Patient outcomes (median 4.6 year follow up):
Among ≥VGPR patients, MRD- was associated with improved PFS compared to patients with MRD+ (3-year PFS 88% vs. 46%, p=0.003), particularly among patients who achieved a complete response (3-year PFS 100% vs. 33%, p=0.001). In contrast, this difference in PFS advantage in VGPR/MRD- compared to those who achieved VGPR/MRD+ did not reach statistical significance (p=0.14)
OS difference was not seen between MRD- and MRD+ groups (3-year OS 96% vs. 84%, p=0.17)
MRD- compared with MRD+ among deep responders was associated with lower level of involved light chain (involved free light chain, median 1.1 vs. 1.7mg/dL; p=0.02) and higher frequency of renal response (100% vs. 68%; p=0.005) . When assessing independent organ function, this difference was not evident in cardiac response
- Conclusion 1. Despite the retrospective nature of this study with the inherent selection bias to include primarily transplant eligible patients, this work aims at offering novel, robust surrogate endpoint for the design of clinical trials, as well as for optimizing individual patients’ treatment
- Conclusion 2. There may be value in bone marrow biopsy/aspirate at end of therapy in AL amyloidosis patients who achieve VGPR/CR. Presence of MRD is associated with reduced PFS in this group of patients.
- Conclusion 3. The sensitivity of the current standard assay for serum free light chain detection does not discern between MRD positive vs negative among VGPR/CR patients.
- Conclusion 4. This study is notable for presenting one of the largest patient cohorts for end of treatment MRD assessment and applying uniform flow cytometric techniques.
MRD assessment in AL amyloidosis is not yet standardized. Of interest, a study using next generation flow for MRD assessment found that 5 out of 12 MRD positive cases had very low residual tumor burden (<3×10-5), which would have not been detected with lower sensitivity assays (Kastritis et al. 2018). This paper assessed 20 AL patients with hemCR. 8 out of 20 patients were MRD(-). 2 out of 8 patients who had ASCT as primary therapy achieved MRD(-) status, versus 6/12 (50%) patients who did not have ASCT as primary therapy (p = 0.264). In two cases aberrant cells were detected at levels between 10−5 and 10−6 Their reported median sensitivity level of next gen flow was 2.3 x 10−6 (range: 2 × 10−6–3.1 × 10-6)
- How does MRD status guide frequency of follow up of patients after therapy?
- If a patient initially achieves MRD neg CR but then progresses to MRD positive CR on repeat follow up, does this indicate progression/ requirement for treatment?
- What is the role of transplant in achieving MRD negative status? The impact of daratumumab in achieving MRD negative status? As per our discussion from last week, looking forward to upcoming ISA abstract from @vsanchorawala regarding role of transplant in this topic!
- Does time to MRD achievement matter and if so, what is the optimal time to assess MRD in AL amyloidosis? Interesting report by Muchtar et al. 2019 in Leukemiajournal, looked at not only the depth of response (in this case nadir iFLC <2mg/dL) but also the impact of time to nadir iFLC on patient outcomes. Patients whose nadir iFLC occurred after 12 months from EOT had significantly longer PFS and OS compared to patients who reached nadir before 12 months. This raises the question as to whether there a role for MRD assessment not only at EOT but also further out from EOT.
Obviously, there are many questions related to the utility and usage of MRD testing in AL amyloidosis – looking forward to the journal club where we can explore this further! -J.Zonder,MD
UPDATE 12/1/19 @ 10:19 pm: link to transcript of tonight’s twitter discussion CLICK HERE.