Fishing for 1q gain is now open in amyloidosis

In this issue of Blood, Chakraborty et al show that the presence of 1q gain in amyloid light chain (AL) amyloidosis is associated with a lower hematological response rate and a worse event-free survival for patients treated with frontline daratumumab given with bortezomib-cyclophosphamide-dexamethasone (Dara-VCD) or daratumumab with bortezomib-dexamethasone (Dara-VD).¹ 

AL amyloidosis is characterized by deposition of insoluble amyloid fibrils of light chains produced by clonal plasma cells, resulting in progressive organ damage. For decades, AL amyloidosis treatment has been empirical, using the drugs and drug combinations developed for multiple myeloma. Since 2022, treatment strategies shifted to evidence-based medicine after the results of 3 clinical trials showing the efficacy of Dara-VCD² or Dara-VD.³ 

Currently, risk assessment of amyloidosis relies mainly on the evaluation of the organ damage (heart and kidney dysfunction).⁴ However, the prognosis is not only dependent on the organ involvement but also on the plasma cell clone.⁵ Unlike multiple myeloma where the impact of cytogenetic abnormalities is well described, studies in AL amyloidosis are rare, especially for patients treated with the new standard of care, Dara-VCD. Indeed, cytogenetic assessment can be challenging due to the low percentage of clonal plasma cells infiltrating the bone marrow. About 50% of patients with AL amyloidosis have the translocation t(11;14), which has been shown to be associated with poor survival in the context of bortezomib treatment.⁶ Hyperdiploidy and del17p were also associated with inferior outcomes. However, in the ANDROMEDA clinical trial evaluating the Dara-VCD combination, organ and hematologic responses rates were not impacted by t(11;14) positivity.

In their retrospective multicenter study, Chakraborty et al investigate the prognostic impact of these cytogenetic abnormalities by fluorescence in situ hybridization (FISH) for patients with newly diagnosed systemic AL amyloidosis treated with frontline Dara-VCD or Dara-VD. This collaborative work included assessment of cytogenetic abnormalities of plasma cells from 283 patients, a large cohort considering the incidence of the disease and the challenges of performing FISH on AL amyloidosis plasma cells. Even though it was not the main objective of this study, it is important to mention that the authors did not observe any difference of outcomes between Dara-VCD and Dara-VD regimens. This study did confirm that with daratumumab-based frontline therapies, t(11;14) is no longer an adverse prognostic factor. More importantly, they show that the presence of 1q gain (22.3% of patients in their cohort) is predictive of an inferior hematological response rate (see figure). This finding is critical as the depth of hematological response is directly associated with outcomes in AL amyloidosis. 1q gain was also associated with a worse event-free survival. The impact on overall survival should be reevaluated after a longer follow-up.

In another study reposted by Szalat et al, patients treated with daratumumab monotherapy, 1q gain also had an inferior major organ deterioration progression-free survival and inferior overall survival.⁷ 

Although hyperdiploidy is considered a marker for a good prognosis for patients with multiple myeloma, the ANDROMEDA study showed that hyperdiploidy was associated with worse prognosis in AL amyloidosis. Here, Chakraborty et al show 1q gain with hyperdiploidy is frequent in amyloidosis, which likely explains the unexpectedly dismal impact of hyperdiploidy in this context. Finally, they show, even if patients numbers are low, the absence of prognostic impact of del17p and high-risk 14q32 translocations (t(4;14), t(14;16), t(14;20)).

Daratumumab was the first-in-class anti-CD38 monoclonal antibody. Since then, other monoclonal antibodies targeting CD38 have been developed such as isatuximab. In multiple myeloma, some studies suggest that the effect of daratumumab in patients with 1q gain is diminished compared with those without 1q gain, and isatuximab seems to show promise in this subclass of patients. However, the impact of this class of monoclonal antibodies is still controversial, and the direct comparison between the 2 anti-CD38 has never been evaluated in a clinical trial.⁸ Clinical trials evaluating isatuximab in AL amyloidosis are ongoing, and it will be interesting to assess specifically the outcomes in the subset of patients harboring 1q gain.

In this study, cytogenetic abnormalities were detected by FISH. Although it is standard in plasma cell disorders, this technique suffers from some limitations. Minor clones in AL amyloidosis can be difficult to detect, and FISH cannot guarantee that the plasma cells being analyzed are clonal. The next-generation sequencing (NGS) panels that have been developed for myeloma detect all abnormalities in 1 technique and now require very few cells.⁹ Using NGS panels would permit studying the incidence and prognostic impact of more cytogenetic abnormalities, including del(1p32), which was shown to have an important prognostic value in myeloma, but also mutations such as TP53. In addition, when the bone marrow infiltration is low, a negative FISH result can be difficult to interpret, whereas NGS ensures that clonal population has been captured.

To conclude, the results of this study provide important data about the prognostic value of cytogenetics for patients with AL amyloidosis treated by modern Dara-based frontline therapy. Patients with 1q gain may not entirely benefit from the therapeutic progress and should ideally be enrolled in clinical trials to eventually improve outcomes for this specific subset of patients.

Conflict-of-interest disclosure: The authors declare no competing financial interests.