (60 MU/day) administration and not sufficient mobilization, we added plerixafor (0,24 mg/kgbw) for up to 4 consecutive days. In 43/62 pts we collected apheresis samples (10μl) analyzed through flow citometry to enumerate clonal residual PCs. The panel used to asses clonality included: CD138 Per-Cp, CD38 APC, CD19 PE-Cy7, CD45 APC-Cy7, cytoplasmic immunoglobulin K chain and L chain. RESULTS At the end of the peripheral blood stem cell (PBSC) collection, pts treated with HD-CTX presented a higher CD34+ absolute count (p=0.0489) and achieved the threshold of 5x106 CD34+ cells/kgbw in a significantly (p=0.006) higher percentage. We found a nearly significant (p=0.0517) lower count of CD34+ PBSCs in pts who received lenalidomide-based regimens before the mobilization. Performing flow citometry on apheresis samples, we observed that the number of the harvested clonal PCs showed a significant correlation (p=0.0115) with the occurrence of post-ASCT relapse. ROC curve analysis investigating the predictive effect of the number of pathological PCs on disease relapse showed an area under the curve of 0,6978 (95% CI 0.5392-0.8564; p=0.0267). Neither BM residual PCs detectable on BM biopsies performed before apheresis (r=-0.1323; p=0.609) nor the type of mobilization scheme (p=0.707) had an impact on the proportion of clonal PCs in the graft. Additionally, we did not observe any statistically significant difference in progression free- (PFS) (p=0.8276) and overall survival (OS) (p=0.2475) between the HD-CTX and G-CSF+P groups. DISCUSSION PBSC mobilization has a succession rate > 85%. Despite the use of HD-CTX to increase PBSC yields and decrease tumor burden, there is not clear evidence of a superior mobilization strategy. Additionally, HD-CTX has a not negligible toxicity and approximately 10% of the pts require hospitalization. Conversely, G-CSF+P is a safe and effective approach also in poor mobilizers. In our study, we observed a significative difference in the apheresis yields (p=0.0489) and in the percentage of pts who achieved the threshold of 5x106 CD34+ cells/kgbw (p=0.006) in favor of HD-CTX. Additionally, the detection of harvested residual clonal PCs could be a promising strategy to recognise pts more likely to relapse after ASCT. Nonetheless, we failed to demonstrate a superior effect of HD-CTX in the clearance of harvested clonal PCs, in agreement with the absence of a different pts' outcome amongst the two mobilization strategies. In conclusion, the choice between the two regimens is challenging and requires careful consideration of multiple factors. Overall, young fit pts, especially in the high-risk setting, should be treated with all appropriate modalities including chemiomobilization followed by double-ASCT. Conversely, in pts candidate to a single-ASCT it is reasonable to use G-CSF+P, since HD-CTX does not improve PFS and OS and add toxicity. The absence of an in-vivo purging effect on apheresis products of chemiomobilization further strengthens a chemotherapy-free mobilization. Disclosures Galimberti: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau.

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

Blood ◽

10.1182/blood.v116.21.2258.2258 ◽

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.

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Autologous transplantation of granulocyte colony-stimulating factor–primed bone marrow is effective in supporting myeloablative chemotherapy in patients with hematologic malignancies and poor peripheral blood stem cell mobilization

Blood ◽

10.1182/blood-2003-02-0440 ◽

2003 ◽

Vol 102 (5) ◽

pp. 1595-1600 ◽

Cited By ~ 25

Author(s):

Roberto M. Lemoli ◽

Antonio de Vivo ◽

Daniela Damiani ◽

Alessandro Isidori ◽

Monica Tani ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood Stem Cell ◽

High Dose Chemotherapy ◽

Stem Cell Mobilization ◽

High Dose ◽

Myeloablative Chemotherapy ◽

Hematopoietic Recovery ◽

Cd34 Cells ◽

Cell Mobilization ◽

Stimulating Factor

AbstractWe assessed the hematopoietic recovery and transplantation-related mortality (TRM) of patients who had failed peripheral blood stem cell mobilization and subsequently received high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF)–primed bone marrow (BM). Studied were 86 heavily pretreated consecutive patients with acute leukemia (n = 21), refractory/relapsed non-Hodgkin lymphoma (n = 41) and Hodgkin disease (n = 17), and multiple myeloma (n = 7). There were 78 patients who showed insufficient mobilization of CD34+ cells (< 10 cells/μL), whereas 8 patients collected less than 1 × 106 CD34+ cells/kg. BM was primed in vivo for 3 days with 15 to 16 μg/kg of subcutaneous G-CSF. Median numbers of nucleated cells, colony-forming unit cells (CFU-Cs), and CD34+ cells per kilogram harvested were 3.5 × 108, 3.72 × 104, and 0.82 × 106, respectively. Following myeloablative chemotherapy, median times to achieve a granulocyte count higher than 0.5 × 109/L and an unsupported platelet count higher than 20 and 50 × 109/L were 13 (range, 8-24), 15 (range, 12-75), and 22 (range, 12-180) days, respectively, for lymphoma/myeloma patients and 23 (range, 13-53), 52 (range, 40-120), and 90 (range, 46-207) days, respectively, for leukemia patients. Median times to hospital discharge after transplantation were 17 (range, 12-40) and 27 (range, 14-39) days for lymphoma/myeloma and acute leukemia patients, respectively. TRM was 4.6%, whereas 15 patients died of disease. G-CSF–primed BM induces effective multilineage hematopoietic recovery after high-dose chemotherapy and can be safely used in patients with poor stem cell mobilization.

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G-CSF Plus Preemptive Plerixafor Versus Cyclophosphamide Plus G-CSF for Autologous Stem Cell Mobilization in Multiple Myeloma: Effectiveness, Safety and Cost Analysis

Blood ◽

10.1182/blood.v124.21.5823.5823 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5823-5823

Author(s):

Ahmad Antar ◽

Zaher Otrock ◽

Mohamed Kharfan-Dabaja ◽

Hussein Abou Ghaddara ◽

Nabila Kreidieh ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Blood ◽

Stem Cell Mobilization ◽

Cell Yield ◽

Fixed Dose ◽

High Dose ◽

Peripheral Blood Cd34 ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Introduction: The optimal stem cell mobilization regimen for patients with multiple myeloma (MM) remains undefined. Most transplant centers use either a chemo-mobilization strategy using cyclophosphamide (CY) and granulocyte-colony stimulating factor (G-CSF) or a steady state strategy using G-CSF alone or with plerixafor in case of mobilization failure. However, very few studies compared efficacy, toxicity and cost-effectiveness of stem cell mobilization with cyclophosphamide (CY) and G-CSF versus G-CSF with preemptive plerixafor. In this study, we retrospectively compared our single center experience at the American University of Beirut in 89 MM patients using fractionated high-dose CY and G-CSF as our past preferred chemo-mobilization strategy in MM patients with our new mobilization strategy using G-CSF plus preemptive plerixafor. The change in practice was implemented when plerixafor became available, in order to avoid CY associated toxicity. Patients and methods: Patients in the CY group (n=62) (Table 1) received either fractionated high-dose CY (n=56) (5g/m2 divided in 5 doses of 1g/m2 every 3 hours) or CY at 50mg/kg/day for 2 doses (n=6). G-CSF was started on day +6 of chemotherapy at a fixed dose of 300 µg subcutaneously every 12 hours. All patients in the plerixafor group (n=27) (Table 1) received G-CSF at a fixed dose of 300 µg subcutaneously every 12 hours daily for 4 days. On day 5, if peripheral blood CD34+ was ≥ 20/µl, apheresis was started immediately. Plerixafor (240 µg/kg) was given 7-11 hours before the first apheresis if CD34+ cell count on peripheral blood on day 5 was <20/µl and before the second apheresis if CD34+ cells on the first collect were <3х106/kg. The median number of prior therapies was 1 (range: 1-3) in both groups. Results: Compared with plerixafor, CY use was associated with higher median peak peripheral blood CD34+ counts (35 vs 111 cells/µl, P= 0.000003), and total CD34+ cell yield (7.5 х 106 vs 15.9 х 106 cells/kg, P= 0.003). All patients in both groups collected ≥4x106 CD34+ cells/Kg. Moreover, 60 (96.7%) and 46 (74.2%) patients in the CY group vs 24 (88.8%) and 6 (22%) patients in the plerixafor group collected >6х106 and >10x106 CD34+ cells/kg, respectively (P=0.16; P<0.00001). Only 4 (6.4%) patients required two apheresis sessions in the CY group compared to 11 (40%) in the plerixafor group (P=0.0001). Conversely, CY use was associated with higher frequency of febrile neutropenia (60% vs 0%; P<0.00001), blood transfusions (27% vs 0%; P<0.00001), platelets transfusion (25% vs 0%; P<0.00001) and hospitalizations (64% vs 0%; P<0.00001). No one required intensive level of care and all recovered. Autografting was successfully performed in all patients using high-dose melphalan with a median time from mobilization to the first transplant of 31 days (range: 16-156) in the CY group compared to 13 days (range: 8-40) in the plerixafor group (P=0.027); and median infused CD34+ cells were 7х106/kg (range: 3.1-15.3) versus 5.27 (2.6-7.45), respectively (P=0.002). The average total cost of mobilization using the adjusted costs based on National Social Security Fund (NSSF) prices in Lebanon in the plerixafor group was slightly higher compared with the CY group ($7964 vs $7536; P=0.16). Conclusions: Our data indicate robust stem cell mobilization in MM patients with either fractionated high-dose CY and G-CSF or G-CSF alone with preemptive plerixafor. The chemo-mobilization approach was associated with two-fold stem cell yield, slightly lower cost (including cost of hospitalization) but significantly increased toxicity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Bortezomib Given in Sequence with Anthracycline and Thalidomide-Containing Regimens Does Not Adversely Affect Stem Cell Mobilization and Engraftment in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.541.541 ◽

2004 ◽

Vol 104 (11) ◽

pp. 541-541

Author(s):

Geoffrey L. Uy ◽

Nicholas M. Fisher ◽

Steven M. Devine ◽

Hanna J. Khoury ◽

Douglas R. Adkins ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Peripheral Blood ◽

Stem Cell Mobilization ◽

High Dose ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Cell Mobilization ◽

High Dose Melphalan

Abstract Bortezomib (VELCADE®) is a selective inhibitor of the 26S proteasome proven to be safe and effective in the treatment of relapsed or refractory multiple myeloma (MM). While high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) remains the standard of care, there is considerable interest in incorporating bortezomib into the initial treatment of MM. However, the role of bortezomib in frontline therapy for MM will depend in part on its effects on subsequent stem cell mobilization and engraftment. We conducted a pilot study of bortezomib administered pretransplant followed by high-dose melphalan with AHSCT. 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 cell mobilization was initiated by administering filgrastim 10 mcg/kg/day subcutaneously on consecutive days until stem cell harvest was completed. Stem cell collection began on day 5 of filgrastim via large volume apheresis (20 L/day) performed daily until a minimum of 2.5 x 106 CD34+ cells/kg were collected. Patients were subsequently admitted to the hospital for high-dose melphalan 100 mg/m2/day x 2 days followed by reinfusion of peripheral blood stem cells 48 hours later. Sargramostim 250 mcg/m2/day subcutaneously was administered starting day +1 post-transplant and continued until the absolute neutrophil count (ANC) ≥ 1,500/mm3 for 2 consecutive days. To date, 23 of a planned 40 patients have been enrolled in this study with 19 patients having completed their initial therapy with bortezomib followed by AHSCT. Patient population consists of 16 male and 7 female patients with the median age at diagnosis of 58 years (range 38–68). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (16), IgA (7) with stage II (9) or stage III (14) disease. Prior to receiving bortezomib, 11 patients were treated with VAD (vincristine, Adriamycin and dexamethasone) or DVd (Doxil, vincristine and dexamethasone), 5 patients with thalidomide and 5 patients with both. Two patients did not receive any prior chemotherapy. All patients successfully achieved the target of 2.5 x 106 CD34+ cells/kg in either one (15/19 patients) or two (4/19 patients) collections with the first apheresis product containing a mean of 5.79 x 106 CD34+ cells/kg. Analysis of peripheral blood by flow cytometry demonstrated no significant differences in lymphocyte subsets before and after treatment with bortezomib. Following AHSCT, all patients successfully engrafted with a median time to neutrophil engraftment (ANC ≥ 500/mm3) of 11 days (range 9–14 days). Platelet engraftment (time to platelet count ≥ 20,000/mm3 sustained for 7 days without transfusion) occurred at a median of 12 days (range 9–30 days). Eleven patients were evaluable for response at 100 days post-transplant. Compared to pre-bortezomib paraprotein levels, 3 patients achieved a CR or near CR, 7 maintained a PR while 1 patient developed PD. We conclude that pretransplant treatment with 2 cycles of bortezomib does not adversely affect stem cell yield or time to engraftment in patients with MM undergoing AHSCT. Updated results and detailed analysis will be available at the time of presentation.

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High-Dose Therapy and Autologous Stem Cell Transplantation for Multiple Myeloma: Analysis from Registry of Monoclonal Gammopathy of Czech Myeloma Group

Blood ◽

10.1182/blood.v120.21.4528.4528 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4528-4528

Author(s):

Roman Hajek ◽

Ivan Spicka ◽

Vladimir Maisnar ◽

Tomas Pika ◽

Evzen Gregora ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Autologous Stem Cell Transplantation ◽

Monoclonal Gammopathy ◽

High Dose ◽

Newly Diagnosed ◽

Time To Progression ◽

Advisory Committees

Abstract Abstract 4528 Background: The role of high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) in the treatment of Multiple Myeloma (MM) continues to evolve in the era of novel agent. Although data from clinical trials with novel agens are very promising, it is evident that ASCT remains the golden standard for all available patients; moreover combination with proteasome inhibitors and immunomodulatory agens will ensure further benefits and prolongation of overall survival to patients. Aim: To investigate the indication, frequency and results of HDM and ASCT in MM patients in the era of novel agens. Methods: Before inclusion to the Registry of Monoclonal Gammopathy (RMG) of the Czech Myeloma Group (CMG), all persons signed the informed consent forms. Out of 1448 newly diagnosed patients (654 aged≤ 65 years) reported in the RMG in the period 2007–2011, 26.7% (386/1448) underwent ASCT as part of primo therapy. A cohort of 229 patients underwent ASCT as part of the first, second and third relapse (R1–3) treatment in the same time period. Time to progression in different disease settings, objective response rate, and safety were included as exploratory outcomes. Efficacy was assed using the IMWG criteria. A distinctive aspect of this analysis involves comparison of frequency of ASCT during this period of time. Results: A total of 59% (386/654) of newly diagnosed patients under 65 years underwent ASCT as part of primo therapy. Frequency of indication between patients with age ≤ 65 years was similar (56–63%) during the last five years. Melphalan 200mg/m2 was the most frequently used HDM (94%) in primo therapy. The same was true for R1 (73%), R2 (46%) but not R3 where most frequent (49%) HDM was melphalan 100mg/m2. Transplant related mortality day+100 ranged between 0.8 to 1.1% during five consecutive years for all treatment settings together and was zero for primo therapy in the year 2007 and 2009–10. Overall responses to ASCT (primo therapy vs. R1 vs. R2 vs. R3) were: ORR 93% (30.5%≥CR) vs. 93% (20%≥CR) vs. 72% (8%≥CR) vs. 54% (4.1%≥CR). Medians of Time to Progression (TTP from the time of ASCT; primo therapy vs. R1 vs. R2 vs. R3) were: 26.2 vs. 15.6 vs. 5.8 vs. 4.8 months and the difference were statistically significant (p<000.1). Conclusion: ASCT is a safe treatment strategy in MM independently of disease advance, although for patients with more advanced disease, reduced dose of melphalan (100mg/m2) should be considered. ASCT is very effective treatment not only for newly diagnosed MM patients but also for patients in the first relapse. The indication in relapse setting should be considered more frequently than is currently common in the shadow of enthusiasm for novel drugs. Acknowledgment: This work was supported by national grants IGA NT12215-4, IGA NT12130-4, GACR P304/10/1395, IGA NT11154-4, MSM 0021622434 Disclosures: Hajek: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maisnar:Janssen Cilag: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer (Schering): Honoraria.

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BKT140 Is a Novel CXCR4 Antagonist with Stem Cell Mobilization and Antimyeloma Effects: An Open-Label First Human Trial In Patients with Multiple Myeloma Undergoing Stem Cell Mobilization for Autologous Transplantation

Blood ◽

10.1182/blood.v116.21.2260.2260 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2260-2260 ◽

Cited By ~ 9

Author(s):

Arnon Nagler ◽

Avichai Shimoni ◽

Irit Avivi ◽

Jacob M. Rowe ◽

Katia Beider ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Stem Cell Mobilization ◽

Employment Equity ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Equity Ownership ◽

Cell Mobilization

Abstract Abstract 2260 Background: BKT140 is a high affinity CXCR4 inhibitor with an extended K off-rate. Pre-clinical studies in animal models with BKT140 showed a robust mobilization of white blood cells (WBC) and hematopoietic stem cells (HSC). Furthermore, BKT140 also showed a direct anti-tumor effect against human-derived multiple myeloma (MM), lymphoma and primary leukemia cells and cell lines in vitro and in vivo, causing significant apoptosis. Aims: To assess BKT140 toxicity (primary endpoints), the mobilization capacity of CD34+ hematopoietic progenitors and CD138 MM cells, and pharmacokinetic (PK) and pharmacodynamic (PD) (secondary endpoints). Methods: 16 MM patients in first CR/PR were included in a phase I/IIa study, in which escalating doses of BKT140 (30, 100,300,900 μg/kg) were administered together with a high-dose cyclophosphamide (Cy) (2 g/m2) and G-CSF (5 μg/Kg) for stem cell mobilization. G-CSF was started on day 5 post Cy and BKT140 was injected subcutaneously (SC) once on day 10. Toxicity, PK, and mobilization capacity (assessed by serial measurements of number of WBC and CD34+ and CD138+ cells) were measured pre- and post BKT140 administration. Results: BKT140 was well tolerated at all doses and none of the patients developed grade II-IV toxicity. BKT140 was rapidly absorbed with no observed lag time, with peak plasma concentrations occurring 0.5h after administration. Clearance was rapid, with a median terminal half-life of 0.69h. BKT140 administration resulted in a significant dose-dependent increase in the number of peripheral blood neutrophils, monocytes, lymphocytes, and CD34+ cells compared to the G-CSF/Cy individual patient baseline. The maximum increase in the number of WBC from baseline was observed within 8h following BKT140 injection, 2.5-, and 3.0-, 4.1- and 4.8-fold, for the 4 BKT140 doses, respectively. Furthermore, BKT140 administration resulted in a significant increase in the mean absolute PB CD34+ cells mobilized (6.6, 7.5, 11.2 and 20.6 ×106/kg) for the 4 BKT140 administered doses, respectively. Moreover, the number of aphaeresis was reduced from 2.25 procedures at the first two BKT140 doses to 1.25 and 1 aphaeresis at the highest BKT140 doses, respectively. An increase in the number of CD138+ cells was observed in 6 out of 6 pts that had CD138+ cells in their blood and were treated with lower doses of BKT140 (30 and 100 μg/kg). Interestingly, in pts that were treated with the highest doses of BKT140 (300 and 900 μg/kg) a reduced number of CD138+ cells was observed in 3 out of 7 pts that had CD138+ cells in their blood, whereas in 4 pts, an increase in the number of CD138+ cells was shown. Three pts who did not have CD138+ cells in their blood were not affected by BKT140. The BKT140 mobilized grafts were used for AutoSCT following 200 mg/m2 melphalan conditioning. Pts received an average of 5.3×106 CD34+ cells/kg. All transplanted pts rapidly engrafted (n=15). The median day for neutrophil (>500/mm3) and platelet (>20,000/mm3, >50,000/mm3,) was on day 11 (range, 0–13), day 11 (range, 0–14), and day 14 (range, 0–23), respectively. Conclusions: The current data suggests that BKT140 can safely be added to G-CSF-based harvesting regimens, can increase CD34+ cell mobilization and reduce the number of collection days. Furthermore, due to its ability to release MM cells from the bone marrow and stimulate their cell death, additional studies are warranted to further evaluate the effect of BKT140 as an anti-MM agent. Disclosures: Nagler: Biokine Therapeutics Ltd: Consultancy. Abraham: Biokine Therapeutics Ltd: Employment, Equity Ownership, Patents & Royalties. Wald: Biokine Therapeutics Ltd: Employment. Shaw: Biokine Therapeutics Ltd: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Eizenberg: Biokine Therapeutics Ltd: Employment, Equity Ownership, Patents & Royalties. Peled: Biokine Therapeutics Ltd: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Influence of Different Dosages of Cyclophosphamide on Stem Cell Mobilization and Engraftment In Newly Diagnosed Multiple Myeloma Patients Treated with a Thalidomide Containing Regimen.

Blood ◽

10.1182/blood.v116.21.3494.3494 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3494-3494

Author(s):

Joost TM De Wolf ◽

Gustaaf Van Imhoff ◽

Gerwin A Huls ◽

Edo Vellenga

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Blood ◽

High Dose ◽

Peripheral Blood Stem Cells ◽

Target Yield ◽

Cd34 Cells ◽

Significant Difference ◽

Blood Stem Cells

Abstract Abstract 3494 Introduction: Treatment of multiple myeloma (MM) patients (<65 yrs) consists of induction chemotherapy for 3–6 months followed by peripheral blood stem cell collection and transplantation. Both high dose cyclophosphamide (HD-C, 2 gr/m2/day, on days 1–2) and lower dosage of cyclophosphamide (1 gr/m2/i.v.on day 1) combined with doxorubicin (15 mg/m2/day, on days 1–4) and dexamethason 40 mg orally, days 1–4 (LD-C) are used, in combination with G-CSF, to mobilize hematopoietic stem/progenitor cells. A great variability was observed in the engraftment of different hematopoietic lineages post-ASCT. Therefore we questioned whether the dose of cyclofosfamide as mobilizing agent might affect the neutrophil and platelet recovery post-ASCT. The studied MM patients were treated with VAD or TAD (Blood 2010;11:115). Peripheral blood stem cells were collected after LD-C and HD-C with the Cobe Spectra; in each collection, 10 – 12 L of blood was processed in 3 – 4 hours. The target yield was 10 × 106/kg CD34+ cells. Results: 92 patients were treated according to VAD and 41 patients with TAD. In the VAD arm 89% of the patients reached the target yield of CD34+ cells after 1 collection compared to 61% in patients treated with TAD (p = 0.0003). The number of CD34+ cells collected at the first day and the total CD34 yield after HD-C or LD-C was significantly higher in patients treated with VAD compared with TAD: 16.6 ± 11.6 × 106/kg vs. 10.4 ± 9.3 × 106/kg (p=0.003), and 16.9 ± 11.1 × 106/kg vs 12.3 ± 8.6 × 106/kg (p=0.02). No significant difference was observed in the total yield of collected CD34+ cells in the VAD arm or TAD arm between HD-C vs. LD-C. In all patients high dose melphalan (200 mg/m2) was used as conditioning regimen followed by reinfusion of peripheral blood stem cells. In the VAD arm no difference in neutrophil and platelet engraftment (absolute neutrophil count > 0.5 × 109/L and platelet count > 20 × 109/L without platelet transfusions) was noticed between patients mobilized with LD-C (22 ±12 days and 23 ±13 days) or HD-C (18 ± 5 (p=0.1) and 21 ±11 days (p=0.5)); in contrast a significant difference was demonstrated in neutrophil and platelet engraftment between patients treated according the TAD arm and mobilized with LD-C (20 ± 8 days and 20 ±19 days) or HD-C (34 ± 11 days (p<0.0001) and 43 ±22 days (p=0.001)). These differences could not be ascribed to differences in the number of infused CD34+ cells: VAD arm: LD-C: 5.7 ± 2.6 × 106/kg, HD-C: 5.7 ± 2.5 × 106/kg: TAD arm: LD-C: 5.2 ± 2.5 × 106/kg and TAD-HD-C 6.4 ± 2 × 106/kg. It might be assumed that the higher dosage of cyclophosphamide had a positive effect on tumor response. However the impaired engraftment was not associated with differences in relapse free survival between the different arms (p = 0.2). In summary these data demonstrate that thalidomide containing regimen in MM patients impair mobilization of stem/progenitor cells and that a mobilization with high dose cyclophosphamide and not low dose cyclophosphamide after treatment with thalidomide prolong the engraftment post-transplantation. Disclosures: No relevant conflicts of interest to declare.

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Successful Stem Cell Mobilization with High-Dose Cytarabine Plus G-CSF after Lenalidomide Therapy for Multiple Myeloma - a Series of Four Cases

Blood ◽

10.1182/blood.v124.21.5831.5831 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5831-5831

Author(s):

Jun Ishiko ◽

Kazuaki Sato ◽

Ruri Kato ◽

Manabu Kawakami ◽

Masashi Nakagawa ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Induction Therapy ◽

Negative Impact ◽

Stem Cell Mobilization ◽

High Dose ◽

Cell Harvesting ◽

Cd34 Cells ◽

High Dose Cytarabine ◽

Cell Mobilization

Abstract Of late years, newly developed agents, such as bortezomib, lenalidomide, thalidomide, are widely used for treatment against multiple myeloma. After induction therapy, candidates for autologous stem cell transplantation are supposed to be followed by stem cell harvesting. There are several reports showing lenalidomide has a negative impact on stem cell mobilization. This opinion tends to let us refrain from using lenalidomide on the myeloma patients who are eligible for transplantation, even lenalidomide is expected promising. We experienced a series of three clinical cases presenting that stem cells were poorly mobilized with cyclophosphamide (CY) plus G-CSF after lenalidomide treatment, but sequential stem cell mobilization was incredibly improved with high-dose cytarabine plus G-CSF. One additional case who was treated with lenalidomide also presented successful stem cell mobilization with high-dose cytarabine plus G-CSF. Here we show all four cases in detail. Case 1: 66 years old male, symptomatic myeloma after smoldering period. After three course of bortezomib induction, the response was insufficient. Sequentially he was treated with lenalidomide (25mg/day, every day for three weeks with one week rest period) and dexamethasone (Dex) (40mg/day, weekly) for two courses, and finally achieved Partial response (PR). First peripheral blood stem cell harvesting was attempted with high-dose CY (2.0 g/m2, day1-2) + lenograstim (5mg/kg daily, on days 7 until leukapheresis), but mobilization was unsuccessful so harvesting was not performed. For subsequent mobilization, high-dose cytarabine was administered at a dose of 2.0 g/m2 twice daily (day1-2) + lenograstim. Second mobilization was markedly improved, and finally 33.0 x 106/kg CD34+ cells were obtained. Case 2: 63 years old male, symptomatic myeloma, IgG type. This patient was treated with bortezomib, CY and Dex but resulted in disease progression. As an alternative therapy, lenalidomide (10mg/day, daily for three weeks with one week rest) and Dex (40mg, weekly) were used for three cycles. The dose of lenalidomide was reduced due to renal dysfunction. PR was obtained, then first harvesting was attempted with high-dose CY + lenograstim, as case 1, and 0.088 x 106/kg of CD34+ cells were collected, which was not sufficient for transplantation. Second mobilization was performed with high-dose cytarabine as case 1, and consequently we could obtain 60.1 x 106/kg of CD34+ cells; the yield was dramatically improved. Case 3: 41 years old female, symptomatic myeloma after one year course of smoldering myeloma. As an induction therapy, bortezomib, CY and Dex were selected, but finally she could not achieved PR after three cycles. We gave up bortezomib-based induction, and then lenalidomide (15-25 mg on day1-21 with 1 week rest) and Dex (40 mg, weekly) were administrated for five courses, followed by PR. As previous two cases, the first peripheral stem cell collection was initiated with high-dose CY + lenograstim, and it was not sufficient (0.059 x 106/kg of CD34+ cells). And the second mobilization with high-dose cytarabine with lenograstim recovered the yield of stem cell up to 6.90 x 106/kg. Case 4: 63 years old male, symptomatic myeloma. He was treated with bortezomib, Dex with/without CY, but this regimen was not very effectual, and CY caused elevation of aminotransferase (CTCAE grade 3). Then lenalidomide (10-15 mg on day 1-21) and Dex (40 mg, weekly) were administrated for four courses, and the patient achieved PR. Due to the adverse effect of liver dysfunction, we could not use high-dose CY for mobilization. For this case, high-dose cytarabine was selected for first mobilization, and it was very successful, 50.2 x 106/kg of CD34+ cells were harvested. The yields of PBSC from all four cases are summarized on Table 1. These four cases suggest mobilization with high-dose cytarabine could be an alternative option for poor mobilizer of myeloma patient treated with lenalidomide-based induction. This fact may enable us to choose lenalidomide, not only bortezomib, for induction even for transplant-eligible cases. Figure 1 Figure 1. Disclosures Ishiko: Celgene: Honoraria.

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