First‑Line Treatment Recommendations for AL Amyloidosis

Eligibility and Preferred Regimens

Approximately 20 % of patients are eligible for autologous stem‑cell transplantation (ASCT); ASCT is reserved for carefully selected individuals with limited organ involvement and good performance status. 1, 2, 3
In transplant‑eligible patients, ASCT may be preceded by a bortezomib‑based induction regimen to improve disease control before transplant. 1, 2
For the majority of patients who are transplant‑ineligible, the FDA‑approved DaraCyborD regimen (daratumumab + cyclophosphamide + bortezomib + dexamethasone) is the standard first‑line therapy, providing rapid and deep hematologic responses that translate into better organ function and survival. 1
Bortezomib‑based combinations such as CyBorD (cyclophosphamide + bortezomib + dexamethasone) and BMDex (bortezomib + melphalan + dexamethasone) remain central components of upfront treatment when daratumumab is not used. 1, 2

The therapeutic goal is to achieve a very good partial response (VGPR) or better, defined as a difference in free light chains (dFLC) < 40 mg/L. 1, 4
A stringent dFLC response (dFLC < 5–20 mg/L) predicts superior organ responses and longer survival. 4
Achieving a complete hematologic response with undetectable minimal residual disease (MRD) by next‑generation flow cytometry is associated with ~90 % renal and ~95 % cardiac response rates. 4, 5
Median time to hematologic response after the first daratumumab dose is approximately 1 week, underscoring the need for early assessment. 4, 5
A complete hematologic response does not guarantee organ improvement; MRD assessment adds prognostic information beyond conventional response criteria. 4, 5

For patients who did not receive daratumumab in the frontline setting, daratumumab‑based therapy is recommended as second‑line treatment, yielding overall response rates of 63–100 % (most achieving VGPR) and a 2‑year overall survival of 74 %. The principal toxicity is infection secondary to hypogammaglobulinemia. 4, 5
If hematologic relapse occurs ≥ 2 years after the last therapy, re‑treatment with the previously effective regimen can be considered. 4, 5
In patients who are not bortezomib‑refractory, repeat bortezomib‑based regimens (CyBorD, BMDex, or bortezomib + dexamethasone) are appropriate. 4, 5
For bortezomib‑refractory disease, pomalidomide + dexamethasone provides a 48 % overall hematologic response with a median time to response of 1.9 months and is better tolerated than lenalidomide. 5
Lenalidomide + dexamethasone may be used with caution in selected patients, recognizing its higher toxicity profile. 4, 5

Lenalidomide is associated with renal deterioration in 66 % of treated patients; only ~50 % of these cases are reversible. 4, 5
Cardiac toxicity manifests as rising NT‑proBNP/BNP levels; patients should be monitored closely for fluid retention and weight gain. 4, 5
Initiate lenalidomide at low doses (5–15 mg/day), with further dose reductions for elderly patients or those with baseline cardiac involvement or elevated creatinine. 5
Pomalidomide is slightly better tolerated and typically produces rapid responses within 1–3 months. 5

*Stage IV survival data were not provided with a citation. 5

More than 69 % of patients present with involvement of multiple organs at diagnosis, emphasizing the systemic nature of AL amyloidosis. 1, 2, 3
Cardiac involvement is the principal determinant of prognosis and mortality in AL amyloidosis. 1, 2, 3
Early initiation of therapy is critical to prevent irreversible organ damage and improve outcomes. 1, 2, 3

Thalidomide should be avoided in AL amyloidosis because of its high toxicity profile. 4, 5

AL amyloidosis affects approximately 10 individuals per million per year, with a late onset and an equal distribution between sexes【6】.

Because its early manifestations are nonspecific and mimic other diseases, misdiagnosis is common, leading to frequent diagnostic errors【6】.