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A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.
Treatment options for patients with multiple myeloma (MM) have evolved with the introduction of powerful new therapeutic agents. Although there has been a recent trend to delay autologous stem cell transplantation (ASCT) until relapse, because of high response rates obtained with new regimens , high-dose chemotherapy followed by ASCT, which is associated with improved survival, remains the goal for most patients with MM. The selection of induction therapy, therefore, must take into consideration the potential impact on the ability to collect enough stem cells for future transplantation. In addition, the goal for the absolute number of stem cells to be collected has increased because of studies reporting a survival benefit with tandem ASCT, as well as the potential use of high-dose chemotherapy with stem cell rescue as salvage therapy [1,3–5].
Lenalidomide (Revlimid®; Celgene, NJ), an oral immunomodulatory (IMiD)® drug, in combination with dexamethasone, has demonstrated impressive clinical activity in patients with both relapsed or refractory [6,7] and newly diagnosed MM . Three recent studies reported decreased stem cell yields when granulocyte-colony stimulating factor (G-CSF) was used for stem cell mobilization following lenalidomide induction therapy in patients with MM [1,9,10]. In 1 study, decreased stem cell yield correlated with longer duration of lenalidomide therapy, and the authors recommended collecting stem cells within 6 months of initiating lenalidomide-based therapy to minimize the risk of mobilization failures . Paripati et al.  also showed a trend toward increasing difficulty of stem cell collection with longer duration of lenalidomide-based induction therapy for MM, notably with a 100% failure rate for those patients who had received >10 cycles. These results were not corroborated in a third study, however .
In an effort to clarify the above issues, we examined if the addition of cyclophosphamide (Cy) to G-CSF as a mobilization regimen would facilitate the collection of adequate stem cells for at least 2 ASCTs in patients who had induction therapy with the BiRD (Biaxin® [clarithromycin]/Revlimid® [lenalidomide]/dexamethasone) regimen.
Patients with stage II and III MM were treated as part of a phase II study of the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD) therapy, as previously published . All patients received lenalidomide and dexamethasone in 28-day cycles. Dexamethasone 40 mg was given orally once weekly. Lenalidomide 25 mg/day was given orally on days 1–21 of each 28-day cycle. Concurrent medications included: clarithromycin 500 mg given orally twice daily; aspirin 81 mg/day for deep-vein thrombosis prophylaxis; omeprazole 20 mg/day for gastrointestinal prophylaxis; and trimethoprim or sulfamethoxazole 1 double-strength tablet twice daily for Pneumocystis carinii pneumonia prophylaxis, 3 times a week. Patients were advised to undergo stem cell collection after achieving a maximum disease response or disease plateau, and all patients must have achieved at least a partial response (PR) according to the international uniform response criteria for MM. BiRD therapy was with-held for a minimum of 14 days prior to stem cell mobilization. In this nonrandomized study, 28 patients underwent an attempt at stem cell mobilization and collection. Stem cell mobilization was performed either with G-CSF alone at a dose of 10 μg/kg/day for 5–10 consecutive days until 10×106/kg CD34+ stem cells had been collected, or with G-CSF plus Cy, 3 g/m2 once only, a day prior to the initiation of G-CSF as described above. Collection success was defined by the collection of at least 4 × 106/kg CD34+ stem cells, which would be the minimum number of CD34+ cells to support 2 ASCT. Patients who wished to continue BiRD therapy elected to mobilize with G-CSF alone, and those who chose to proceed to ASCT immediately after maximum response received Cy plus G-CSF. In total, G-CSF alone was given to 9 patients, and 19 patients received Cy plus G-CSF. One patient who failed to collect an adequate number of stem cells with G-CSF alone requested remobilization with Cy plus G-CSF.
The number of CD34+ stem cells collected, the ability to collect sufficient stem cells for 2ASCTs,and the impact of duration of BiRD therapy on stem cell collection was compared between mobilization regimens. The relative lenalidomide dose intensity for each patient was calculated as the ratio of the dose of lenalidomide received (accounting for dose reductions) to the intending dose of lenalidomide in the BiRD regimen. The total lenalidomide dose delivery was calculated as the relative lenalidomide dose intensity multiplied by the number of BiRD cycles prior to stem cell collection. For example, a patient who had not had any dose reduction in lenalidomide after 7 cycles of BiRD would have a total lenalidomide dose delivery of 7. Mann-Whitney U-tests and Fisher’s exact tests were used to calculate P values, as appropriate.
There were no differences in the baseline characteristics of patients who were treated either with G-CSF alone (9 patients) or Cy plus G-CSF in combination (20 patients) (Table 1).
Significantly moreCD34+ cells were collected with Cy plus G-CSF (median 14.2 × 106/kg) than with G-CSF alone (median 3.1 × 106/kg; P<.0001) (Table 2 and Figure 1). All patients who received Cy plus G-CSF for stem cell mobilization obtained a sufficient amount of CD34+ cells for 2 ASCTs, compared with only 33%of patients who attempted stem cell mobilization with G-CSF alone (P<.0001). The 3 patients in the G-CSF group who had successful collections had received< 6 cycles of BiRD. The extent of BiRD therapy prior to stem cell mobilization ranged from 2–27 cycles in both groups. The number of cycles of BiRD was not significantly associated with the success of stem cell harvests (median 7 cycles [range: 4–23] for unsuccessful harvests versus 7 cycles [range: 2–27] for successful harvests; P = .91) or with the absolute number of CD34+ stem cells collected (Spearman rank correlation coefficient 0.20; P=.31). Similarly, the absolute dose of lenalidomide received prior to mobilization was not significantly associated with success of collection (median total lenalidomide dose delivery of 7.5 [range 7–23] for unsuccessful harvests versus 7 [range: 2–27] for successful harvests; P = .30). Of note, only 1 patient in this study had a dose reduction in lenalidomide during BiRD therapy prior to mobilization, from 25 mg/day to 10 mg/day for days 1–21 of a 28-day cycle. This patient was in the group mobilized with G-CSF alone, and failed adequate stem cell collection.
ASCT is a powerful therapeutic option for MM that has been shown to prolong overall survival (OS) . In addition, tandem transplants have become an option for certain patients [4,5], and robust stem cell collections are now required. Consequently, any induction therapy used to reduce tumor burden prior to ASCT must not hinder stem cell mobilization and harvesting for double transplants.
Although Cy and G-CSF have been used for successful stem cell mobilization , this combination has not been shown to increase response to, or improve, overall outcomes after ASCT . Furthermore, Desikan and colleagues  have shown that G-CSF alone mobilized adequate CD34+ stem cells more rapidly and with less morbidity in patients with MM than the combination of Cy plus G-CSF. Yet, these studies were conducted in patients without exposure to lenalidomide. More than 6 cycles of lenalidomide-based induction therapy has been shown to inhibit collection of CD34+ cells for ASCT using mobilization with G-CSF alone , and our study is germane to the increasing incorporation of this drug into modern MM treatment. The rationale for inclusion of Cy as part of a myeloma mobilization regimen in a patient with prior lenalidomide treatment should be to increase stem cell yield to allow ASCT, and also to potentially minimize resource wastage by decreasing the number of apheresis sessions and failed collections overall. All the patients mobilized with Cy plus G-CSF in this study collected sufficient CD34+ cells for 2 transplants compared with 33% of those mobilized with G-CSF alone, providing a strong argument for the inclusion of Cy for stem cell mobilization after treatment with the BiRD regimen. We show that there was no association of duration of BiRD therapy, or the total lenalidomide dose received, with successful CD34+ cell collection, and thus, the number of lenalidomide-based therapy cycles should not be a limiting factor in stem collection. This a striking contrast to the experiences reported by Paripati et al.  and Kumar et al.  and suggests the role the Cy may play in mobilizing stem cells even after prolonged exposure to lenalidomide therapy. All 3 successful collections in the G-CSF alone group were in patients treated with <6 cycles of BiRD; therefore, patients who receive shorter lenalidomide courses may collect adequate CD34+ cells without the addition of Cy.
The use of clarithromycin caused no bone marrow toxicity in the BiRD regimen, and we therefore hypothesize that the use of clarithromycin had no effect on the stem cell collection outcomes we observed [8,16]. This report validates the Mayo Clinic experience of the suppressive effect of lenalidomide on stem cell mobilization, as well as the success achieved using G-CSF plus Cy for stem cell collection after lenalidomide therapy [1,17,18]. In conclusion, we recommend continuing lenalidomide- based induction therapy until the desired tumor reduction goal has been achieved, and using Cy plus G-CSF for stem cell mobilization to ensure successful stem cell harvest prior to ASCT. This would particularly apply to those patients who have been treated with lenalidomide for longer than 6 months.
This work was supported in part by a SCOR grant from The Leukemia & Lymphoma Society and an NCI K23 Award: CA109260-01. Research funds were also provided by Celgene Corporation. The authors also acknowledge the support of the Hermione foundation. In preparation of this manuscript, the authors received editorial/writing support from Excerpta Medica, which was funded by Celgene Corporation. The authors, however, were fully responsible for contents and editorial decisions for this manuscript.