Background Establishing a curative strategy for multiple myeloma (MM) remains a significant challenge. While cure is defined as a sustained disease-free remission after treatment discontinuation, not all patients still achieve this outcome. However, recent results with CAR-T therapy offer considerable promise, with some patients experiencing long-term (5+ years) disease-free survival following treatment completion (Voorhees PM. ASCO2025 #7507). Conversely, conventional therapies with novel agents have shown limited disease-free intervals, and treatment interruptions often lead to relapse. The mechanism of CAR-T therapy suggests that anti-tumor effects by MM-targeted T cells contribute to this prolonged remission. Extended disease-free intervals correlate with improved outcomes. Therefore, it is crucial to identify the underlying factors in patients with such long-term remission. This study aims to comprehensively analyze the genetic background of this patient subgroup.

Methods We analyzed 282 newly diagnosed MM patients retrospectively (National Center for Global Health and Medicine and Tokyo-Kita Medical Center, 2007-2025). Clinical specimens from our institutional biobank underwent genetic analysis.

Results Among our cohort, we identified two patients who maintained remission for 10+ years despite discontinuing anti-MM treatment, with contrasting clinical courses. The first patient maintained treatment-free remission for 14 years after discontinuing thalidomide (Thal) maintenance, following remission induction and tandem autologous stem cell transplantation (ASCT). In contrast, the second patient presented with multiple bone lesions and primary refractoriness. Despite aggressive recurrence after tandem ASCT, salvage with VTD-PACE and an additional ASCT proved effective. This patient has since maintained remission for 12 years without anti-MM treatment.

We investigated factors dedicated to their clinical courses, from both tumor and host background. In both cases, Whole-exome sequencing revealed no mutations in genes such as KRAS, MYC, or TP53, related to MM progression (Bolli N. Nat Commun 2014;5:2997), nor ASXL1 and TET2, leading to CHIP (Lionetti M. Blood2023;146(5):571). Therefore, we performed HLA typing to investigate the host immune factors. Patients in this subgroup shared a haplotype containing HLA-B*46, predominantly distributed in East Asia. Given the frequency of this haplotype in Japan, this result is considered statistically significant.

Discussion Dimopoulos reported that usage of Thal was associated with Ultra-Long-Term survival (ASH2024 #1948). Our cases also received Thal before treatment discontinuation, maintaining remission not only for Long-Term (LT) but also with Treatment-Free status. These suggest that Thal may be effective for long-term disease control. However, among long-term survivors, patients in remission with Treatment-Free are extremely rare. Therefore, additional factors are likely necessary to achieve LT Treatment-Free R. Genomic analysis of our cases revealed no tumor-specific mutations that could explain the clinical course. However, haplotype sharing, including HLA-B*46, was identified as an immunological background factor. A cohort of Japanese MM patients enrolled in clinical trial (JCOG1105) showed no significant difference in the prevalence of the HLA-B*46 haplotype compared to healthy individuals (Ri M. Cancer Sci 112(12)5011). Nevertheless, given its significant association with our subgroup, the HLA-B*46 haplotype may be essential for maintaining LT-TFR. While rare in Europe and the US, the HLA-B*46 haplotype is relatively frequent in East Asia, including Japan and China. Considering the lower incidence of myeloma in East Asia than in Africa and Europe, the HLA-B*46 haplotype might confer a protective effect against myeloma. Thal is approved for myeloma and leprosy in Asia. Regarding leprosy, immune surveillance by HLA-B*46 allele provides greater protection than the others. This effect may have contributed to the increased frequency of this allele in Asia, as reported (Hilton HG. Cell Rep. 2017;19(7):1394). These results suggest a potential correlation between the efficacy of Thal and the coverage of specific immune surveillance.

Conclusion We identified a patient subgroup achieving Treatment-Free Remission for 10+ years. This clinical status represents the closest approximation to a cure in MM. Given the rarity of such cases, we need further analysis of this patient subgroup.

This content is only available as a PDF.
2025
Sign in via your Institution