Relapsed/refractory patients

Case Study | Triple refractory MM patient with sustained response to daratumumab monotherapy

Daratumumab has been heralded a game changer in Multiple Myeloma (MM) as it drives strong responses, both as a monotherapy and in combination with backbone regimens. Daratumumab is slowly edging towards use as a frontline therapy, but recent approvals currently place it firmly in the relapsed setting.

The SIRIUS clinical trial assessed the efficacy of daratumumab in heavily pre-treated MM patients who had received at least 3 prior lines of therapy including a PI and an IMiD or whose disease was double refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). The median duration of response was 7.6 months, but one patient stood out as his clinical response lasted 3.5 years with the eradication of Minimal Residual Disease (MRD), despite having a del(17p) high-risk cytogenetic profile.

To further understand the reason for such a deep and durable response, the patient was studied by Saad Z. Usmani and colleagues from the Levine Cancer Institute/Carolinas Health Care System, USA, and the case study was published in Experimental Hematology & Oncology in February 2018.

Key Highlights:
  • 2011: 70-year-old male presented with a plasmacytoma of the right eleventh rib
  • Bone Marrow (BM) biopsy = 10% clonal plasma cells; negative 24-h urine protein electrophoresis; serum protein level = 0.3 g/dL (IgA kappa) and kappa-to-lambda ratio = 1.96
  • October 2011: MM diagnosis was given (IgA kappa) – stage 1 by the International Staging System (ISS)
  • Detection of 17p deletion by fluorescence in situ hybridization (FISH) in 7.5% of plasma cells
  • December 2011–June 2012, pt received induction therapy of:
    • One cycle of lenalidomide and dexamethasone (minimal response)
    • Five cycles of bortezomib, lenalidomide, and dexamethasone (partial response)
  • September 2012: pt received an Autologous Stem Cell Transplant (ASCT) and achieved a very good partial response (VGPR)
  • Pt received maintenance therapy of Weekly bortezomib (1.3 mg/m2) plus lenalidomide (10 mg daily on days 1–21 of each 4-week cycle) until disease progression in March 2013
  • April 2013: pt received: pomalidomide (4 mg orally on Days 1–21 of each 4-week cycle) and bortezomib weekly (1.5 mg/m2), and dexamethasone
  • Pt achieved a partial response (PR) prior to disease progression after 6 cycles
  • October 2013: pt was enrolled in the SIRIUS study and received daratumumab monotherapy
    • No reported infusion reactions
    • After 28 days pt achieved a PR
    • After 56 days pt achieved a VGPR
    • May 2014 (194 days after the first infusion): pt achieved a stringent Complete Response (sCR), marked by no detectable disease by IMWG criteria
  • Daratumumab was continued at 16 mg/kg once every 4 weeks and sCR maintained for over 3.5 years (as of May 2017)
  • Assessment of pt’s baseline immune profile prior to first dose of daratumumab:
    • Pt’s baseline peripheral levels of natural killer, B, and T cells (CD3, CD4, CD8) were similar to the levels of other pts enrolled in the study
    • Pt had elevated baseline levels of regulatory T cells compared with other pts: all patients = 23 x 106/L (variance = 14.24) and case study patient = 51 x 106/L
  • All pts had an expansion of clonal T-cells (predominantly CD8+) but this patient had the highest expansion – approximately 800% from baseline in 3 months and this was sustained for 32 months
  • Regulatory T-cells were decreased by 67% at the 3-month mark
  • December 2015: pt was MRD negative at 10−5 sensitivity threshold

The efficacy of daratumumab monotherapy in an elderly patient who relapsed after five lines of therapy, including ASCT, was described and attributed to a notably increased T-cell population. The first response was observed within a month and sCR was achieved after 194 days and maintained for over 3.5 years. This study therefore further highlights the strong immunomodulatory effect of daratumumab, which includes CD8+ T-cell expansion and increased T-cell clonality, as well as a decrease in regulatory immune cell populations. The question going forward is why certain patients are more likely to have expanded T-cell populations compared to others, and what factors can determine this outcome.

References
  1. Usmani S. Z. et al. Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma. Experimental Hematology & Oncology. February 2018. DOI: 10.1186/s40164-018-0096-7
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