Functional High-Risk Multiple Myeloma

Mr. S. is a 62-year-old male with new onset back pain and fatigue. A bone marrow biopsy and imaging were conducted due to high suspicion of multiple myeloma. FISH studies conducted on his bone marrow biopsy were negative for del(17p), t(4:14), t(14;16) or t(14;20), and del(1p32). There was evidence of 1q21 gain. A whole-body low-dose CT confirmed multiple lytic lesions in the lumbar spine and pelvis. There was no evidence of extramedullary plasmacytomas. The ISS Stage II criteria combined with standard-risk cytogenetics and normal lactate dehydrogenase (LDH) placed Mr. Stone in the R-ISS II (Revised International Staging System Intermediate Risk) category.¹ 

Mr. S. received induction therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd) for 4 cycles and underwent autologous stem cell transplantation (ASCT) 4 months after diagnosis. A bone marrow biopsy at day 100 post-ASCT confirmed a complete response (CR) with no detectable measurable residual disease (MRD) by next-generation sequencing. He was started on lenalidomide maintenance therapy. 

Mr. S.'s disease unexpectedly progressed 11 months after ASCT, manifesting as anemia and a reappearance of an M spike while on lenalidomide maintenance, meeting the definition of functional high-risk multiple myeloma (FHRMM) due to the early relapse (within 12 to 18 months of ASCT) despite initial intermediate/standard-risk genetic features.²A repeat bone marrow biopsy at the time of relapse confirmed an acquired del17p on FISH studies. 

Given the diagnosis of functional high-risk multiple myeloma and the acquisition of a new high-risk cytogenetic marker (del 17p), a highly effective novel therapy was warranted. 

The decision was made to pursue CAR T-cell therapy. Due to a significant wait time for product manufacturing, Mr. S. was started on a bridging therapy to rapidly reduce the tumor burden and prevent further end-organ damage. Mr. S. successfully underwent leukapheresis to collect his T-cells, and after a 6-week manufacturing period, Mr. S. received lymphodepleting chemotherapy with fludarabine and cyclophosphamide and then infusion of his B-cell maturation antigen (BCMA)-directed CAR T-cells. He developed grade 2 cytokine release syndrome (CRS) on day 4 post-infusion, which was managed successfully with tocilizumab and supportive care.³He did not experience immune effector cell-associated neurotoxicity syndrome (ICANS). The 3-month post-CAR T-cell therapy assessment showed a stringent complete response (sCR), which was confirmed by a bone marrow biopsy with negative MRD. The aggressive nature of his FHRMM disease was successfully managed with this high-potency cellular therapy. 

Discussion: 

Functional high-risk multiple myeloma is a concept that moves beyond static initial genetic profiling (like FISH at diagnosis) and incorporates the kinetic behavior of the disease. FHRMM is primarily defined by poor response to initial therapy or early relapse, typically defined as progression within 12 to 18 months of starting frontline therapy or after achieving an initial response with ASCT.² The R-ISS combines standard clinical factors (beta-2 microglobulin and albumin) with high-risk cytogenetics and LDH to provide a more refined prognostic assessment than the original ISS. R-ISS Stage I, II, and III have approximately a median overall survival of 83, 62, and 29 months respectively. ¹

Mr. S. was initially R-ISS II. His subsequent FHRMM classification overrode this prognosis, demonstrating that early relapse is the most significant indicator of high-risk disease kinetics, often leading to a survival more aligned with, or even worse than, R-ISS III.² 

CAR T-cell therapy has revolutionized the treatment of relapsed/refractory multiple myeloma. Historically, CAR T-cell therapy was reserved for heavily pre-treated patients but due to the extremely poor prognosis of FHRMM, there is a strong rationale for moving highly potent agents like CAR T-cells into earlier lines of therapy, especially in the first relapse setting.^4,5 For Mr. S., his early relapse and acquired high-risk genetics made him an ideal candidate for CAR T-cell therapy to maximize depth and duration of response. Achieving an sCR with negative MRD is the optimal outcome, as demonstrated by Mr. S. This depth of response is strongly associated with improved progression-free and overall survival, potentially overcoming the poor prognosis conferred by FHRMM.5 

The primary toxicities associated with CAR T-cell therapy are CRS and ICANS. CRS results from the massive, rapid release of inflammatory cytokines (like IL-6) by activated T-cells. It typically manifests as high fever, fatigue, hypotension, and hypoxia. Management follows consensus grading3 (American Society for Transplantation and Cellular Therapy criteria), including supportive care, tocilizumab, and corticosteroids. ICANS is less understood than CRS but linked to inflammation and damage to the blood-brain barrier. Symptoms include confusion, seizures, aphasia, and motor weakness and requires the initiation of corticosteroids alongside supportive care. 

References 

1. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869. doi:10.1200/JCO.2015.61.2267 
2. Multiple Myeloma Working Group (IMWG) Consensus. Definition of functional high-risk multiple myeloma (FHRMM) is generally considered progression/relapse within 12-18 months of initial therapy or ASCT. https://www.myeloma.org/videos/does-it-mean-have-functional-high-risk-multiple-myeloma 
3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758  
4. Banerjee, R. Functional high-risk myeloma: CAR-T optimizes outcomes at relapse | Rahul Banerjee, MD | #IMS2025. YouTube. September 25, 2025. Accessed November 20, 2025. https://www.youtube.com/watch?v=VnFFL49Wv14 
5. Kumar SK, et al. (2022). Efficacy and safety of idecabtagene vicleucel (ide-cel; bb2121) in patients with relapsed/refractory multiple myeloma: updated results from KarMMa. Journal of Clinical Oncology, 40(16), 7506.