Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective and an essential part of post remission therapy for treatment of both intermediate and high-risk Acute Myeloid Leukemia (AML) [1] .
Allo-HSCT is also used to cure many other high-risk hematological diseases [2] , although its role in treatment of multiple myeloma (MM) has been questioned [3] .
We report the case of a 56 years old woman who was concomitantly diagnosed with AML and monoclonal gammopathy of undetermined significance (MGUS), was submitted to alloHSCT because of AML relapse after first line therapy and presented MGUS progression to MM after alloHSCT.
Case report
A 56-years-old woman, without any significant medical history was diagnosed with normal karyotype AML. Molecular analysis showed NPM1 mutation without FLT3 mutation or duplication. First line therapy was a combination of 3 + 7 standard induction and 3 high dose cytarabine consolidations. Relapse was diagnosed one year later and a second complete remission (CR) was achieved after rescue therapy with combination of gemtuzumab ozogamicin (GO), daunorubicine and cytarabine. Allo HSCT from non-sibling 10/10 HLA-matched related donor was performed after myeloablative reduced-toxicity conditioning regimen (i.v busulfan 12.8 mg/kg – fludarabine). Graft source was peripheral blood stem cells (PBSC) (9 × 10 6 CD34+ cells/kg). Both donor and recipient was seronegative for cytomegalovirus (CMV) and toxoplasma and positive for Epstein-Barr virus (EBV). Short course methotrexate (MTX) and cyclosporine were used as GVH prophylaxis. Neutrophil engraftment (500/mm3) was observed on day 20 and platelet on day 40. No acute or chronic graft versus host disease (GVHD) was observed. On September 2022, ten years after HSCT AML was still in CR and considered to be cured.
IgGk MGUS was diagnosed concomitantly with AML. M component was 18 g/l, without myeloma-defining events. None of the bone marrow aspirations performed during AML follow-up showed plasma cells excess. HSCT had no impact on the quantity of paraprotein produced by the gammopathy.
More than three years after transplant, symptomatic anemia appeared, revealing kappa light-chain multiple myeloma with 11% dysplastic bone marrow (BM) plasma cells. Karyotype with myeloid culture was 46 XY in all the mitoses; FISH on CD138+ purified plasma cells showed that 93% were 46XX and 60% harbored del17p. The M component was stable at 11 g/l, there was no bone lesion, the renal function and serum calcium level were normal.
Intensive treatment was planned and patient received four bortezomib, lenalidomide and dexamethasone (VRD) cycles as induction treatment followed by aHSCT conditioned with melphalan (200 mg/m2). Finally, the patient received another 5 VRD cycles as a consolidation treatment. Dose intensity of bortezomib and lenalidomide needed to be adapted during these cycles due to cytopenias.
In order to perform aHSCT, PBSC were mobilized using subcutaneous granulocyte-colony stimulating factor (G-CSF) 10 µg/kg daily starting 5 days prior to PBSC harvesting plus SC plerixafor 240 µg/kg 10 h prior to PBSC harvesting. This first harvest sequencing resulted in the collection of 2.07.106 CD34+ cells/kg. Six weeks later, a second identical harvest sequence collected 0.62.106 CD34+ cells/kg for a total of 2.69 × 106 CD34+ cells/kg.
At the end of this treatment phase, patient was considered in very good partial response (VGPR).
The patient relapsed two years later and treatment with pomalidomide dexamethasone was initiated. Three months later active bone lesion developed and light chains continued to progress, a new treatment with daratumumab-pomalidomide-dexamethasone was successfully introduced with achievement of VGPR. Medical history is detailed in Fig. 1 .
Discussion
This report describes MGUS progression to multiple myeloma despite successful allo-HSCT treatment for AML. It also describes the feasibility to harvest PBSC and perform aHSCT after allo-HSCT procedure.
Although aHSCT remains standard myeloma treatment [4] , the role of allo-HSCT against MM has always been debated. Allo-HSCT has been used for several decades in MM patients [3] . Even though the tolerability of conditioning regimens, supportive care, and donor-matching have improved [5] , standard allogeneic transplantation is still associated with a high treatment-related mortality (TRM), and cannot be offered to most patients with MM. Previous studies have reported the combined use of a RIC regimen and allo-HSCT treatment following an earlier autologous transplantation. These tandem auto-allo transplants, however, have produced discordant results: a graft vs myeloma effect probably exists (less relapses, plateau of survival curves in some studies), but is not translated automatically into an improved survival rate probably outpassed by TRM [6] , [7] , [8] .
Since MM is in the “new agents era”, with very high efficacy of treatments in most of the patients, indications for the use of allo HSCT have become rare [9] .
Our patient‘s disease course illustrates the lack of efficacy of graft vs myeloma effects. Despite the success of allo-HSCT in curing concomitant AML, proving the existence of GVL effects, MGUS evolved to symptomatic high risk multiple myeloma. Cytogenetic analysis of purified tumoral plasma cells, which were mostly of female origin confirmed the recipient origin of the disease.
The major challenge in the treatment of this patient was the mobilization of PBSC. It is a rare situation, in a patient who already underwent an allo-HSCT. We could not find any data regarding the feasibility and the success rate of a stem cell mobilization after allo-HSCT in the literature. We chose not to use chemomobilization (to avoid toxicity), and to systematically use plerixafor because of the antecedent of allo HSCT and lenalidomide treatment which is associated with sub optimal stem cell mobilization [10] . Plerixafor, is a selective inhibitor of C-X-C chemokine receptor type 4 (CXCR4), which blocks its interaction with C-X-C motif chemokine 12 (CXCL12) and facilitates HSC egress from bone marrow. Plerixafor and granulocyte-colony stimulating factor (G-CSF) combination is well tolerated, improves HSC mobilization compared to G-CSF alone [11] , and is able to overcome lenalidomide mobilization inhibition [12] .
G-CSF and Plerixafor were used in order to yield 1.33+0.74+0.62 × 10 6 CD34+ cells/kg. The total of 2.69 × 10 6 CD34+ cells/kg was slightly below the optimal target (3–5 × 10 6 CD34+ cells/kg), but is above the minimal recommended number of 2 × 10 6 CD34+ cells/kg. [13] Post transplant aplasia lasted only seven days and the tolerance of the aHSCT was quite good, there were no severe infections. Furthermore, despite the need to adapt the dose intensity of the five consolidations cycles, in the second treatment phase, the patient subsequently tolerated toxic treatments like pomalidomide.
In summary, there are two important messages according to this case. On one hand, this is an example of progression of recipient MGUS to myeloma despite a successful allogeneic HSCT. On the other hand, this is a positive example on the viability of hematopoietic stem cells in patient who has already received both high dose myelotoxic chemotherapy and allogeneic HSCT.
Author contributions
FDC took care of the patient, performed the literature search and wrote the manuscript. AS, PA, JK took care of the patient and reviewed and corrected the manuscript. SB and VF provided the flow cytometry reports and biological analysis. PA, JVM supervised the literature analysis.
Informed consent
I, the undersigned, authorize Dr de CHARRY to use my clinical history as well as the medical iconography resulting from my examinations medical within the framework of a scientific publication in a medical journal (Leukemia research report).
I understand that:
The information will be published without mention of my name and the publishing newspaper will do everything it can to guarantee my anonymity. I understand, however, that absolute anonymity cannot be guaranteed. It's possible that someone, somewhere - perhaps someone who would look after me if I were hospitalized or a member of my family - could identify me.
The text of the article will be edited for style, grammar correction, consistency and length. –
The information is likely to be published by newspaper, which is distributed worldwide. The journal is primarily aimed at doctors, but is seen by many people who are not doctors, including journalists. - The information will also be posted on the journal website: -
The information may also be used in whole or in part in other publications and products published by the journal group
The journal will not authorize information to be used for advertising or packaging purposes or to be used out of context.
I can revoke my consent at any time before publication, but once the information has been promised for publication ('going to press'), it does not it will no longer be possible to revoke the consent
Financial disclosure or funding
None
Declaration of Competing Interest
The authors have no financial disclosure or funding and no conflict of interest.
Acknowledgement
We thank the patient for permission to present her case.
References
1. Döhner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., Ebert B.L., Fenaux P., Godley L.A., Hasserjian R.P., Larson R.A., Levine R.L., Miyazaki Y., Niederwieser D., Ossenkoppele G., Röllig C., Sierra J., Stein E.M., Tallman M.S., Tien H.F., Wang J., Wierzbowska A., Löwenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345–1377. doi: 10.1182/blood.2022016867.
2. Majhail N.S., Farnia S.H., Carpenter P.A., Champlin R.E., Crawford S., Marks D.I., et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American society for blood and marrow transplantation. Biol. Blood Marrow Transplant J. Am. Soc. Blood Marrow Transplant. 2015;21(11):1863–1869. doi: 10.1016/j.bbmt.2015.07.032.
3. Kumar S. Stem cell transplantation for multiple myeloma. Curr. Opin. Oncol. 2009;21(2):162–170. doi: 10.1097/CCO.0b013e328324bc04.
4. Rajkumar S.V. Multiple Myeloma: 2018 update on Diagnosis, Risk-stratification and Management. Am. J. Hematol. 2018;93(8):981–1114. doi: 10.1002/ajh.25117.
5. 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(11):1110–1120. doi: 10.1056/NEJMoa065464.
6. Gahrton G., Iacobelli S., Björkstrand B., Hegenbart U., Gruber A., Greinix H., et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013;121(25):5055–5063. doi: 10.1182/blood-2012-11-469452.
7. Armeson K.E., Hill E.G., Costa L.J. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013;48(4):562–567. doi: 10.1038/bmt.2012.173.
8. Wirk B., Byrne M., Dai Y., Moreb J.S. Outcomes of salvage autologous versus allogeneic hematopoietic cell transplantation for relapsed multiple myeloma after initial autologous hematopoietic cell transplantation. J. Clin. Med. Res. 2013;5(3):174–184. doi: 10.4021/jocmr1274w.
9. Gonsalves W.I., Buadi F.K., Ailawadhi S., Bergsagel P.L., Chanan Khan A.A., Dingli D., et al. Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. Bone Marrow Transplant. 2019;54(3):353–567. doi: 10.1038/s41409-018-0264-8.
10. Kumar S., Dispenzieri A., Lacy M.Q., Hayman S.R., Buadi F.K., Gastineau D.A., 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(9):2035–2042. doi: 10.1038/sj.leu.2404801.
11. DiPersio J.F., Stadtmauer E.A., Nademanee A., Micallef I.N.M., Stiff P.J., Kaufman J.L., et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720–5726. doi: 10.1182/blood-2008-08-174946.
12. Costa L.J., Abbas J., Hogan K.R., Kramer C., McDonald K., Butcher C.D., et al. Growth factor plus preemptive ('just-in-time’) plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure. Bone Marrow Transplant. 2012;47(11):1403–1408. doi: 10.1038/bmt.2012.60.
13. Giralt S., Costa L., Schriber J., Dipersio J., Maziarz R., McCarty J., et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol. Blood Marrow Transplant J. Am. Soc. Blood Marrow Transplant. 2014;20(3):295–308. doi: 10.1016/j.bbmt.2013.10.013.