MYD88 L265P is the hallmark mutation of Waldenström macroglobulinemia, present in >90% of...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-WM-MYD88-L265P-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-WM`
Sources	`SRC-ESMO-WM-2024` `SRC-NCCN-BCELL-2025`

Red Flag Origin

Definition	MYD88 L265P is the hallmark mutation of Waldenström macroglobulinemia, present in >90% of WM. Drives constitutive NF-κB activation through BTK. iNNOVATE (Dimopoulos NEJM 2018) and the iNNOVATE long-term follow-up established ibrutinib + rituximab > placebo + rituximab regardless of prior therapy; MYD88-L265P-positive disease has the highest response rate to BTKi monotherapy (ORR ~90%, major-response ~70%) while MYD88-WT WM responds poorly. Routes 1L symptomatic WM with MYD88-L265P toward BTKi-based therapy (ibrutinib, zanubrutinib per ASPEN, or ibrutinib + rituximab) over DRC chemoimmuno when chemo-avoidance is preferred (cardiac, frailty, hyperviscosity-controlled).
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-WM-1L

Trigger Logic

{
  "any_of": [
    {
      "finding": "myd88_l265p",
      "value": true
    },
    {
      "finding": "myd88_mutation",
      "value": "positive"
    },
    {
      "finding": "myd88_status",
      "value": "L265P"
    },
    {
      "finding": "BIO-MYD88-L265P",
      "value": "positive"
    }
  ],
  "type": "biomarker"
}

Notes

CXCR4 WHIM-like mutations (~30-40% of WM) co-occur with MYD88-L265P and reduce BTKi major-response rate (~30% with CXCR4-mut vs ~70% in CXCR4-WT) — order CXCR4 alongside MYD88 to risk-stratify BTKi response; CXCR4-mut + cardiac comorbidity favors zanubrutinib (ASPEN) or bortezomib-based DRC. MYD88-WT WM (~10%) is biologically distinct, often IgM-MGUS-like or marginal-zone-overlap, and BTKi response very low (ORR ~30%, major <10%) — for MYD88-WT WM prefer chemoimmuno (DRC/BR) or proteasome-inhibitor regimens. Detection: allele-specific PCR on bone-marrow CD19-sorted cells (peripheral blood lower sensitivity); sequencing alone misses ~10% of L265P due to low tumor fraction.

Used By

Algorithms

ALGO-WM-1L - ALGO-WM-1L
ALGO-WM-2L - ALGO-WM-2L