influence of thalidomide treatment on peripheral

Leukemia (2007) 21, 1294–1299 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu

ORIGINAL ARTICLE Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield I Breitkreutz1,11, HM Lokhorst2, MS Raab1, B van der Holt3, FW Cremer1, D Herrmann4, A Glasmacher5, IGH Schmidt-Wolf5, IW Blau6, H Martin7, H Salwender8, A Haenel9, P Sonneveld10 and H Goldschmidt1 1

Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 2Department of Hematology, University Medical Center, Utrecht, The Netherlands; 3Department of Trials & Statistics-HOVON Data Center, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; 4Cytonet GmbH, Heidelberg, Germany; 5Department of Internal Medicine I, University of Bonn, Bonn, Germany; 6Department of Internal Medicine III; CBF, University of Berlin, Berlin, Germany; 7 Department of Internal Medicine; University of Frankfurt, Frankfurt, Germany; 8Department of Internal Medicine, AKA, Hamburg, Germany; 9Department of Internal Medicine III, Clinic Chemnitz GmbH, Chemnitz, Germany and 10Department of Hematology, Erasmus University Medical Center Rotterdam, The Netherlands

In a phase III randomized, multicenter study, the Germanspeaking Myeloma-Multicenter Group (GMMG) and the DutchBelgian Hemato-Oncology Cooperative Group (HOVON) group investigated the influence of thalidomide (Thal) on the outcome of peripheral blood stem cell (PBSC) collection in multiple myeloma (MM) before peripheral autologous blood stem cell transplantation (ABSCT). We analyzed the data of 398 myeloma patients after induction with Thal, doxorubicin and dexamethasone (TAD) in comparison with vincristine, doxorubicin and dexamethasone (VAD) followed by mobilization with cyclophosphamide, doxorubicin, dexamethasone (CAD) and PBSC collection. Within both the study groups, patients treated with TAD showed to collect significantly fewer CD34 þ cells compared with VAD (GMMG, TAD: median 9.8 106/kg; range 2.0–33.6; VAD: median 10.9 106/kg range 3.0–36.0; P ¼ 0.02) (HOVON, TAD: median 7.4 106/kg; range 2.0–33.0; VAD: median 9.4 106/kg; range 0.0–48.7; P ¼ 0.009). However, engraftment after peripheral autologous stem cell transplantation showed no difference between Thal and VAD groups. We conclude that Thal as a part of induction regimen is associated with better response rates (GMMG-HD3: CR/PR 79%, VAD: CR/PR 58%; HOVON-50: TAD: CR/PR 81%, VAD: CR/PR 61%), but significantly affects the yield of PBSC collection. Nevertheless, the number of total CD34 þ cells collected was sufficient for double autologous transplantation in 82% of the Thal patients, with at least 2.5 106/kg CD34 þ cells. Leukemia (2007) 21, 1294–1299. doi:10.1038/sj.leu.2404661; published online 22 March 2007 Keywords: multiple myeloma; thalidomide; initial therapy; peripheral blood stem cell collection; hematopoetic reconstitution; autologous blood stem cell transplantation

Introduction Multiple myeloma (MM) is an incurable disease that accounts for approximately 1% of all malignancies and 10% of all hematological cancers. High-dose therapy with melphalan and autologous blood stem cell transplantation (ABSCT) improve the Correspondence: Dr I Breitkreutz, Dana-Farber Cancer Institute, The Jerome Lipper Multiple Myeloma Center, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. E-mail: [email protected] 11 Iris Breitkreutz, MD, performed this work at the University of Heidelberg, Department of Hematology/Oncology, INF 410, 69120 Heidelberg, Germany. Received 29 September 2006; revised 15 February 2007; accepted 21 February 2007; published online 22 March 2007

complete remission as well as the event-free and overall survival rates.1 Thalidomide (Thal) is used for the treatment of erythema nodosum leprae and cachexia from acquired immunodeficiency syndrome as well as therapy for MM patients with relapsed, refractory, or previously untreated disease.2–5 The remarkable anti-myeloma effect of Thal has been well described and is the result of targeting both MM cells and their bone marrow microenvironment, which leads to inhibition of MM cell growth, proliferation, adhesion and anti-angiogenesis.2,6 The protocol of the German-speaking Myeloma-Multicenter Group (GMMGHD3) and of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON-50) investigates in a multicenter phase 3 trial the effect of Thal on survival and outcome of MM patients in a high-dose chemotherapy therapy setting with maintenance therapy.7 As successful peripheral blood stem cell (PBSC) collection remains a key factor for a high-dose chemotherapy strategy, we here investigate the influence of Thal on PBSC collection analyzing the data of 398 MM patients enrolled in the GMMG-HD3- and HOVON-50 trial, respectively.

Materials and methods Inclusion criteria of the GMMG-HD3 group (Germany, Austria and Switzerland) and the HOVON-50 study (The Netherlands and Belgium) were newly diagnosed MM with Salmon & Durie stage II and III, age 18–65 years inclusive, WHO performance status 0–3, negative test for pregnancy and written informed consent according to the Declaration of Helsinki. Patients with pretreatment of p2 courses with alkylating agents and local radiotherapy with adequate blood count reconstitution were accepted. We analyzed PBSC collection data from 398 patients of the GMMG-HD3- and HOVON-50 trial. Patients were randomized to receive either VAD or TAD. VAD consisted of three cycles of vincristine 0.4 mg/day intravenous (i.v.), 30 min on days 1–4), doxorubicin 9 mg/m2/day (i.v., 30 min on days 1–4) and dexamethasone 40 mg orally (days 1–4, 9–12, 17–20). TAD consisted of Thal (100–400 mg/day), doxorubicin 9 mg/m2/ day (i.v., 30 min on days 1–4) and dexamethasone 40 mg orally (days 1–4, 9–12, 17–20). Thal dose escalation was administered in case of good tolerability up to 400 mg/day orally (GMMGHD3) and 200 mg/day (HOVON-50), respectively. Second and third courses of VAD/TAD were started at days 29 and 57. Lowmolecular-weight heparin (LMWH, nadroparine 2850 IU, 5700 IU 490 kg, subcutaneous (s.c.) was administered to patients

Thalidomide in multiple myeloma I Breitkreutz et al

1295 receiving TAD from day 1 of induction therapy. Thal was stopped 2 weeks and LMWH 1 week before mobilization chemotherapy. Of the 398 patients, 193 had been randomized to TAD and 205 patients to VAD group. Stem cells were mobilized with CAD (cyclophosphamide 1 g/m2/day, i.v., on day 1; doxorubicin 15 mg/m2/day, i.v., on days 1–4; dexamethasone 40 mg orally, days 1–4) and granulocyte colonystimulating factor (G-CSF) (Filgrastim 600 mg/day or Lenograstim 526 mg/day, s.c.) starting 5 days after the end of chemotherapy and continuing until the end of PBSC. CAD was administered 4– 6 weeks after the end of initial therapy. At 3–5 weeks after PBSC, patients received one (HOVON-50) or two (GMMG-HD3, after 3–6 months) courses of high-dose chemotherapy with melphalan (200 mg/m2 ,i.v., 100 on days 3 and 2) each followed by ABSCT on day 0 with at least 2.5 106/kg CD34 þ cells. Patients randomized to VAD received maintenance therapy with ainterferon (3 106 IU, three times weekly). Patients in the TAD group received Thal (50 mg/day) without LMWH. Wilcoxon-rank sum test was used to compare the result of PBSC yield of TAD to VAD groups. The reported p-values are two-sided and a significance level of a ¼ 0.05 was used.

Results and discussion

PBSC collection VAD has been considered the standard therapy for many years because of the good response rate and the lack of stem cell injury.1 The promising anti-myeloma effect of Thal was first reported by Singhal et al.2–4 and several subsequent studies confirmed the activity of Thal in relapsed and refractory MM. Since Munshi et al. described their concerns about Thal effects

Table 1

on PBSC collection (Munshi N et al. Blood 1999; 94: 578a, abstract), several groups have focused on PBSC yield following Thal administration, suggesting Thal to diminish the yield of PBSC, possibly via immunomodulatory effects.8–11 Our data confirm these previous concerns and show that Thal plus AD significantly diminish the outcome of PBSC compared with VAD in both the GMMG and the HOVON groups (Table 1). TAD patients of the GMMG-HD3 group resulted in a median CD34 þ yield of 9.8 106/kg cells (2.0–33.6) and 10.9 106/kg cells (3.0–36.0; P ¼ 0.02) in the VAD patients. Within the HOVON-50 group, TAD patients reached a median CD34 þ yield of 7.4 106/kg cells (2.0–33.0) versus 9.4 106/kg (0.0– 48.7; P ¼ 0.009) in VAD patients. In line with our results, Pitini et al.12 reported a significantly lower CD34 þ yield in PBSC collection after mobilization with cyclophosphamide and continuous administration of Thal, similar to the group of Zervas et al.13 For a single ABSCT 7% of VAD and 4% of TAD-treated patients (GMMG-HD3) and 5% of the patients within the VADand 3% within the TAD group (HOVON-50) were not able to reach sufficient CD34 þ yield. Moreover, 14% within both VAD and TAD groups (GMMG-HD3) and 13% of VAD as well as 18% of the patients treated with TAD did not reach sufficient CD34 þ cell yield for double ABSCT (data not shown). These results are mainly due to a discrepancy of the HOVON-50 protocol performing single ABSCT compared with the GMMGHD3 protocol performing double ABSCT. Thus, in the HOVON50 group, less PBSC were needed and were stopped earlier. Similarly, Cavo et al. reported that 80% of all patients treated with Thal/Dex who proceeded to PBSC collected adequate stem cell yields even for double ABSCT, that was confirmed by other groups as well.14–16 Moreover, Weber et al.5 reached adequate

Patient characteristics and mobilization data GMMG-HD3

Enrolment data Female/male (no. of patients) Age (years) Maximum two cycles of alkylating agents (no. of patients)

VAD (n ¼ 105)

TAD (n ¼ 93)

VAD (n ¼ 100)

TAD (n ¼ 100)

40/65 59 (37–66) 2

38/55 56 (38–66) 0

41/59 55 (36–65) 2

33/67 56 (34–65) 0

Thalidomide data Median dose (g/3 months) Median treatment duration (weeks) Mobilization data Median time from CAD to first leukapheresis (days) Mobilization with CTX alone (no. of patients) Median total CD34+ cells collected ( 106/kg) Median days of leukapheresis (no.) CAD/bone marrow harvests Remission before mobilization (%) -CR -PR -Response rate Plasma cells infiltrate before mobilization (%) G-CSF (no. of patients) GM-CSF (no. of patients)

HOVON-50

27.7 (5.5–50.6) 8.8 (3.1–13.5)

15.4 (3.2–39.8) 10.4 (3.3–19.9)

13 (9–21) 13 (11–21) 11 (9–24) 11 (7–52) 1 2 10.9 (3.0–36.0) 9.8 (2.0–33.6) (P ¼ 0.02) 9.4 (0.0–48.7) 7.4 (2.0–33.0) (P ¼ 0.009) 1 (1–7) 1 (1–6) 1 (1–4) 1 (1–4) 1 0 58 58

2 77 79

2 59 61

5 76 81

5 (0–40) 105 0

5 (0–43) 93 0

5 (0–84) 100 0

2 (0–53) 98 2

Abbreviations: CR, complete response; CTX, cyclophosphamide; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte/ macrophage-colony stimulating factor; NA, not applicable; PR, partial response. Data from GMMG-HD3 and HOVON-50 MM patients are presented at time of enrolment, mobilization as well as duration and dose of Thal administration. A statistically significant difference in PBSC yield after VAD or TAD treatment was found within the GMMG-HD3 and the HOVON-50 group, respectively. Values are presented as median with range unless otherwise specified. Leukemia


1296 results via mobilization with G-CSF alone after Thal/Dex administration. Importantly, one leukapheresis was sufficient in 75% (VAD) and 70% (TAD) of the HOVON-50 group for single ABSCT and 60% (VAD) and 45% (TAD) in the GMMG group for double ABSCT. For GMMG-HD3, a median time from CAD to leukapheresis of 13 days in TAD11–21 and 13 days in VAD patients (9–21) was observed. The HOVON-50-data showed a median time to leukapheresis in TAD patients of 11 days (7–52) and 11 days (9–24) for VAD patients. In line with our results, Ghobrial et al.17 showed no difference between Thal and control group regarding the number of days of leukapheresis, but they remarked that patients from the Thal group were not likely to collect sufficiently in 1 day, similar to the group of Ahmad et al.18 who administered Thal continuously during leukapheresis. In contrast, Desikan et al.10 described difficulties in harvesting stem cells in one patient receiving Thal continuously during PBSC, which is reported by other groups as well (Munshi N et al., Blood 1999; 94: 578a, abstract).

Possible factors influencing mobilization results Several factors have been described to have an adverse effect on PBSC. Of importance, many others and our study group19 have reported on the negative influence of alkylating agents on stem cell harvest, so a strict maximum of two cycles of alkylating chemotherapy was allowed before enrolment into GMMGHD3- and HOVON-50 trial. Out of 398 patients, alkylating agents such as melphalan were given in four patients before start with induction regimen (Tables 1). As a result, no influence of alkylating agents could be seen on CD34 þ yield within the GMMG-HD3 and HOVON-50 study groups. G-CSF was used for mobilization according to the GMMG-HD3 and HOVON-50

Table 2

protocol, as performed by many other groups (Table 2), and just 2 patients received granulocyte–macrophage colony-stimulating factor (GM-CSF) instead of G-CSF (Table 1).

Response rate and treatment related toxicities before PBSC An interim analysis revealed a superior response rate for TAD compared with VAD in the GMMG-HD3- (TAD: CR/PR 79%, VAD: CR/PR 58%) as well as in the HOVON-50 study group (TAD: CR/PR 81%, VAD: CR/PR 61%). The median of plasma cell infiltration before PBSC was comparable in VAD and TAD of both study groups (Table 1). These results suggest that the significantly lower yield in PBSC after Thal pretreatment is not correlated with the response rate. Significantly better response rates in Thal/Dex as induction regimen in newly diagnosed MM have recently been described in comparison with VAD while showing a lower CD34 þ cell yield.15 The superiority of a Thal/ Dex containing treatment has already been shown in several clinical trials with relapsed MM.20,21 In newly diagnosed MM, several clinical trial phase II and III, including Thal/Dex as induction regimen were performed, showing response rates of 60–70%,5,22,23 which is similar to our findings. Treatment related toxicities greater than grade 2 according to Common Toxicity Criteria (CTC) in the VAD group were limited to cardiovascular dysfunction such as arrhythmia and general constitutional symptoms such as fatigue in HOVON-50- and GMMG-HD3-patients. In TAD-treated patients, peripheral polyneuropathy, general constitutional symptoms as well as impaired gastrointestinal function such as constipation were observed (Table 3), similar to other groups.24 The incidence of deep vein thrombosis occurred in HOVON-50/GMMG-HD3 patients after treatment with VAD or TAD was currently

Literature regarding thalidomide administration and following peripheral blood stem cell collection in MM patients Mobilization regimen

Thal dose/regimen

CD34+ ( 106 kg)

Leukapheresis (days)

No. of patients

Munshi et al. Blood 1999; 94: 578a (abstract) Desikan et al.10

CAD

400 mg/day VAD-DCEP n ¼ 4 cycles

NA

25 with Thal 25 control group

CTX+G-CSF

NA Thal/Pred/DCEP

19 (0.41–44) with Thal 21 (3.5–63) control group (P ¼ 0.06) NA

NA

3

Ahmad et al.18

CTX+G-CSF

NA

NA

NA

Pitini et al.12

CTX+G-CSF

NA T-VAD n ¼ 3 cycles 400 mg/day

NA

10 with Thal NA

Ghobrial et al.17

200 mg/day+Dex n ¼ 4 cycles 200 mg/day+Dex n ¼ 3 cycles

2 (1–6)

24 with Thal

Weber et al.5

CTX (3 g/m2)/GCSF G-CSF

3.7 (1–12) with Thal 7.8 (2.6–18) control group (P ¼ 0.01) 9.0 (2.9–19) with Thal 7.7 (NA)

NA

43 control group 21

Zervas et al.13

CTX (4 g/ m2)

9.2 (3–67.7) (P ¼ 0.99) 4 (2.5–8.5)

2 (1–3)

37

Cavo et al.14 Cavo et al.15

CTX (7 g/m2) CTX (7 g/m2)

200 mg/day+VAD n ¼ 4 cycles 200 mg/day+Dex 200 mg/day+Dex n ¼ 4 cycles

7.1 (NA) 7.85 (NA) with Thal

2 (1–4) 2 (NA)

Abdelkefi et al.16

CTX (4.5 g/m2)/ G-CSF

100–400 mg/day n ¼ 3 cycles

10.5 (NA) control group NA

NA

91% of 200 patients 4

Abbreviations: CTX, cyclophosphamide; DCEP, dexamethasone, cyclophosphamide, etoposide, cisplatin; NA, not applicable. Data are presented including mobilization regimen, thalidomide dose and regimen, numbers of CD34+ collected, number of patients proceeded to leukapheresis, number of days of leukapheresis and number of cycles given. Values are presented as median with range unless otherwise specified. Leukemia


1297 Table 3

Toxicity Overall no. (%) VAD (n ¼ 205)

Constitutional Peripheral neuropathy Gastrointestinal Cardiovascular

10 (5) 5 (2) 1 (0.5) 7 (3)

GMMG-HD3 no. (%)

HOVON-50 no. (%)

TAD (n ¼ 193)

VAD (n ¼ 105)

TAD (n ¼ 93)

VAD (n ¼ 100)

TAD (n ¼ 100)

12 (6) 14 (7)

5 (5) 2 (2)

6 (6) 8 (9)

5 (5) 3 (3)

6 (6) 6 (6)

9 (5) 5 (3)

0 (0) 2 (2)

3 (3) 1 (1)

1 (1) 5 (5)

6 (6) 4 (4)

Incidence of severe adverse events more than grade 2 according to Common Toxicity Criteria (CTC). Patients with thalidomide treatment showed a higher incidence of peripheral neuropathy and gastrointestinal impairment such as constipation compared with control group. Constitutional symptoms and cardiovascular dysfunction were similar in both treatment groups.

Table 4

Engraftment GMMG-HD3

Time to ABSCT after start induction regimen (days) Median days until WBC 41 109/l Median days until ANC 41 109/l Median days until PLT 4100 109/l Median days until PLT 450 109/l Median RBC transfused Median PLT transfused Median days in the hospital

HOVON-50

VAD (n ¼ 105)

TAD (n ¼ 93)

VAD (n ¼ 100)

TAD (n ¼ 100)

153 (121–208) 14 (7–21) NA

152 (120–252) 14 (10–22) NA

161 (119–427) 14 (9–28) 21 (9–220)a

161 (119–256) 14 (9–31) 22 (9–139)b

20 (9–538)c NA 2 (0–16) 1 (0–12) 20 (5–31)

24 (10–796)d NA 2 (0–50) 2 (0–28) 20 (6–98)

13 2 1 16

NA (4–23) (0–10) (0–4) (12–24)

14 2 1 17

NA (10–21) (0–7) (0–11) (11–38)

Abbreviations: ABSCT, autologous blood stem cell transplantation; ANC, absolute neutrophil count; NA, not applicable; PLT, platelet; RBC, red blood cell count; WBC, white blood cells count. Data from GMMG-HD3 and HOVON-50 MM patients are presented at time of hematopoetic reconstitution after first ABSCT. No statistically significant difference in engraftment after first ABSCT was found within the GMMG-HD3 and the HOVON-50 group, respectively. Values are presented as median with range unless otherwise specified. a,b Not reached by two patients. c Not reached by one patient. d Not reached by four patients.

evaluated by Minnema et al.25 and showed that LMWH effectively reduced thalidomide-associated venous thromboembolism (VTE).

Hematopoetic reconstitution after first ABSCT Several factors have been identified to affect adversely hematopoetic reconstitution, including alkylating agents, inadequate stem cell dose, previous radiotherapy and prolonged induction treatment.19,26,27 According to the GMMG-HD3 and HOVON-50 protocol, first ABSCT was strictly performed after three cycles of induction regimen and 4–6 weeks after mobilization with CAD, so the median time proceeding to ABSCT was comparable in VAD versus TAD in both study groups (Table 4). Whereas Thal can affect PBSC outcome, a recent trial showed that patients treated with Thal showed no substantial difference in engraftment compared with control group after ABSCT.17 Here, we determined if VAD or TAD treatment affected engraftment after first ABSCT. First, we focused on the number of days until white blood cell count (WBC), absolute neutrophil count (ANC) and platelets (PLT) reached the criteria of recovery. Successful engraftment of WBC and ANC was defined as 41 109/l. PLT engraftment was defined the first day reaching 450 or 100 109/l without PLT transfusion, respectively. Patients did not receive G-CSF after ABSCT, and engraftment data were closely monitored. Importantly, no difference was found in the recovery of WBC, ANC or PLT in either VAD or TAD after first ABSCT (Table 4). Similarly,

Ahmad et al.18 showed that hematopoetic reconstitution (ANC40.5 109/l, PLT 420 109/l) occurred between 12 and 16 days after ABSCT, pretreated with VAD and Thal. We next investigated if an influence could be seen on the number of PLT or red blood cells (RBC) transfused during engraftment time, and no difference was found in both treatment groups. Finally, we compared the median time of ABSCT until discharge from hospital and did not find any statistically significant difference in both groups (Table 4). We conclude that while lowering CD34 þ yield after CAD, Thal treatment before stem cell harvest does not delay hematopoetic reconstitution compared with VAD after high-dose melphalan and ABSCT.

Mobilization after Thal induction regimen- current literature Although many groups reported on contrary results after Thal administration before PBSC, strong similarities can be found in the treatment procedure of each group (Table 2) as well as in comparison with the GMMG-HD3- and HOVON-50 trial. Importantly, control groups without Thal showed a better PBSC harvest compared with groups treated with Thal. Rajkumar et al.23 reported that MM patients undergoing PBSC after induction regimen with Thal/Dex, stem cell harvest was successful in 90% of Thal-treated patients. Furthermore, the group of Ghobrial et al.17 showed comparable results in both the Thal treated and the control group. However, it is worth Leukemia


1298 mentioning that the number of patients undergoing PBSC was often small, just one group reported on 200 patients.15 All groups reported on 3–4 cycles with Thal treatment before proceeding to stem cell harvest. This is of importance as prolonged pretreatment with Thal may also influence stem cell harvest. Nevertheless, if data were presented, most groups showed sufficient PBSC yield from patients treated with Thal for a single ABSCT.

Future directions: lenalidomide and bortezomib in MM as induction therapy Thal has been widely used for treatment in MM, but new and highly effective as well as considerably safer treatments in MM are currently being investigated as relapse therapy and induction regimen before high-dose therapy. Several clinical studies have analyzed the efficacy of lenalidomide (Revlimid), an analog of Thal, in MM. Richardson et al.28 reported that lenalidomide is well tolerated and may be safer and more effective than Thal. The efficacy of lenalidomide29 and bortezomib (Velcade) in relapsed MM have been widely described.30–32 A recent publication of phase II clinical trials showed promising response rates after lenalidomide/ dexamethasone in newly diagnosed MM patients.33 Clinical phase III trials are now ongoing to investigate further the efficacy of lenalidomide and bortezomib in newly diagnosed MM before high-dose therapy. However, as there are still just a few data published regarding the influence of lenalidomide or bortezomib on PBSC,34 the analyses of these trials should also focus on the influence of these novel agents on PBSC, with a maximum of 4–6 cycles to prevent negative effects on CD34 þ yield.

Conclusion With respect to our results and the current controversy, we summarize that treatment with Thal resulted in a statistically significant lower number of CD34 þ cells. However, from at least 82% of the patients within the Thal group, a CD34 þ yield for even double ABSCT could be harvested. TAD showed better response rates than VAD while having a lower yield of PBSC. Furthermore, neither TAD nor VAD treatment before stem cell harvest showed a delay in hematopoetic reconstitution after first ABSCT. We also showed that collection with CAD is successful after VAD and TAD treatment and that one leukapheresis is often sufficient. Nevertheless, the knowledge of the median time from mobilization therapy to PBSC allows administration of CAD in an outpatient setting, a highly economical consideration. But since some difficulties have been described from continuous application of Thal during stem cell collection, Thal should be stopped before mobilization therapy to prevent further influence on PBSC yield. Data on the influence of newer regimens like lenalidomide and bortezomib on PBSC are still very limited and the results of ongoing clinical trials are awaited.

Acknowledgements We thank Olga Kien, Marion Schaeffner-Fank and Jana Schlenzka, MD, from the GMMG clinical trial center, Department of Hematology and Oncology at the University of Heidelberg and the National Center of Tumor Diseases Heidelberg, and Christiane Hei from the Data Center of the National Center of Tumor Diseases Heidelberg, Germany; Petra Westveer and Edwin van Stein from the HOVON Data Center, Erasmus MC-Daniel den Leukemia

Hoed Cancer Center, Rotterdam, The Netherlands, for data management and Douglas W McMillin from the Dana-Farber Cancer Institute, The Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Boston, USA, for proofreading.

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