STEM CELL COLLECTION

The minimal dose of CD34+ cells/Kg to be collected for a single autologous transplant is 2 million, but the optimal dose for rapid platelet recovery is 5 million.

Mobilization strategies in multiple myeloma include:
  - Single agent G-CSF
  - Chemotherapy + G-CSF
    Cyclophosphamide is the most commonly used mobilization chemotherapy.
  - Plerixafor

A peripheral blood CD34 content of <10 CD34+ cells/mcL on the day before collection predicts poor mobilization and collection failure.

 

 

Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of patients with multiple myeloma.
J Hematother. 1996 Aug;5(4):339-49.
Lemoli RM, Cavo M, Fortuna A.
Apheresis products of MM patients treated with cyclophosphamide 4-7 g/m2 and G-CSF contained an average of 0.7% of myeloma cells (range, 0.2-2.7%).

Mobilization of CD34+ cells in elderly patients (>/= 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen.
Br J Haematol. 2003 Feb;120(3):413-23.
Morris CL, Siegel E, Barlogie B, Cottler-Fox M, Lin P, Fassas A, Zangari M, Anaissie E, Tricot G.
Among 984 myeloma patients who underwent mobilization of peripheral blood stem cells, 106 patients were aged 70 years or older. Older age correlated inversely with CD34+ yield, and it remained an adverse factor even after multivariate analysis. The effect of age was incremental, and there was no specific age threshold associated with collection failure.

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens.
Blood. 2009 Aug 27;114(9):1729-35.
Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson PG, Durie BG, Rajkumar SV; International Myeloma Working Group.
These authors gave the following suggestions for stem cell mobilization:
  - Collect the stem cells after 3-4 cycles of induction therapy
  - In patients <65 years old and <4 cycles of induction therapy - use G-CSF alone
  - In patients <65 years old and >4 cycles of lenalidomide - use G-CSF + Cyclophosphamide
  - In patients >65 years old - use G-CSF + reduced-dose cyclophosphamide
    or G-CSF + plerixafor before the second leukapheresis if <2 million CD34+ cells/Kg collected with the first leukapheresis
For second attempt after collection failure with G-CSF, 3 options are suggested:
 1) G-CSF + cyclophosphamide
 2) G-CSF + plerixafor
 3) GM-CSF 10 mcg/Kg/day SC x 2 days, followed by G-CSF 16 mcg/Kg/day SC until completion of stem cell collection

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).
Leukemia. 2009 Oct;23(10):1904-12.
Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Kumar S, Munshi NC, Dispenzieri A, Kyle R, Merlini G, San Miguel J, Ludwig H, Hajek R, Jagannath S, Blade J, Lonial S, Dimopoulos MA, Einsele H, Barlogie B, Anderson KC, Gertz M, Attal M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Sezer O, Mateos MV, Cavo M, Joshua D, Turesson I, Chen W, Shimizu K, Powles R, Richardson PG, Niesvizky R, Rajkumar SV, Durie BG; IMWG.

 

MOBILIZATION CHEMOTHERAPY

A combination of dexamethasone, cyclophosphamide, etoposide, and cisplatin is less toxic and more effective than high-dose cyclophosphamide for peripheral stem cell mobilization in multiple myeloma.
Haematologica. 2002 Oct;87(10):1041-5.
Corso A, Arcaini L, Caberlon S, Zappasodi P, Mangiacavalli S, Lorenzi A, Rusconi C, Troletti D, Maiocchi MA, Pascutto C, Morra E, Lazzarino M.
This study compares the efficacy of two mobilization regimens in 116 myeloma patients:
  - HD-Cy (high-dose cyclophosphamide, 4 g/m2) (61 patients)
  - DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) (55 patients)
G-CSF 5 mg/Kg/day was started 48 hours after chemotherapy.
DCEP was a better regimen than HD-Cy:
  - Median number of CD34+ cells harvested was similar (5.9 vs 5.8 million CD34+ cells/Kg)
  - The target of 4 million CD34+ cells/Kg was reached in 59% of HD-Cy patients and 75% of DCEP patients
  - Poor mobilizers (<2 million CD34+ cells/Kg) were 21% with HD-Cy and 13% with DCEP
  - Neutropenic fever: 18% with HD-Cy and 0% with DCEP
  - WHO grade >II extra-hematologic toxicities (microhematuria, cystitis, infections): 13% with HD-Cy and 0% with DCEP

A simplified approach to stem cell mobilization in multiple myeloma patients not previously treated with alkylating agents.
Bone Marrow Transplant. 2003 Dec;32(12):1113-7.
Lerro KA, Medoff E, Wu Y, Seropian SE, Snyder E, Krause D, Cooper DL.
This is a retrospective study of 50 consecutive myeloma patients who underwent the following mobilization regimen:
  - Cyclophosphamide 1.5 g/m2 IV in 500 mL NS, given as outpatient on a Friday (day -10)
  - Prehydration with 500 ml in 500 ml, posthydration with 1 L. Uroprophylaxis with MESNA was not administered
  - G-CSF 10 mcg/Kg SC qd was started on the following Monday (day -7)
  - Apheresis was scheduled to begin on Monday of the following week (day 0)
  - A peripheral blood CD34+ cell count >20/mcL was used to begin apheresis
Results:
  - Median stem cell collection was 4.88 million CD34+ cells/kg per apheresis
  - 44 patients (88%) collected >5 million CD34+ cells/kg within 2 days
  - 36 patients (72%) collected >10 million CD34+ cells/kg
  - The mobilizing program was highly predictable. 2 patients (4%) required weekend apheresis
  - This regimen was well tolerated. 1 patient required hospitalization for neutropenic fever

High-dose cyclophosphamide with or without etoposide for mobilization of peripheral blood progenitor cells in patients with multiple myeloma: efficacy and toxicity.
Bone Marrow Transplant. 2004 Jul;34(1):69-76.
Gojo I, Guo C, Sarkodee-Adoo C, Meisenberg B, Fassas A, Rapoport AP, Cottler-Fox M, Heyman M, Takebe N, Tricot G.
77 myeloma patients underwent stem cell mobilization with:
  - Cyclophosphamide 4.5 g/m2 alone (28 patients, Group 1)
  - Cyclophosphamide 4.5 g/m2 + etoposide 2 g/m2 (49 patients, Group 2)
Results:
  - A median of 22.4 million CD34+ cells/kg were collected on the first day of leukapheresis (range 0.59-114.7)
  - The addition of etoposide resulted in similar stem cell yields but higher toxicity
  - RR including minimum response by EBMT criteria was 45% in Group 1 and 56% in Group 2.
  - Patients requiring hospitalization, mainly for neutropenic fever: 25% in Group 1 and 75% in Group 2.
  - Prior RT inhibited CD34+ cell yield

Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.
Bone Marrow Transplant. 2009 Apr;43(8):619-25.
Gertz MA, Kumar SK, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Gastineau DA, Winters JL, Litzow MR.
370 MM patients were mobilized using CY and growth factors, and 346 using growth factors alone. Patients receiving CY had higher stem cell yields than those receiving the growth factors only (2 vs 4 median number of apheresis sessions). Patients treated with CY required more time for engraftment of platelets and neutrophils. Platelet engraftment, defined as a level >50,000, in 75% of patients was obtained at day +39 in the group mobilized with CY, and at day +18 in the group mobilized with growth factors only. Results for neutrophil engraftment were similar. These authors suggested to lengthen the period between the completion of apheresis and the stem cell reinfusion in patients mobilized with CY, because they believe that CY damages the bone marrow microenvironment.

Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma.
Am J Hematol. 2009 Dec;84(12):809-14.
Nakasone H, Kanda Y, Ueda T, Matsumoto K, Shimizu N, Minami J, Sakai R, Hagihara M, Yokota A, Oshima K, Tsukada Y, Tachibana T, Nakaseko C, Fujisawa S, Yano S, Fujita H, Takahashi S, Kanamori H, Okamoto S; Kanto Study Group of Cell Therapy.
This retrospective study in 146 myeloma patients compared 3 different strategies of stem cell collection. The median number of CD34+ million cells/Kg was:
  - 2.0 with G-CSF alone
  - 5.27 with cyclophosphamide 2-4 g/m2 + G-CSF
  - 13.85 with etoposide 500 mg/m2/day days 1-3 + G-CSF
There was no difference in progression-free survival among the 3 regimens, therefore the antimyeloma effect of cyclophosphamide and etoposide is questionable.

Chemomobilization with Etoposide is Highly Effective in Patients with Multiple Myeloma and Overcomes the Effects of Age and Prior Therapy.
Biol Blood Marrow Transplant. 2011 Jan;17(1):141-6.
Wood WA, Whitley J, Moore D, Sharf A, Irons R, Rao K, Serody J, Coghill J, Gabriel D, Shea T.
152 patients received etoposide 375 mg/m2 on days 1 and 2, followed by G-CSF 5 mcg/Kg twice daily from day 3. Mobilization was successful in 100% of cases, and 94% of patients collected in a single day. Median number of CD34+ cells/Kg was 12 × 10(6).

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.
J Clin Apher. 2015 Jun;30(3):176-82.
Tuchman SA, Bacon WA, Huang LW, Long G, Rizzieri D, Horwitz M, Chute JP, Sullivan K, Morris Engemann A, Yopp A, Li Z, Corbet K, Chao N, Gasparetto C.

This study questions the use of cyclophosphamide as mobilization strategy for collecting stem cells in patients with multiple myeloma, because it increased toxicity and it did not improve long-term outcomes. Patients underwent stem cell collection with either G-CSF alone (73 patients) or cyclophosphamide + G-CSF (94 patients). Results:
  - Total CD34 cells/Kg collected: 5.8 million with C-CSF vs 12 million with cyclophosphamide + G-CSF
  - Hospitalizations due to complications: 0% with G-CSF vs 14% with cyclophosphamide + G-CSF
  - Overall survival was similar in the two groups

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.
Bone Marrow Transplant. 2015 Dec;50(12):1513-8. doi: 10.1038/bmt.2015.190. Epub 2015 Aug 24.
Uy GL, Costa LJ, Hari PN, Zhang MJ, Huang JX, Anderson KC, Bredeson CN, Callander NS, Cornell RF, Perez MA, Dispenzieri A, Freytes CO, Gale RP, Garfall A, Gertz MA, Gibson J, Hamadani M, Lazarus HM, Kalaycio ME, Kamble RT, Kharfan-Dabaja MA, Krishnan AY, Kumar SK, Kyle RA, Landau HJ, Lee CH, Maiolino A, Marks DI, Mark TM, Munker R, Nishihori T, Olsson RF, Ramanathan M, Rodriguez TE, Saad AA, Savani BN, Schiller GJ, Schouten HC, Schriber JR, Scott E, Seo S, Sharma M, Ganguly S, Stadtmauer EA, Tay J, To LB, Vesole DH, Vogl DT, Wagner JL, Wirk B, Wood WA, D'Souza A.
This is a retrospective study of 968 patients with myeloma who underwent an autologous stem cell collection. The stem cells were collected either with growth factors alone (i.e., G-CSF or GM-CSF) (519 pts), or with mobilization chemotherapy (cyclophosphamide in 338 pts, etoposide in 55 pts, cyclophosphamide + etoposide in 21 patients, or VDT-PACE/similar in 35 patients) (449 pts). The authors found there there was no significant difference of clinical outcomes between the two groups. Results:
  - Progression-free survival at 3 years: 43% with growth factors alone, and 40% with chemotherapy (p=0.33)
  - Overall survival at 5 years: 62% with growth factros alone, and 60% with chemotherapy (p=0.76)
The conclusion is that mobilization chemotherapy does not contribute to disease control in multiple myeloma.

 

DOSE OF CYCLOPHOSPHAMIDE

Low-dose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilization in patients with multiple myeloma.
Bone Marrow Transplant. 2003 Mar;31(5):347-51.
Jantunen E, Putkonen M, Nousiainen T, Pelliniemi TT, Mahlamäki E, Remes K.
Retrospective study of 57 patients with newly diagnosed myeloma previously treated with VAD. Mobilization regimen was:
  - Low-dose cyclophosphamide, 1.2-2 g/m2 + G-CSF (25 patients, Group 1)
  - Intermediate-dose cyclophosphamide, 4 g/m2 + G-CSF (32 patients, Group 2)
Results:
  - At least 2 million CD34+ cells/Kg were collected with a single apheresis from 88% of patients in Group 1 and 84% of patients in Group 2
  - Mobilization failure occurred in 1 patient (4%) in Group 1 and 0 patients in Group 2
  - Patients in Group 1 had less toxicity, including lower frequency of fever (20 vs 73%), and less need for platelet transfusions (0 vs 24%)

Intermediate-Dose versus Low-Dose Cyclophosphamide and Granulocyte Colony-Stimulating Factor for Peripheral Blood Stem Cell Mobilization in Patients with Multiple Myeloma Treated with Novel Induction Therapies.
Biol Blood Marrow Transplant. 2012 Jul;18(7):1128-35.
Hamadani M, Kochuparambil ST, Osman S, Cumpston A, Leadmon S, Bunner P, Watkins K, Morrison D, Speir E, Deremer D, Kota V, Jillella A, Craig M, Awan F.
This study compares outcomes of stem cell collections in 123 myeloma patients who underwent the collection within 1 year of starting therapy with novel agents. Mobilization regimen was:
  - Low-dose cyclophosphamide, 1.5/m2 + G-CSF (68 patients)
  - Intermediate-dose cyclophosphamide, 3-4 g/m2 + G-CSF (55 patients)
Stem cell yield was superior in patients who received intermediate-dose cyclophosphamide (16.6 vs 7.5 million CD34+ cells/Kg).

Comparison of two dose levels of cyclophosphamide for successful stem cell mobilization in myeloma patients.
J Cancer Res Clin Oncol. 2016 Dec;142(12):2603-2610.
Winkelmann N, Desole M, Hilgendorf I, Ernst T, Sayer HG,3, Kunert C, Mügge LO, Hochhaus A, Scholl S.
This is a retrospective study which compared outcomes of stem cell collection in two groups of patients with multiple myeloma, one (48 patients) that received "intermediate-dose" cyclophosphamide, 2.5 g/m2, and another (53 patients) that received "high-dose" cyclophosphamide, 4 g/m2. Collection failure was define as the inability to collect more than 5 million CD34+ cells/Kg. Results:
  - Median time to apheresis: 11 days with 2.5 g/m2, and 12 days with 4 g/m2
  - Median CD34+ cells/Kg: 8.3 with 2.5 g/m2, and 7.6 with 4 g/m2
  - Neutropenic fever: 15% with 2.5 g/m2, and 34% with 4 g/m2 (p=0.08)
  - Collection failure: 10% with 2.5 g/m2, and 16% with 4 g/m2
The authors conclude that mobilization cyclophosphamide with 2.5 g/m2 is effective and safer than with 4 g/m2.

 

STEM CELL COLLECTION WITH PEGFILGRASTIM

Fixed-dose single agent pegfilgrastim for peripheral blood progenitor cell mobilization in patients with multiple myeloma.
Br J Haematol. 2006 Jun;133(5):533-7.
Hosing C, Qazilbash MH, Kebriaei P, Giralt S, Davis MS, Popat U, Anderlini P, Shpall EJ, McMannis J, Körbling M, Champlin RE.
In this phase II study, pegfilgrastim 12 mg SC x1 was administered in 19 patients with multiple myeloma for stem cell mobilization. The median number of stem cells collected was 8.4 million CD34+ cells/kg (range: 4.1-15.8), and the median number of apheresis procedures was 2 (range: 1-5). Toxicities were similar to those seen with filgrastim, i.e., mainly bone pain/myalgias.

Mobilization of peripheral blood stem cells in myeloma with either pegfilgrastim or filgrastim following chemotherapy.
Haematologica. 2008 Nov;93(11):1739-42.
Tricot G, Barlogie B, Zangari M, van Rhee F, Hoering A, Szymonifka J, Cottler-Fox M.
After mobilization chemotherapy with DT-PACE, patients received either filgrastim bid or peg-filgrastim 6 mg SC on days +6 and +13 (the second dose was held if WBC were >100,000 by day +13). The authors considered peg-filgrastim the standard of care for stem cell mobilization because of its advantages:
  - Lower median number of growth factor injections (2 vs 26)
  - Higher median number of CD34+ cells/kg collected on day 1
  - Higher percentage of patients who collected 15 million CD34+ cells/Kg in 3 days
  - Faster neutrophil recovery after transplant

 

STEM CELL COLLECTION WITH PLERIXAFOR

Plerixafor (AMD3100) inhibits the SDF-1 alpha/CXCR4 interaction between the marrow stroma and the CD34+ cells.
SDF-1 (Stromal cell-Derived Factor 1) is a chemotactic factor for stem cells and a growth factor for MM.
CXCR4 is a chemokine receptor expresses by MM cells and endothelial cells but not stromal cells.

Advantages of plerixafor, when compared with mobilization chemotherapy:
  - No risk of chemotherapy-induced complications, such as febrile neutropenia
  - Fewer days of G-CSF administration
  - Fewer days of apheresis
  - Reduced risk of mobilization failures

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.
Bone Marrow Transplant. 2008 Feb;41(4):331-8.
Calandra G, McCarty J, McGuirk J, Tricot G, Crocker SA, Badel K, Grove B, Dye A, Bridger G.
AMD3100 given with G-CSF mobilized CD34+ cells in approximately 71% of myeloma patients who failed stem cell collection. The most common toxicities of AMD3100 were gastrointestinal reactions, injection site reactions, and paresthesias. No serious adverse events were observed.

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.
DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, Hosing C, Früehauf S, Horwitz M, Cooper D, Bridger G, Calandra G; 3102 Investigators.
Blood. 2009 Jun 4;113(23):5720-6.
This is an international double-blind randomized phase III study comparing G-CSF + placebo vs G-CSF + plerixafor for stem cell collection in multiple myeloma. G-CSF was given at the dose of 10 mcg/Kg SC qd for 4 days, and plerixafor 240 mcg/Kg SC was started on day 4, with the plan of apheresis on day 5. The primary endpoint was to collect at least 6 million CD34+ cells/Kg within 2 days of apheresis. Results:
  - 53 of 154 (34%) patients in the placebo group reached the endpoint (and 56% in 4 days)
  - 106 of 148 (72%) patients in the plerixafor group reached the endpoint (and 54% in 1 day)
Plerixafor was well tolerated. Most common adverse events of plerixafor: injection site reactions and GI disturbances.

Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization.
Bone Marrow Transplant. 2010 Jan;45(1):39-47.
Dugan MJ, Maziarz RT, Bensinger WI, Nademanee A, Liesveld J, Badel K, Dehner C, Gibney C, Bridger G, Calandra G.

Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilizers, including assessment of tumor cell mobilization.
Bone Marrow Transplant. 2010 Jan;45(1):63-8.
Tricot G, Cottler-Fox MH, Calandra G.
20 patients with myeloma who were poor mobilizers received plerixafor for stem cell collection. Apheresis was successful (at least 2 million CD34+ cells/Kg) in 15 patients. Plerixafor did not mobilize myeloma cells.

Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies.
Bone Marrow Transplant. 2013 Oct;48(10):1279-84.
Awan F, Kochuparambil ST, Falconer DE, Cumpston A, Leadmon S, Watkins K, Deremer D, Jillella A, Craig M, Hamadani M.
Mobilization chemotherapy with intermediate-dose cyclophosphamide, 3-4 g/m2 + G-CSF (55 patients) provided a higher median number of stem cells that G-CSF + plerixafor (33 patients): 16.6 vs 11.6 million CD34+ cells/Kg. Although the total cost of collection was higher in the plerixafor group, we should note that 16% of patients in the cyclophosphamide group experienced neutropenic fever.

 

STEM CELL COLLECTION AFTER RADIATION THERAPY

Local irradiation prior to stem cell harvest has no influence on CD34+ yield: a quantitative analysis.
Ann Hematol. 2006 Jan;85(1):38-44.
Rinn JP, Schwella N, Wollmer E, Jaques G, Heinzel-Gutenbrunner M, Strassmann G, Gross MW, Movassaghi K, Neubauer A, Ritter M.
Among 114 patients with multiple myeloma, 53 (47%) patients received RT prior to mobilization chemotherapy. 84% of them received high-dose cyclophosphamide followed by G-CSF. The study found no difference of CD34+ cell counts between irradiated and non-irradiated patients. Dose of RT did not influence the yield of CD34+ cells, but RT decreased the number of mobilized stem cells when the time elapsed since the last irradiation was short.

 

STEM CELL COLLECTION AFTER MELPHALAN

Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma.
Haematologica. 2002 Aug;87(8):846-50.
Boccadoro M, Palumbo A, Bringhen S, Merletti F, Ciccone G, Richiardi L, Rus C, Bertola A, Giaccone L, Omedè P, Musto P.
In this study, 89 patients with myeloma underwent mobilization with cyclophosphamide 3 g/m2 followed by G-CSF 10 mcg/kg from day 3 to the last day of the leukapheresis.
An adequate collection of stem cells (defined as a total of at least 2 million CD34+ cells/Kg) was obtained in 59 patients (66%):
 - 92% of patients treated with non-alkylating therapy (e.g., VAD)
 - 56% of patients treated with oral melphalan
 - 23% of patients treated with IV melphalan
Therefore, patients who are potential candidates for autologous steam cell transplant should not receive conventional alkylating therapy prior to collection of stem cells.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial.
Bone Marrow Transplant. 2005 Mar;35(5):441-7.
Gupta S, Zhou P, Hassoun H, Kewalramani T, Reich L, Costello S, Drake L, Klimek V, Dhodapkar M, Teruya-Feldstein J, Hedvat C, Kalakonda N, Fleisher M, Filippa D, Qin J, Nimer SD, Comenzo RL.
32 patients with multiple myeloma underwent stem cell mobilization with melphalan 60 mg/m2 IV, followed by G-CSF 10 mcg/kg/day.
Results:
  - Median mobilization days: 16 (12-30)
  - Median CD34+ cells/kg: 12.1 million (2.6-52.8) in 2 days (1-5)
  - 4 patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in 5 leukaphereses
  - RR: 34%, with  CR 9%
  - 14 patients (44%) required hospitalization for neutropenic fever

 

STEM CELL COLLECTION AFTER LENALIDOMIDE

Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients.
Leukemia. 2008 Jun;22(6):1280-1.
Mazumder A, Kaufman J, Niesvizky R, Lonial S, Vesole D, Jagannath S.
These authors observed low stem cell yield after lenalidomide induction therapy. With G-CSF 10 mcg/Kg for 4 days, 12 of 28 patients (43%) failed to collect a sufficient number of CD34+ cells/Kg for even one transplant. 3 patients also failed collection after plerixafor. The authors conclude that patients with prior exposure to lenalidomide should undergo mobilization chemotherapy with cyclophosphamide.

Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma.
Leukemia. 2008 Jun;22(6):1282-4.
Paripati H, Stewart AK, Cabou S, Dueck A, Zepeda VJ, Pirooz N, Ehlenbeck C, Reeder C, Slack J, Leis JF, Boesiger J, Torloni AS, Fonseca R, Bergsagel PL.
In this report, 9 of 20 patients (45%) previously treated with lenalidomide failed stem cell collection.

Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.
Biol Blood Marrow Transplant. 2008 Jul;14(7):795-8.
Mark T, Stern J, Furst JR, Jayabalan D, Zafar F, LaRow A, Pearse RN, Harpel J, Shore T, Schuster MW, Leonard JP, Christos PJ, Coleman M, Niesvizky R.
In this study, 28 patients with newly diagnosed myeloma were were treated with clarithromycin, lenalidomide, and dexamethasone (BIRD), and they underwent stem cell collection with either G-CSF or cyclophosphamide + G-CSF. All patients mobilized with cyclophosphamide + G-CSF collected sufficient stem cells for 2 autologous stem cell transplants, whereas only 33% of patients mobilized with G-CSF alone reached the same goal. No correlation was found between duration of prior lenalidomide therapy and success of stem cell collection.

Plerixafor (Mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide.
Bone Marrow Transplant. 2011 Mar;46(3):350-5.
Micallef IN, Ho AD, Klein LM, Marulkar S, Gandhi PJ, McSweeney PA.

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.
Bone Marrow Transplant. 2016 Mar;51(3):372-6. doi: 10.1038/bmt.2015.236. Epub 2015 Oct 5.
Silvennoinen R, Anttila P, Säily M, Lundan T, Heiskanen J, Siitonen TM, Kakko S, Putkonen M, Ollikainen H, Terävä V, Kutila A, Launonen K, Räsänen A, Sikiö A, Suominen M, Bazia P, Kananen K, Selander T, Kuittinen T, Remes K, Jantunen E.
In this randomized study of stem cell collection after induction therapy with lenalidomide, 35 patients received G-CSF10 mcg/Kg, and 34 patients cyclophosphamide 2 g/m2 IV followed by G-CSF 5 mcg/Kg. The target stem cell yield was 3 million CD34+ cells/Kg. The apheresis was started when the circulating CD34+ cells were >10 x10(6) on day +5 with G-CSF or day +10 with cyclophosphamide + G-CSF. The collection with cyclophosphamide was more effective, because the target was achieved in 94% vs 77% of patients.

 

 


 

PURGING

At present time, purging of peripheral blood collection products is not necessary before SCT for multiple myeloma (although some studies have indicated that patients without contaminating myeloma cells in the apheresis products have a clinical advantage).

 

Monoclonal plasma cells in the blood stem cell harvest from patients with multiple myeloma are associated with shortened relapse-free survival after transplantation.
Bone Marrow Transplant. 1997 Feb;19(4):337-42.
Gertz MA, Witzig TE, Pineda AA, Greipp PR, Kyle RA, Litzow MR.
These authors counted the circulating tumor cells in the blood stem cell harvest from 33 myeloma patients. They found that patients with elevated monoclonal plasma cells (0.2 million/L) had a median relapse-free survival of 6.2 months, whereas patients with <0.2 million cells/L had a median relapse-free survival of 22.5 months (p = 0.008). These findings do not necessarily indicate that the circulating plasma cells in the apheresis products were responsible for relapse, because they may only reflect increased tumor burden.

Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
J Clin Oncol. 2001 Sep 1;19(17):3771-9.
Stewart AK, Vescio R, Schiller G, Ballester O, Noga S, Rugo H, Freytes C, Stadtmauer E, Tarantolo S, Sahebi F, Stiff P, Meharchard J, Schlossman R, Brown R, Tully H, Benyunes M, Jacobs C, Berenson R, White M, DiPersio J, Anderson KC, Berenson J.

Negative selection of peripheral blood stem cells to support a tandem autologous transplantation programme in multiple myeloma.
Br J Haematol. 2002 Jan;116(1):202-10.
Barbui AM, Galli M, Dotti G, Belli N, Borleri G, Gritti G, Bellavita P, Viero P, Comotti B, Barbui T, Rambaldi A.
In this study, 60 patients with newly diagnosed multiple myeloma were randomized to receive either unmanipulated or purged stem cells. Negative selection was obtained in vitro by monoclonal antibodies, in order to  eliminate contaminating neoplastic cells. In unmanipulated apheresis products, these authors found a median of 1 tumor cell per 100 normal cells (range: 10-10,000), and manipulation in vitro obtained a 3-4 log reduction. Despite the purging, all patients had minimal residual disease by PCR after stem cell transplant. At 3 years, the event-free survival was 40% in the non-purged arm and 72% in the purged arm (p= 0.05), and there was no difference in overall survival (83% in both arms).

Peripheral blood stem cell contamination evaluated by a highly sensitive molecular method fails to predict outcome of autotransplanted multiple myeloma patients.
Br J Haematol. 2003 Feb;120(3):405-12.
Galimberti S, Morabito F, Guerrini F, Palumbo GA, Azzará A, Martino M, Benedetti E, Di Raimondo F, Petrini M.
Apheresis products from 51 autotransplanted patients were tested by PCR. 69% of harvests were contaminated when evaluated for IgH rearrangement. Median overall survival was 33 months. The survival at 70 months was 72% in patients transplanted with PCR-negative stem cells, and 48% in patients transplanted with contaminated precursors, but the difference was not statistically significant. Purging reduced contamination of up to 3 logs, but 80% of purged harvests remained PCR-positive, and purging did not improve response or survival.

Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.
Haematologica. 2007 Aug;92(8):1083-90.
Bourhis JH, Bouko Y, Koscielny S, Bakkus M, Greinix H, Derigs G, Salles G, Feremans W, Apperley J, Samson D, Björkstrand B, Niederwieser D, Gahrton G, Pico JL, Goldschmidt H; European Group for Blood and Marrow Transplantation.
This multicentre randomized phase III study evaluated the efficacy of CD34+ selection in 111 patients with newly diagnosed myeloma undergoing autologous stem cell transplantation. One group underwent CD34+ selection, which depleted tumor cells by a median of 2.2 logs. No significant difference in terms of 5-year survival, event free survival, and relapse rate was observed between the two groups. Reinfused tumor cells were probably not the cause of relapse after autologous transplant, because of a similar relapse rate between patients who received grafts with detectable tumor cells and those who received grafts with no detectable tumor cells.

Contaminating tumour cells in autologous PBSC grafts do not influence survival or relapse following transplant for multiple myeloma or B-cell non-Hodgkin's lymphoma.
Bone Marrow Transplant. 2009 Feb;43(3):223-8.
Ho J, Yang L, Banihashemi B, Martin L, Halpenny M, Atkins H, Sabloff M, McDiarmid SA, Huebsch LB, Bence-Bruckler I, Giulivi A, Allan DS.
158 patients with either NHL or MM undergoing autologous SCT were assessed for clonal IgH CDR3 gene rearrangements using PCR. No improvement in overall survival (OS) or PFS for MM or NHL was observed in patients with PCR-negative PBSC grafts compared with PCR-positive patients. Since MM patients with contaminating tumour cells in their PBSC  grafts did not have worsened OS or PFS, purging strategies may not be necessary in MM.

Contamination of autologous peripheral blood progenitor cell grafts predicts overall survival after high-dose chemotherapy in multiple myeloma.
J Cancer Res Clin Oncol. 2009 Apr;135(4):637-42.
Kopp HG, Yildirim S, Weisel KC, Kanz L, Vogel W.
This study evaluates the outcomes of 60 patients with multiple myeloma who underwent mobilization chemotherapy + G-CSF, followed by autologous stem cell transplantation. The number of CD38+/CD138+ cells/kg in the apheresis products was determined by flow cytometry. Levels >4.5 x 10,000 plasma cells/kg were defined as "high plasma cell contamination" (16 patients), while lower levels were defined as "low or absent plasma cell contamination" (44 patients). Results:
  - Median PFS was 33.5 months (range: 11-99 months) in the high-contamination group and 47 months (range: 8-148 months) in the low-contamination group (p=0.15)
  - Median overall survival was 53 months (range: 11-119 months) in the high-contamination group and 114 months (range: 8-158 months) in the low-contamination group (p=0.012)
The authors conclude that patients with apheresis products containing >4.5 x 10,000 plasma cells/kg have a significantly reduced overall survival. It was unclear whether the reduced survival in the high contamination group was directly due to the reinfused plasma cells, or instead the high contamination of grafts reflected a higher residual tumor mass or a more aggressive behavior of myeloma cells prior to the stem cell transplant.

Assessment of tumoral plasma cells in apheresis products for autologous stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2016 Aug;51(8):1143-5.
Wuillème S, Lok A, Robillard N, Dupuis P, Stocco V, Migné H, Dusquesne A, Touzeau C, Tiab M, Béné MC, Moreau P.
This is a prospective study that analyzed the clinical outcomes of the contamination of the apheresis products by myeloma plasma cells. 43 patients received 3-4 cycles of induction chemotherapy with a modern triplet regimen, i.e, VTD (bortezomib, thalidomide, dexamethasone), VCD (bortezomib, cyclophosphamide, and dexamethasone), or KRD (carfilzomib, lenalidomide, and dexamethasone). The median number of myeloma plasma cells in the apheresis collections was 0%. With a single-tube, seven-color flow cytometry, 10 (23%) samples showed presence of myeloma plasma cells in the collection products at the time of stem cell collection, with a range of 0.05-76% of the total plasma cell number. At the time of reinfusion, myeloma plasma cells were detectable in 4 of 22 (18%) samples. This difference was not statistically significant, indicating that normal plasma cells and myeloma cells do not behavior differently after thawing. Interestingly, there was a clinical advantage in those patients without contamination by myeloma plasma cells. The progression rate was higher in those patients with contaminating myeloma plasma cells in the apheresis product: after a median follow-up of 15 months, their median progression-free survival was 16 months, whereas it was not reached in the other group of patients.

 

 


Giampaolo Talamo, M.D.