How to Treat Isolated Leptomeningeal Relapse of Multiple Myeloma 11 Years after Autologous Stem Cell Transplantation (ASCT)

Abstract

Post transplant relapse of Multiple Myeloma (MM) in the central nervous system (CNS) is rare and it is almost always associated with systematic relapse and in most instances, shortly after initial treatment. We did not encounter reports of relapse isolated to the CNS ten years post-transplant. In October 2009, a 49-year-old male presented with an IgG lambda MM, ISS II. He was treated with Bortezomib/Dexamethasone, autologous PBSCT, followed by two years maintenance with Lenalidomide, attaining stringent CR, confirmed by PET/CT. He discontinued follow up and returned after 11y/8m progression free survival, in June 2021 with paraplegia due to cauda equina syndrome. NMR consistent with leptomeningeal infiltration, single focal intramedullary lesion at L1 level without bone affectation. No MM defining criteria (CRAB). Normal levels of serum Immunoglobulins (IGs), serum and urine immunofixation, and serum free light chains. Flow cytometry negative in bone marrow. Spinal tap was unsuccessful and through an Ommaya reservoir, that was placed after NMR showed evidence of cranial leptomeningeal involvement, CSF showed infiltration by countless malignant plasma cells. Patient received immediate conformational radiotherapy and biweekly IT methotrexate and hydrocortisone. A month later his course was complicated by left leg proximal deep vein thrombosis and pulmonary embolism which was treated with Apixaban. Given the rarity of this type of relapse, we questioned the appropriateness of the treatment and searched the literature with respect to the accessibility of the CNS by the different novel drugs used to treat MM in order to determine the most effective strategy. In addition to corticosteroids, there is clinical evidence that thalidomide crosses the blood-brain barrier (BBB), in murine models pomalidomide also has good penetration into the CNS. Both have a penetration of 30 to 40% into the CSF. Among proteasome inhibitors, only marizomib has been observed to cross the BBB in a murine model, while bortezomib does not. With respect to anti CD38 monoclonal antibodies, mass spectrometry at 12, 15, and 19 days after daratumumab infusion showed antibody levels in CSF 71 times less than in serum on the three sample days. It is not known if weekly doses of daratumumab could attain therapeutic levels in CSF. We found only 14 cases of isolated CNS relapse in patients with MM treated with ASCT with a median interval between transplant and relapse of 3 months (0.5-96m), with only one reported relapse 7.5 years after autologous transplant and the median overall survival was only 3 months. Two cases died in less than a month and only one case survived for a year after the CNS relapse.To date, our patient has received 12 cycles of Pomalidomide/dexamethasone with progressive improvement, now he is able to carry on his life unassisted and there is no evidence of MM relapse anywhere. The rarity of this case scenario highlights the lack of knowledge regarding the best approach to CNS MM relapse. There is no evidence of the effectiveness of methotrexate and Ara C, in MM, and no novel drug can be instilled into the CSF. We conclude that the systemic use of pomalidomide and dexamethasone should be the best approach of MM isolated CNS relapse. Further investigations will clarify if other novel drugs are active in this context.