Successful hematopoietic stem‑cell mobilization with plerixafor plus granulocyte‑colony stimulating factor in multiple myeloma patients treated with pomalidomide

Kota Yoshifuji1 · Takashi Toya1 · Hiroto Adachi1 · Masahiro Fujita1 · Atsushi Wada1 · Ryosuke Konuma1 · Yuya Kishida1 · Tatsuya Konishi1 · Akihito Nagata1 · Yuta Yamada1 · Satoshi Kaito1 · Takuma Kumagai1 · Kyoko Inamoto1 · Megumi Akiyama1 · Aiko Igarashi1 · Yuho Najima1 · Noriko Doki1 · Takeshi Kobayashi1 · Kazuhiko Kakihana1 · Hisashi Sakamaki1 · Kazuteru Ohashi1

Abstract

Autologous stem-cell transplantation is an effective procedure for the treatment of multiple myeloma, and involves the collection of hematopoietic stem cells (HSCs). However, in some patients, HSCs in the bone marrow fail to mobilize. Pomalidomide upregulates CXCR4 in hematopoietic stem cells, in a manner similar to that of lenalidomide, and is, thus, likely to have a negative impact on hematopoietic stem-cell mobilization in multiple myeloma patients. Here, we report the two cases in which hematopoietic stem cells were mobilized using plerixafor plus granulocyte-colony stimulating factor after exposure to lenalidomide and pomalidomide. Use of plerixafor with a sufficient washout period may lead to successful mobilization following pomalidomide use, although further study of this potential use is needed.

Keywords Pomalidomide · Stem-cell mobilization · Multiple myeloma · Plerixafor · CXCR4

Introduction

Lenalidomide (LEN)-containing induction regimen followed by autologous stem-cell transplantation (ASCT) is the preferable therapy in multiple myeloma (MM) patients eligible [1]. The collection of hematopoietic stem cells (HSCs) is the essential step for ASCT. However, there are some risk factors for poor HSC mobilization such as increasing age, advanced or refractory disease, and previous mobilization failure [2, 3]. Lenalidomide has also a negative impact on HSC mobilization in patients with MM [4–6], as LEN increases HSC surface expression of CXCR4, thereby causing HSCs to remain in the bone marrow (BM) niche [7]. Although some cases with MM that is refractory to LEN might be administered pomalidomide (POM), another immunomodulatory drug, before stem-cell collection, there have been no reports regarding the influence of POM on HSC mobilization. Pomalidomide is also reported to increase CXCR4 expression on the surface of HSCs and presumed that exposure to POM disturbs mobilization [7]. Here, we present two cases who achieved successful mobilization with plerixafor plus granulocyte-colony stimulating factor (G-CSF) after exposure to POM. This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital (Permission number: 2227).

Case report

Case 1

A 55-year-old man who was diagnosed with symptomatic MM, IgG kappa type, achieved a partial response (PR) after 4 cycles of VRD [bortezomib (BOR) 1.3 mg/m2 subcutaneously (SC) on days 1, 4, 8, 11, LEN 25 mg orally (PO) on days 1–14, and dexamethasone (DEX) 40 mg PO on days 1, 4, 8, 11 every 21 days]. Although HSC mobilization was attempted using cyclophosphamide (CPM) [2 g/m2 intravenously (IV) on days 1, 2], filgrastim (400 µg/m2 SC on days 7–17), and meloxicam (10mg PO on days 10–16), the treatment failed. Moreover, IgG levels gradually increased thereafter. Subsequently, KPD (carfilzomib 20 mg/m2 on days 1, 2 of cycle 1, then 27 mg/m2, IV on days 1, 2, 8, 9,15, 16, POM 4 mg PO on days 1–21, and DEX 40 mg PO on days 1, 8, 15, 22 every 28 days) was started after 1 cycle of DCEP (DEX 40 mg, CPM 400 mg/m2, etoposide 40 mg/m2, and cisplatin 10 mg/m2 IV on days 1–4). Due to febrile neutropenia, it became necessary to decrease the dose to 2 mg. After a further 4 cycles of KPD, he once again achieved a PR. After 1 cycle of KD, which was used to wash out POM, a second HSC mobilization was tried with plerixafor (0.24 mg/kg SC on day 4) plus filgrastim (400 µg/m2 SC on days 1–4), with 9.86 × 106 CD34 + cells/kg and then collected. He received autologous hematopoietic stem-cell transplantation (ASCT) with high-dose melphalan (200 mg/m2 IV on day-2) as a conditioning regimen, and achieved neutrophil engraftment at day 12 and platelet recovery ≥ 20 × 109/L at day 14 after transplantation (Fig. 1a).

Case 2

A 59-year-old woman was diagnosed with symptomatic MM, IgG kappa type. After undergoing thoracic spine decompression surgery and radiation therapy for thoracic extramedullary lesions, she was treated with 4 cycles of VRD (BOR 1.3 mg/m2 SC on days 1, 4, 8, 11, LEN 25 mg PO on days 1–14, and DEX 40 mg PO on days 1, 4, 8, 11 every 21 days). However, only a minor response was achieved. As a result, she then received 3 cycles of PCD (POM 4 mg PO on days 1–21, CPM 300 mg/m2 PO on days 1, 8, 15, 22 and DEX 40 mg PO on days 1, 8, 15, 22), which led to her achieving a PR. It was necessary to discontinue POM on day 14 of cycle 3 due to neutropenia. Filgrastim (400 µg/m2 SC on days 1–4) was introduced for HSC mobilization, and the circulating peripheral blood CD34 + cell counts on day 4 were as low as 4.5 cells/µL. Therefore, plerixafor (0.24 mg/ kg SC on day 4) was used, and 4.11 × 106 CD34 + cells/kg was collected. She received 4 cycles of PCD additionally and achieved VGPR. Then, she received ASCT with highdose melphalan (200 mg/m2 IV on day-2) as a conditioning regimen, and achieved neutrophil engraftment at day 12 and platelet recovery ≥ 20 × 109/L at day16 after transplantation (Fig. 1b).

Discussion

In these days, the use of combination with immunomodulatory drugs, proteasome inhibitors, and dexamethasone in induction therapy has increased rates of complete response Successful hematopoietic stem-cell mobilization with plerixafor plus granulocyte-colony and improved outcomes, and LEN-containing therapy followed by autologous stem-cell collection is a popular treatment option among patients who are eligible for ASCT [1, 8]. However, some patients are refractory or relapsed to induction therapy including LEN, and additional therapies including POM are necessary before HSC mobilization. POM is a novel second-generation immunomodulatory drug that is effective in patients with MM that is refractory to bortezomib and LEN therapy [9–12]. However, POM as well as LEN induce localization of CXCR4 to HSC surface and enhance the interaction with stromal cell-derived factor-1α (SDF-1α), which is essential for localization of HSCs into BM niche, and is expected to contribute to poor mobilization [7]. There are many reports about poor mobilization after exposure to LEN [4–6], but no clinical reports which examined the efficacy of mobilization after LEN as well as POM therapy. However, considering that LEN administration itself can prevent adequate stem-cell collection and that POM is assumed to interrupt HSC mobilization in vitro, it seems valid that exposure to LEN followed by POM could be an obstacle to HSC mobilization. It seems quite difficult to conduct a prospective study to evaluate the efficacy of stem-cell collection after POM exposure, because these cases are quite rare, and therefore, we believe that this case report could become a guide for such patients.
We could successfully harvest HSCs after the use of POM and a few factors for the successful mobilization are assumed. First, we used plerixafor for the mobilization. Plerixafor is used in combination with G-CSF for HSC mobilization in patients with multiple myeloma [13–15]. Plerixafor selectively and reversibly binds to CXCR4 and blocks its interaction with SDF-1α, thereby releasing HSCs from BM into peripheral blood [15]. The reason that most patients exposed to LEN exhibit successful mobilization with plerixafor plus G-CSF is probably due to the plerixafor-induced downregulation of CXCR4 [16]. Therefore, plerixafor administration might also help to overcome the influence of POM exposure.
Second, in the current cases, we used a 4-week washout period between the last POM dose and the mobilization. After the final exposure to LEN, most experts recommend a washout period of 2–4 weeks [17]. Therefore, the washout period in the current cases might be another reason for the successful mobilizations.
The findings of this study are limited by several factors. In case 1, the first HSC mobilization with CPM plus G-CSF was failed when MM was still active. Then, we selected KPD after 1 cycle of DCEP, because triplet regimens improve outcomes when compared to doublets [18], and KPD was reported to be effective for relapse or refractory MM [10]. Then, second HSC mobilization with plerixafor plus G-CSF was succeeded when MM was controlled by KPD. Therefore, we cannot deny that disease status was also affected to HSC mobilization. In case 2, the HSC mobilization without plerixafor was not tried. However, we checked the circulating peripheral blood CD34+ cell counts on day 4 of G-CSF, and the level was as low as 4.5 cells/μL. It is reported that plerixafor improves the HSC mobilization outcomes for patients who have peripheral blood CD34+ cell counts < 10/ μL on day 4 of G-CSF [19]. Therefore, we consider that preemptive use of plerixafor was a key to sufficient stemcell collection. Moreover, we suppose that the HSC surface expression of CXCR4 decreases and the interaction with SDF-1α becomes weak after period to washout POM. However, no previous report mentioned about it, and we do not have bone marrow samples before and after washout period, and so, unfortunately, we cannot check the exact expression levels of CXCR4. Therefore, this is the future issue to prove the accuracy of our hypothesis and to clarify the appropriate period to wash out POM.
This is the first report to provide details on the HSC mobilization after exposure to LEN followed by POM and to suggest the possible role of plerixafor and washout period for successful stem-cell collection. Further studies are warranted to examine the influence of POM on HSC mobilization.

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