Multiple myeloma with ISS stage 3 — β2-microglobulin ≥5.5 mg/L — high-risk presentation;...

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

ID	`RF-ISS-3`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-MM`
Sources	`SRC-ESMO-MM-2023` `SRC-NCCN-MM-2025`

Red Flag Origin

Definition	Multiple myeloma with ISS stage 3 — β2-microglobulin ≥5.5 mg/L — high-risk presentation; supports four-drug daratumumab-anchored 1L and transplant pursuit when feasible; trigger for R-ISS / R2-ISS upgrade with cytogenetics
Clinical direction	intensify
Category	risk-score
Shifts algorithm	ALGO-MM-1L

Trigger Logic

{
  "any_of": [
    {
      "comparator": ">=",
      "finding": "beta2_microglobulin_mg_per_l",
      "threshold": 5.5
    },
    {
      "finding": "iss_stage",
      "value": "3"
    },
    {
      "finding": "iss_risk_group",
      "value": "high"
    }
  ],
  "type": "composite_score"
}

Notes

ISS-3 (β2M ≥5.5) median OS ~29 mo in the original cohort, improved substantially in the daratumumab era. ISS-3 alone is not a sufficient intensification trigger — cytogenetics drive the upgrade to R-ISS (Palumbo 2015) and R2-ISS (D'Agostino 2022). When ISS-3 co-occurs with high-risk cytogenetics + LDH-high, R-ISS-3 emerges and warrants the most intensive 1L (RF-R-ISS-3-HIGH-RISK). Direction `intensify` reflects the four-drug-1L preference over triplet for ISS-3 even when cytogenetics standard.

Used By

Algorithms

ALGO-MM-1L - ALGO-MM-1L