Myeloma

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)

Article metrics

Abstract

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.

Introductory overview

Current status of stem cell mobilization in multiple myeloma

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today.1 High-dose therapy with ASCT remains the treatment associated with the highest complete remission rate and when compared with conventional chemotherapy is associated with improvements in survival. The role of high-dose therapy in the context of novel anti-myeloma therapies such as thalidomide, bortezomib, lenalidomide and combinations is being re-explored, but it is likely that high-dose therapy will remain an important component of frontline and relapsed myeloma therapy for the next 5–10 years. Table 1 demonstrates the myeloma transplant activity as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Group for Blood and Marrow Transplant (EBMT). Of particular interest is the continued increase in the number of autotransplants performed for myeloma, even after the approval of bortezomib and lenalidomide.

Table 1 Transplant activity (a) in North America and Europe as reported to the centers for international blood and marrow transplant research (CIBMTR); (b) in Europe as reported to the European group for blood and marrow transplant (EBMT)

Stem cell procurement for ASCT has traditionally been guided by one of the two strategies:

  1. a)

    Marrow harvesting: involving direct penetration and aspiration of the marrow from the bones (usually the iliac crests) through multiple marrow aspirations to collect a total of 500–1000 ml of a blood and marrow mixture.

  2. b)

    Stem cell mobilization using colony-stimulating factors with or without prior chemotherapy.

Table 2 provides a summary of the current pros and cons of each collection method and the current proportion of patients as reported to the CIBMTR that undergo each procedure.

Table 2 Pros and Cons of commonly used mobilization strategies in patients with myeloma

Stem cell mobilization for myeloma patients is primarily (but not exclusively) performed using filgrastim granulocyte-colony stimulating factor (GCSF) alone or after cyclophosphamide chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy.

With the advent of plerixafor (AMD3100), a novel stem cell mobilization agent, as well as novel induction regimens, it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On 1 June, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma in the context of plerixafor. This article is focused on the current role of ASCT, pros and cons of current mobilization approaches, factors influencing the success of collection and ideal cell doses in the context of plerixafor. The impact of novel agents on the stem cell collection process, possible mechanisms involved and approaches to improve stem cell collection in these patients are not part of this paper but will be addressed in a separate set of recommendations from our group.

Issues in stem cell collection

Is there an optimum CD34+ cell dose to be infused?

In the setting of allogeneic bone marrow transplantation, the beneficial effects of higher stem cell doses as determined by the numbers of nucleated cells or CD34+ cells has been confirmed in multiple retrospective analysis for both T-cell depleted and non-T-cell depleted transplants.2, 3, 4 The improvement in outcomes is due to decreases in non-relapse mortality from improved hematologic reconstitution and lower rates of infection. However, in the setting of allogeneic peripheral blood stem cell transplantation, increases in the CD34+ cell dose infused has not translated into improvement in outcomes in most retrospective analysis. On the contrary, high CD34+ cell doses have been associated with increase in risks of chronic GVHD and increases in mortality, with the possible exception of high risk patients receiving reduced intensity regimens.5, 6, 7, 8

In the setting of autologous peripheral blood stem cell transplantation, CD34+ cell doses of >3 million/kg have been associated with better outcomes, primarily due to faster hematologic recovery and lower incidence of infectious and bleeding complications.9, 10, 11 Bensinger et al demonstrated that infusing doses of <2 million CD34 per kg was associated with slower hematologic recovery and worse outcomes, whereas patients receiving >5 million CD34 per kg seemed to have a faster robust platelet recovery. These data have been used to support the current patterns of practice with a minimal dose of 2 million CD34 per kg and an ‘optimal’ dose of 4–6 million CD34+ cells/kg or greater.9

Studies addressing the impact of the CD34+ cell dose have been primarily retrospective and have included heterogeneous groups of patients receiving a variety of conditioning regimens. Weaver et al11 in 1995 analysed data on 692 patients. A CD34+ cell dose of >5 million CD34+ cells/kg appeared to be optimal, and only doses of >12.5 million CD34+ cells were associated with a faster platelet engraftment. Benedetti et al and Ketterer et al have reported that very large numbers of CD34+ cells/kg (>15 million CD34+ cells/kg) after high-dose melphalan administration can eliminate severe thrombocytopenia and platelet transfusion requirements.12, 13 In most studies, CD34 dose was not associated with different outcomes with the exception of a retrospective study performed by Oran et al14 demonstrating that increasing CD34 doses were associated with improved outcomes in patients with amyloidosis who underwent ASCT. Thus, although retrospective analysis suggests a strong dose–response relationship between CD34+ cell dose and rate of neutrophil and platelet recovery after myeloablative therapy, the impact of the benefit has been small. However, all these studies have been retrospective and included heterogeneous populations of patients receiving a variety of conditioning regimens.

Conclusion

The issue of optimal CD34 dosing in the setting of ASCT for myeloma requires a prospective clinical trial designed to address this issue. The results of such a study could alter the current recommendations for both the threshold and ‘optimal CD34 dosing’ schedules.

Is there an optimal dose of CD34+ cells to be collected?

The current minimal threshold CD34 cell dose to be infused is agreed to be 2 million CD34 cells/kg for a single transplant. However, the current optimal dose for ideal platelet recovery is considered to be 4–6 million CD34 cells/kg.10 Persistent thrombocytopenia post-allogeneic SCT has been associated with severe acute GVHD and poor survival.15 In the setting of autologous transplant, poor platelet recovery post-autologous transplant or secondary platelet failure has been observed in 8% of autograft recipients and was seen in the context of CMV infection or in patients receiving bone marrow as a stem cell source. Secondary failures of platelet recovery were associated with a higher risk of death.16

Conclusion/assessment

The committee suggested that a minimum target of 4 million CD34+ cells/kg be collected and that if feasible an average of 8–10 million CD34+ cells/kg be collected. These targets would allow most patients with myeloma to undergo at least two autografts with an optimal CD34 dose during the course of their disease.

Is there a standard collection strategy for patients with multiple myeloma?

Table 3 summarizes the most recent studies looking at a variety of strategies for stem cell collection in myeloma. Most of these studies have been retrospective and involved small number of patients.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Notwithstanding these drawbacks, the following conclusions are reasonable based on the evidence available:

Table 3 Representative studies of various mobilization strategies13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24

Conclusion/assessment

  1. a)

    Both GCSF alone (non-pegylated) or chemotherapy followed by GCSF are reasonable strategies for stem cell collection. The data regarding stem cell collection after single agent pegylated GCSF is much more limited than for non-pegylated GCSF, but supports the use of this agent for stem cell collection.

  2. b)

    Most trials suggest that more CD34+ cells can be collected after chemomobilization than after GCSF only mobilization. However, the failure rate (in terms of ‘minimal collection criteria’ noted above) with chemomobilization is similar to the failure rate with GCSF alone. In addition, chemomobilization has not demonstrated superior outcomes.18

  3. c)

    Higher doses of cyclophosphamide are associated with more toxicity, and doses over 4 g/m2 probably offer no benefit.

  4. d)

    Novel mobilization strategies need to be further explored looking at improving yields, efficiency, and cost issues.

  5. e)

    Impact of novel mobilization strategies on graft constitution and the relevance of graft constitution to transplant outcomes also require further research.

  6. f)

    Collections should be attempted between the second and fourth induction cycle regardless of response to therapy. In patients who have primary refractory myeloma without response to combinations including novel agents, mobilization with chemotherapy and GCSF is the practice.

What factors predict successful stem cell collection?

Very few studies have systematically assessed all known risk factors that can impact stem cell collection. Most retrospective studies addressing mobilization have identified patient age, method of mobilization, time to stem cell mobilization, number of prior regimens, and prior melphalan and/or radiation exposure as predictors of mobilization failing to achieve a minimal dose.29, 30, 31, 32, 33, 34, 35

More recently, exposure to lenalidomide has been associated with failure to mobilize adequate numbers of stem cells using growth factors alone. This inability to collect may be overcome by chemomobilization.31, 32, 33, 34 This may have an impact on the choice of induction therapy. It should be noted, however, that preliminary data indicate successful harvest with the addition of plerixafor in 85% of 50 patients previously treated with lenalidomide who failed to collect 2 million CD34+ cells with G-CSF alone (preliminary findings: CUP post hoc analysis).

Likewise, the negative effects of limited melphalan exposure should also be revisited due to the impressive results of melphalan in combination with bortezomib, thalidomide, or lenalidomide.35, 36 Table 4 summarizes the known risk factors and potential strategies to enhance stem cell collection when present.

Table 4 Risk factors for poor stem cell mobilization and potential strategies to overcome them

What will be the impact of plerixafor on stem cell collection strategies in myeloma?

Plerixafor is a bicyclam molecule that inhibits the SDF-1 alpha/CXCR4 binding that occurs between CD34+ stem cells and the marrow stroma. The inhibition of this interaction results in the release of CD34+ stem cells into the blood stream facilitating their collection through apheresis methods.37 Plerixafor in combination with GCSF resulted in increased CD34+ cell mobilization and was shown to be effective in mobilizing adequate stem cells in patients who had failed traditional mobilization techniques (Hard to Mobilize). Plerixafor also decreased the number of apheresis procedures needed to reach the target CD34+ cell dose in most patients.38 Plerixafor in combination with GCSF has also been shown to be more effective as an initial mobilizing regimen than GCSF alone in patients with multiple myeloma.39 The combination of plerixafor plus GCSF resulted in 72% of patients achieving a collection goal of 6 million or more CD34+ per kg in 2 or fewer apheresis procedures versus only 34% for patients receiving GCSF and placebo. Patients achieved 6 million CD34+ cells/kg in a median of 3 fewer days with plerixafor versus G-CSF alone, and collected 3 × as many cells on day 1 than with G-CSF alone (median 6.86 million versus 2.29 million).40 See Table 5 for the potential benefits of plerixafor. The use of plerixafor was both safe and predictable (in terms of cell yields) as a mobilization agent.

Table 5 Potential benefits of plerixafor

Conclusion/assessment

The committee recognized that more studies needed to be done with this agent to better define its role in the treatment of myeloma. These studies need to incorporate pharmacoeconomics and resource utilization endpoints.

What will be the role of high-dose therapy and autologous stem cell transplant for myeloma in the era of novel therapies?

The current paradigm for therapy in multiple myeloma involves determining whether a patient is considered a potential candidate for high-dose therapy consolidation or not. Patients who are considered candidates for high-dose therapy receive induction therapies without melphalan (to prevent stem cell damage). After an average of 2–4 cycles, stem cells are collected and most patients proceed to high-dose melphalan therapy followed by autologous stem cell infusion.

This paradigm is supported by the results of multiple randomized trials demonstrating a higher complete remission rate and longer event-free survival in high-dose therapy recipients.41 With the advent of novel induction therapies containing either bortezomib, lenalidomide or combinations that result in complete remission rates of up to 30% and VGPR rates of over 50%, the role of both single and tandem high-dose therapy consolidation for transplant eligible patients needs to be re-explored in the context of well designed clinical trials. An important aspect of new trials will be the role of planned up front transplant versus transplant at the time of subsequent relapse. In addition, the value of a major response, such as VGPR, using novel induction strategies and the subsequent need to perform transplantation or not deserve further study. Both the timing and number of transplants recommended continue to be controversial.

Conclusion/assessment

The general consensus from the advisory board was that high-dose melphalan was still recommended for eligible patients, and that stem cell collection early in the course of therapy should be attempted in all transplant eligible patients. The advisory board recommended more studies looking at optimizing collection strategies after exposure to novel therapies (particularly lenalidomide-based combinations) with plerixafor and G-CSF or plerixafor plus chemotherapy.

There is considerable interest in the role of novel transplant approaches combined with the new induction strategies. Longer term follow-up is required to assess the ultimate impact of the various approaches to therapy.

In the United States, certain financial considerations also need to be taken into account particularly that some third party payers (that is, Medicare and some private insurance carriers) do not pay for ‘harvest and hold’ nor is tandem autografting routinely covered.

Under what circumstances is double autologous transplant considered, for example, as part of a protocol?

Although various randomized trials and retrospective analysis have shown that tandem autologous transplant have a superior event-free survival than single transplants, the benefit may not apply in the era of novel therapies.42, 43, 44 Likewise, the benefit of tandem transplants may be limited to patients failing to achieve at least a 90% reduction of tumor burden after the initial induction and first high-dose therapy consolidation.42, 43 Second, the use of post-transplant maintenance with thalidomide may abrogate the benefits of a second autograft as demonstrated by Abdelkafi et al.45 The use of second autologous transplants as salvage therapy for some patients has been shown to result in long disease-free intervals in patients with long remission after their first autograft.46

The committee recognized that the role of tandem transplantation will need to be reevaluated in the era of IMID's and proteosome inhibitors. This can only be done in the context of well done prospective trials. Recent meta-analysis, as well as post hoc analysis of previously performed randomized trials have been criticized due to lack of statistical power or methodologic flaws.47, 48

Conclusion/assessment

The consensus of the advisory board was that double autologous transplant has a place in clinical trials, primarily in younger patients. In practice, a second transplant may be replaced by novel agents, or be considered, for example, if there was no response to therapy with novel agents and a first transplant. High response rates with combination therapies including bortezomib, lenalidomide, thalidomide, and alkylators were noted.

The age limit for transplant was also discussed in the context of a delayed transplant translating into older patients receiving high-dose therapy as salvage therapy. The differences between North America and Europe were noted, and the fact that age per se is not an adequate criterion for determining therapy was noted. Further study of plerixafor and GCSF mobilization is particularly warranted in older myeloma patients deemed eligible for high-dose therapy.

Is mini allogeneic transplant still a research therapy?

The committee agreed that this strategy may be useful for some young patients with compatible siblings depending on the patient's response to therapy and other prognostic factors. The current literature provides conflicting data. The results of the prospective IFM trials in high risk patients demonstrated no benefit for an auto/mini allo strategy in regards to overall and event-free survival.49 These results contrast with retrospective analysis demonstrating a potential benefit of allografting for some subsets of patients with specific cytogenetics abnormalities and cannot be compared with the results obtained by the Italian group that demonstrated a survival and event-free survival benefit for recipients of the auto/mini allo approach as the Italian study included all patients in their analysis.50 The Spanish Group performed a study looking at the role of a second autograft versus a reduced intensity allograft in patients failing to achieve a very good partial response after initial induction therapy and high dose consolidation and reported a higher CR rate for the recipients of the reduced intensity allograft, but no improvement in survival.51 Allografting has been reported to change the prognostic implications of some of the poor risk cytogenetic profiles.52

Conclusion/assessment

All these studies involved relatively small number of patients, the large North American Trial performed through the Blood and Marrow Transplant Clinical Trials Network will provide invaluable information regarding this issue, but the results will not be available for 2 years. In the meantime, allografting should continue to be explored in the context of clinical trials in carefully selected patients as frontline therapy or as salvage therapy.

What are the main goals of autologous transplant?

As for other forms of therapy, the goals of autologous transplant are to achieve the maximum depth and duration of response leading to the best overall survival.

The target depth of response surrogate varies from trial to trial. Although CR is a target, the new uniform response criteria identify VGPR plus CR as a better collective category for cross-trial comparisons. In addition, stringent CR (sCR) may prove to be a more decisive and predictive endpoint.53

It is recognized that PR and/or VGPR populations can include patients with post-therapy MGUS states with a good prognosis. Thus, detailed prognostic factor and risk assessment are required to fully evaluate short- and long-term outcomes.

Executive summary

Multiple myeloma is the most common indication for ASCT in the world today. Its role in the context of novel therapies, however, is currently being re-explored. Although high-dose therapy will remain an important component of anti-myeloma therapy, whether it will be considered as consolidation for all eligible patients or used more as salvage therapy remains to be defined. Notwithstanding, optimizing stem cell collection either early or later in the course of the disease will be an integral component of myeloma treatment planning. The advent of Plerixafor (a novel stem cell mobilization agent) as well as novel induction regimens will likely change the current standards for stem cell transplant and mobilization. How these standards will change depend on the result of current and future prospective trials. Likewise, current standards regarding optimal CD34 dose for autografting in myeloma may need to be re-explored particularly if prospective trials determine that higher doses of CD34+ cells impact patient outcomes (such as quality of life, post-transplant symptom burden, and hematopoietic recovery).

Conflict of interest

S Giralt: Advisory Board for Celgene, Millennium, Novartis, and Genzyme; E Stadtmauer: Advisory Board for Genzyme; J Harousseau: Received Honoraria from Genzyme and Amgen, Advisory Board for Celgene and Janssen-Cilag; A Palumbo: Advisory Board for Ortho Biotech and Celgene; W Bensinger: Advisory Board for Celgene and Millennium, Research funding from Genzyme, Millennium, Celgene, AstraZeneca and Novartis; R Comenzo: Advisory Board for Millennium and Ortho Biotech; S Kumar: Clinical trial funding from Celgene, Millennium, Genzyme; N Munshi: Advisory Board for Celgene; R Kyle: No disclosures; J San Miguel: Advisory Board for Millennium, Janssen-Cilag, and Celgene; H Ludwig: Clinical trial funding from Schering-Plough, Janssen-Cilag, and participation in Speaker's Bureau for Amgen, Roche, Janssen-Cilag; J Blade: Honorarium for lectures and Advisory Board for Celgene, Janssen-Cilag. Research grant from Celgene; S Lonial: Consultant for Millennium, Celgene, Novartis, and BMS; H Einsele: Advisory Board for Celgene and Ortho Biotech; P Tosi: No disclosures; P Sonneveld: Advisory Board for Ortho Biotech and Celege; O Sezer: Clinical trial/research funding from Janssen-Cilag, Merck, and Novartis. Speaker's Bureau for Amgen, Celgene, Merck, Novartis, Ortho Biotech, Pharmion, and Roche; M Cavo: No disclosures; P Richardson: Advisory Board for Celgene and Millennium; SV Rajkumar: No disclosures; B Durie: Advisory Board for Celgene and Millennium.

References

  1. 1

    Pasquini MC, He V, Perez WS . CIBMTR summary slides part 1. CIBMTR Newsletter 2006; 12: 5–7.

  2. 2

    Mavroudis D, Read E, Cottler-Fox M, Couriel D, Molldrem J, Carter C et al. CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies. Blood 1996; 88: 3223–3229.

  3. 3

    Bittencourt H, Rocha V, Chevret S, Socié G, Espérou H, Devergie A et al. Association of CD34 cell dose with hematopoietic recovery, infections, and other outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 99: 2726–2733.

  4. 4

    Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose. Blood 1997; 89: 4226–4235.

  5. 5

    Przepiorka D, Smith TL, Folloder J, Khouri I, Ueno NT, Mehra R et al. Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 1999; 94: 1465–1470.

  6. 6

    Perez-Simon JA, Diez-Campelo M, Martino R, Sureda A, Caballero D, Canizo C et al. Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Blood 2003; 102: 1108–1113.

  7. 7

    Zaucha R, Gooley T, Bensinger WI, Heimfeld S, Chauncey TR, Zaucha R et al. CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation. Blood 2001; 98: 3221–3227.

  8. 8

    Mohty M, Bilger K, Jourdan E, Kuentz M, Michallet M, Bourhis JH et al. Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation. Leukemia 2003; 17: 869–875.

  9. 9

    Desikan KR, Tricot G, Munshi NC, Annaissie E, Spoon D, Fassas A et al. Preceding chemotherapy, tumour load and age influence engraftment in multiple myeloma patients mobilized with granulocyte colony-stimulating factor alone. Br J Haematol 2001; 112: 242–247.

  10. 10

    Bensinger W, Appelbaum F, Rowley S, Storb R, Sanders J, Lilleby K et al. Factors that influence collection and engraftment of autologous peripheral blood-stem cells. J Clin Oncol 1995; 13: 2547–2555.

  11. 11

    Weaver CH, Hazelton B, Birch R, Palmer P, Allen C, Schwartzberg L et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood 1995; 86: 3961–3969.

  12. 12

    Benedetti G, Patoia L, Giglietti A, Alessio M, Pelicci P, Grignani F . Very large amounts of peripheral blood progenitor cell eliminate severe thrombocytopenia after high-dose melphalan in advanced breast cancer patients. Bone Marrow Transplant 1999; 24: 971–979.

  13. 13

    Ketterer N, Salles G, Raba M, Espinouse D, Sonet A, Tremisi P et al. High CD34+ cell counts decrease hematologic toxicity of autologous peripheral blood progenitor cell transplantation. Blood 1998; 91: 3148–3155.

  14. 14

    Oran B, Malek K, Sanchorawala V, Wright DG, Quillen K, Finn KT et al. Predictive factors for hematopoietic engraftment after autologous peripheral blood stem cell transplantation for AL amyloidosis. Bone Marrow Transplant 2005; 35: 567–575.

  15. 15

    Kim DH, Sohn SK, Jeon SB, Baek JH, Kim JG, Lee NY et al. Prognostic significance of platelet recovery pattern after allogeneic HLA-identical sibling transplantation and its association with severe acute GVHD. Bone Marrow Transplant 2006; 37: 101–108.

  16. 16

    Bruno B, Gooley T, Sullivan KM, Davis C, Bensinger WI, Storb R et al. Secondary failure of platelet recovery after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: 154–162.

  17. 17

    Desikan KR, Barlogie B, Jagannath S, Vesole DH, Siegel D, Fassas A et al. Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma. J Clin Oncol 1998; 16: 1547–1553.

  18. 18

    Alegre A, Tomás JF, Martínez-Chamorro C, Gil-Fernández JJ, Fernández-Villalta MJ, Arranz R et al. Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone. Bone Marrow Transplant 1997; 20: 211–217.

  19. 19

    Demirer T, Ayli M, Ozcan M, Gunel N, Haznedar R, Dagli M et al. Mobilization of peripheral blood stem cells with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF): a randomized evaluation of different doses of rhG-CSF. Br J Haematol 2002; 116: 468–474.

  20. 20

    Arora M, Burns LJ, Barker JN, Miller JS, Defor TE, Olujohungbe AB et al. Randomized comparison of granulocyte colony-stimulating factor versus granulocyte-macrophage colony-stimulating factor plus intensive chemotherapy for peripheral blood stem cell mobilization and autologous transplantation in multiple myeloma. Biol Blood Marrow Transplant 2004; 10: 395–404.

  21. 21

    Gojo I, Guo C, Sarkodee-Adoo C, Meisenberg B, Fassas A, Rapoport AP et al. 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; 34: 69–76.

  22. 22

    Dingli D, Nowakowski GS, Dispenzieri A, Lacy MQ, Hayman S, Litzow MR et al. Cyclophosphamide mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma. Clin Lymphoma Myeloma 2006; 6: 384–388.

  23. 23

    Lefrère F, Zohar S, Ghez D, Delarue R, Audat F, Suarez F et al. The VAD chemotherapy regimen plus a G-CSF dose of 10 microg/kg is as effective and less toxic than high-dose cyclophosphamide plus a G-CSF dose of 5 microg/kg for progenitor cell mobilization: results from a monocentric study of 82 patients. Bone Marrow Transplant 2006; 37: 725–729.

  24. 24

    Bruns I, Steidl U, Kronenwett R, Fenk R, Graef T, Rohr UP et al. A single dose of 6 or 12 mg of pegfilgrastim for peripheral blood progenitor cell mobilization results in similar yields of CD34+ progenitors in patients with multiple myeloma. Transfusion 2006; 46: 180–185.

  25. 25

    Barlogie B, Anaissie E, van Rhee F, Pineda-Roman M, Zangari M, Shaughnessy J et al. The Arkansas approach to therapy of patients with multiple myeloma. Best Pract Res Clin Haematol 2007; 20: 761–781.

  26. 26

    Hiwase DK, Bollard G, Hiwase S, Bailey M, Muirhead J, Schwarer AP . Intermediate-dose CY and G-CSF more efficiently mobilize adequate numbers of PBSC for tandem autologous PBSC transplantation compared with low-dose CY in patients with multiple myeloma. Cytotherapy 2007; 9: 539–547.

  27. 27

    Zappasodi P, Nosari AM, Astori C, Ciapanna D, Bonfichi M, Varettoni M et al. DCEP chemotherapy followed by a single, fixed dose of pegylated filgrastim allows adequate stem cell mobilization in multiple myeloma patients. Transfusion 2008; 48: 857–860.

  28. 28

    Pelus LM . Peripheral blood stem cell mobilization: new regimens, new cells, where do we stand. Curr Opin Hemato 2008; 15: 285–292.

  29. 29

    Perea G, Sureda A, Martino R, Altés A, Martínez C, Cabezudo E et al. Predictive factors for a successful mobilization of peripheral blood CD34+ cells in multiple myeloma. Ann Hematol 2001; 80: 592–597.

  30. 30

    de la Rubia J, Blade J, Lahuerta JJ, Ribera JM, Martínez R, Alegre A et al. Effect of chemotherapy with alkylating agents on the yield of CD34+ cells in patients with multiple myeloma. Results of the Spanish Myeloma Group (GEM) Study. Haematologica 2006; 91: 621–627.

  31. 31

    Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Fuadi SK, Gastineau DA et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007; 21: 2035–2042.

  32. 32

    Mazumder A, Kaufman J, Niesvizky R, Lonial S, Vesole D, Jagannath S . Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia 2007; 22: 1280–1281.

  33. 33

    Paripati H, Stewart AK, Cabou S, Dueck A, Zepeda VJ, Pirooz N et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia 2008; 22: 1282–1284.

  34. 34

    Mark T, Stern J, Furst J, Jayabalan D, Zafar F, LaRow A et al. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Biol Blood Marrow Transplant 2008; 14: 795–798.

  35. 35

    Tricot G, Jagannath S, Vesole D, Nelson J, Tindle S, Miller L et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood 1995; 85: 588–596.

  36. 36

    Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callera V et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized, controlled trial. Blood 2008; 112: 3107–3114.

  37. 37

    Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica 2008; 93: 560–565.

  38. 38

    Grignani G, Perissinotto E, Cavalloni G, Carnevale Schianca F, Aglietta M . Clinical use of AMD3100 to mobilize CD34+ cells in patients affected by non-Hodgkin's lymphoma or multiple myeloma. J Clin Oncol 2005; 23: 3871–3872.

  39. 39

    Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, McCarty JM, Rowley SD et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 2005; 106: 1867–1874.

  40. 40

    Dipersio JF, Stadtmauer EA, Nademanee AP, Stiff P, Micallef I, Angell J et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, comparative trial of AMD3100 (Perixafor) + G-CSF vs G-CSF + placebo for mobilization in multiple myeloma (MM) patients for autologous hematopoietic stem cell (aHSC) transplantation. Blood 2007; 110 abstract 445, 137a.

  41. 41

    Koreth J, Cutler CS, Djulbegovic B, Behl R, Schlossman RL, Munshi NC, Richardson PG et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 2007; 3: 183–196.

  42. 42

    Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349: 2495–2502.

  43. 43

    Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007; 25: 2434–2441.

  44. 44

    Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135: 158–164.

  45. 45

    Abdelkafi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB et al. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 2008; 111: 1805–1810.

  46. 46

    Mehta J, Tricot G, Jagannath S, Ayers D, Singhal S, Siegel D et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft. Bone Marrow Transplant 1998; 21: 887–892.

  47. 47

    Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B . Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 2009; 21: 100–106.

  48. 48

    Mehta J, Singhal S . Current status of autologous hematopoietic stem cell transplantation in myeloma. Bone Marrow Transplant 2008; 42 (Suppl 1): S28–S34.

  49. 49

    Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: 3474–3480.

  50. 50

    Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.

  51. 51

    Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: 3591–3593.

  52. 52

    Schilling G, Hansen T, Shimoni A, Zabelina T, Pérez-Simón JA, Gutierrez NC et al. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia 2008; 22: 1250–1255.

  53. 53

    Durie BGM, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2008; 20: 1467–1473.

Download references

Author information

Correspondence to S Giralt.

Appendix

Appendix

International Myeloma Working Group

Rafat Abonour, Indiana University School of Medicine, Indianapolis, IN, USA

Ray Alexanian, MD Anderson, Houston, TX, USA

Kenneth Anderson, DFCI, Boston, MA, USA

Michael Attal, Purpan Hospital, Toulouse, France

Herve Avet-Loiseau, Institute de Biologie, Nantes, France

Ashraf Badros, University of Maryland, Baltimore, MD, USA

Leif Bergsagel, Mayo Clinic Scottsdale, Scottsdale, AZ, USA

Joan Bladé, Hospital Clinica, Barcelona, Spain

Bart Barlogie, M.I.R.T. UAMS Little Rock, AR, USA

Regis Batille, Institute de Biologie, Nantes, France

Meral Beksac, Ankara University, Ankara, Turkey

Andrew Belch, Cross Cancer Institute, Alberta, Canada

Bill Bensinger, Fred Hutchinson Cancer Center, Seattle, WA, USA

Mario Boccadoro, University of Torino, Torino, Italy

Michele Cavo, Universita di Bologna, Bologna, Italy

Wen Ming Chen, MM Research Center of Beijing, Beijing, China

Tony Child, Leeds General Hospital, Leeds, United Kingdom

James Chim, Department of Medicine, Queen Mary Hospital, Hong Kong

Ray Comenzo, Memorial Sloane-Kettering, New York City, NY, USA

John Crowley, Cancer Research and Biostatistics, Seattle, WA, USA

William Dalton, H. Lee Moffitt, Tampa, FL, USA

Faith Davies, Royal Marsden Hospital, London, England

Cármino de Souza, Univeridade de Campinas, Caminas, Brazil

Michel Delforge, University Hospital Gasthuisberg, Leuven, Belgium

Meletios Dimopoulos, Alexandra Hospital, Athens, Greece

Angela Dispenzieri, Mayo Clinic, Rochester, MN, USA

Brian GM Durie, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA

Hermann Einsele, Universitätsklinik Würzburg, Würzburg, Germany

Thierry Facon, Centre Hospitalier Regional Universitaire de Lille, Lille, France

Dorotea Fantl, Socieded Argentinade Hematolgia, Buenos Aires, Argentina

Jean-Paul Fermand, Hopitaux de Paris, Paris, France

Rafael Fonseca, Mayo Clinic Scottsdale, Scottsdale, AZ, USA

Gosta Gahrton, Karolinska Institute for Medicine, Huddinge, Sweden

Morie Gertz, Mayo Clinic, Rochester, MN, USA

John Gibson, Royal Prince Alfred Hospital, Sydney, Australia

Hartmut Goldschmidt, University Hospital Heidelberg, Heidelberg, Germany

Philip Greipp, Mayo Clinic, Rochester, MN, USA

Roman Hajek, Brno University, Brno, Czech Republic

Izhar Hardan, Tel Aviv University, Tel Aviv, Israel

Jean-Luc Harousseau, Institute de Biologie, Nantes, France

Hiroyuki Hata, Kumamoto University Hospital, Kumamoto, Japan

Yutaka Hattori, Keio University School of Medicine, Tokyo, Japan

Joy Ho, Royal Prince Alfred Hospital, Sydney, Australia

Vania Hungria, Clinica San Germano, Sao Paolo, Brazil

Shinsuke Ida, Nagoya City University Medical School, Nagoya, Japan

Peter Jacobs, Constantiaberg Medi-Clinic, Plumstead, South Africa

Sundar Jagannath, St Vincent's Comprehensive Cancer Center, New York, NY, USA

Hou Jian, Shanghai Chang Zheng Hospital, Shanghai, China

Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia

Michio Kawano, Yamaguchi University, Ube, Japan

Nicolaus Kröger, University Hospital Hamburg, Hamburg, Germany

Shaji Kumar, Department of Hematology, Mayo Clinic, MN, USA

Robert Kyle, Department of Laboratory Med. and Pathology, Mayo Clinic, MN, USA

Juan Lahuerta, Grupo Espanol di Mieloma, Hospital Universitario, Madrid, Spain

Jae Hoon Lee, Gachon University Gil Hospital, Incheon, Korea

Xavier LeLeu, Hospital Huriez, CHRU Lille, France

Suzanne Lentzsch, UPMC Cancer Pavillion, Pittsburgh, PA, USA

Henk Lokhorst, University Medical Center Utrecht, Utrecht, The Netherlands

Sagar Lonial, Emory University School of Medicine, Atlanta, GA, USA

Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna, Austria

Angelo Maiolino, Rua fonte da Saudade, Rio de Janeiro, Brazil

María-Victoria Mateos, University Hospital of Salamanca, Spain

Jayesh Mehta, Northwestern University, Chicago, IL, USA

GianPaolo Merlini, University of Pavia, Pavia, Italy

Joseph Mikhael, Mayo Clinic, Scottsdale, AZ, USA

Philippe Moreau, University Hospital, Nantes, France

Gareth Morgan, Royal Marsden Hospital, London, England

Nikhil Munshi, Diane Farber Cancer Institute, Boston, MA, USA

Yana Novis, Hospital SírioLibanês, Bela Vista, Brazil

Amara Nouel, Hospital Rutz y Paez, Bolivar, Venezuela

Robert Orlowski, MD Anderson, Houston, TX, USA

Antonio Palumbo, Cathedra Ematologia, Torino, Italy

Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina

Linda Pilarski, University of Alberta, Alberta, Canada

Raymond Powles, Leukaemia and Myeloma, Wimbledon, England

Ruben Niesvizky, Weill Medical College of Cornell University, New York, NY, USA

S Vincent Rajkumar, Mayo Clinic, Rochester, MN, USA

Donna Reece, Princess Margaret, Toronto, Canada

Tony Reiman, Cross Cancer Institute, Alberta, Canada

Paul Richardson, Dana Farber Cancer Institute, Boston, MA, USA

Angelina Rodriquez Morales, Bonco Metro Politano de Sangre, Caracas, Venezuela

Orhan Sezer, Department of Hem/Onc, Universitatsklinikum Charite, Berlin, Germany

John Shaughnessy, M.I.R.T. UAMS, Little Rock, AR, USA

Kazuyuki Shimizu, Nagoya City Midori General Hospital, Nagoya, Japan

David Siegel, Hackensack, Cancer Center, Hackensack, NJ, USA

Jesus San Miguel, University of Salamanca, Salamanca, Spain

Chaim Shustik, McGill, Toronto, Canada

Seema Singhal, Northwestern University, Chicago, IL, USA

Pieter Sonneveld, Erasmus MC, Rotterdam, The Netherlands

Andrew Spencer, The Alfred Hospital, Melbourne, Australia

Edward Stadtmauer, University of Pennsylvania, Philadelphia, PA, USA

Keith Stewart, Mayo Clinic Scottsdale, Scottsdale, AZ, USA

Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia Seragnoli, Bologna, Italy

Guido Tricot, Huntsman Cancer Institute, Salt Lake City, UT, USA

Ingemar Turesson, Department of Hematology, Malmo University, Malmo, Sweden

Brian Van Ness, University of Minnesota, Minneapolis, MN, USA

Ivan Van Riet, Brussels Vrija University, Brussels, Belgium

Robert Vescio, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA

David Vesole, Loyola University Chicago, IL, USA

Anders Waage, University Hospital, Trondheim, Norway NSMG

Michael Wang, M.D. Anderson, Houston, TX, USA

Donna Weber, MD Anderson, Houston, TX, USA

Jan Westin, Sahlgrenska University Hospital, Gothenburg, Sweden

Keith Wheatley, University of Birmingham, Birmingham, United Kingdom

Dina B Yehuda, Department of Hematology, Hadassah University Hospital, Hadassah, Israel

Jeffrey Zonder, SWOG, Department of Hem/Onc, Karmanos Cancer Institute, MI, USA

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • myeloma
  • plerixafor
  • stem cell collection
  • high-dose therapy
  • IMWG
  • guidelines

Further reading