Thiotepa intrathecal injections for myelomatous central nervous system involvement

The worldwide incidence of multiple myeloma (MM) has been rising continuously, representing an overall increase 126% from 1990 to 2016 in almost all regions, regardless socio-demographic status and availability sensitive diagnostic techniques.1 Though remarkable progress made, the disease is still currently incurable. Nearly 13% patients will develop extramedullary due natural accumulation mutations, evolutionary pressure or development sanctuaries where tumour cells are protected therapeutic drugs.2 In particular, central nervous system (CNS) involvement a critical prognostic indicator, with survival less than 6 months.3-9 Because its rarity, there no consensus on optimal treatment. Radiotherapy subject controversy, terms both efficacy toxicity. addition, most available treatments, including cytotoxic agents, monoclonal antibodies, immunomodulators proteasome inhibitor have very-low distribution cerebrospinal axis, blocking effective, curative treatment.10 Several studies tested intrathecal injections methotrexate cytarabine, commonly used lymphoma CNS involvement, but limited success, largely poor these agents against plasma cell disorders.11, 12 Thiotepa, well-known alkylating agent, intravenously for decades, especially conditioning MM autologous stem transplantation (ASCT).13 Additionally, it also injected intrathecally treatment leptomeningeal metastases, without any serious adverse effects, notably case breast cancer.14 Here we conducted retrospective, single-centre study evaluate safety infusion thiotepa 13 consecutively diagnosed cases CNS-invasive (CNS-MM). This was full compliance principles Declaration Helsinki oral consent patients. Between October 2017 March 2020, consecutive CNS-MM (eight harbouring cranial nerve palsies, two altered mental status, one numb chin syndrome, radiculoneuritis paresthesia) were identified at Saint Louis Hospital Paris (Table I). defined either by presence atypical dystrophic fluid (CSF) (confirmed flow cytometry if necessary) and/or clinic-radiological manifestations.3-9, 15, 16 median age those 62 years [range 52–72 years]: three diagnosis, relapse nine refractory (most time after ASCT plus salvage therapy). Aggressive initial observed third revised international staging (R-ISS) 3 thirds R-ISS 2 [three t(4;14), del17p/TP53 mutation, amp1q21/del1p32, t(9;14) t(14;20)]. Magnetic resonance imaging computed tomography documentations revealed (15%) intraparenchymal plasmacytomas, (23%) (69%) osteodural infiltrations. Treatment strategies, which varied according patient characteristics drug availability, shown Table I. All received methylprednisolone combination systemic therapy. Thiotepa administered (IT) total dose 10 mg associated 40 weekly until response progression. A number 1–8] performed each patient. An front-line diagnosis MM. For eight (62%) patients, radiotherapy focal lesions that imaging. criteria as cytological clearance CSF, complete radiological response, partial normalization CSF protein level pleocytosis clinical manifestation. described accordance International Myeloma Working Group. 85% population: neurological symptoms regressed eleven (85%) biological responses cases. five (38%) cases, cleared level. Among responders, 80% experienced context After progression disease, four (31%) continued receive second-line therapy (8%) third-line None underwent allogeneic stem-cell transplantation. At evaluation, seven (54%) alive. Finally, post calculated follow-up period 20 months 2–141 months]. survival, using Kaplan-Meier method date first injection last death, estimated 17 (Fig 1). had specific complications, such cytopenias, IT use nor signs tolerance, except pain who scopically guided injections. conclusion, this highlights need reconsider our practices management invasion seems be increasing since new anti-plasma evidenced latest published rates, average around 2–3%.8 effective found recent anti-myeloma diffusion across blood–brain barrier. report analysis CNS-MM. Although retrospective not designed studying efficacy, feasibility toxicity standard care compare infrequent situation. Thus, appears least twice previously studies, more half methotrexate, cytarabine methylprednisolone.3-9 These encouraging results could explained majority invasive dural damage. However, evidence surrounding outcome reflect efficiency agent thiotepa. regard, methylprednisolone, responsive IT. As cancer, confirmed excess radiotherapy. issue may rapidly lead death. association us strategy thiotepa, studies.3, 15 Moreover, target should considered, particularly symptomatic. Prospective, multicentre essential improve provide better understanding penetrance current future agents.