Is low alkaline phosphatase (ALP) associated with multiple myeloma or lytic lesions?

Is Low ALP Related to Myeloma or Lytic Lesions?

Yes, low or normal alkaline phosphatase (ALP) levels are characteristically associated with multiple myeloma and lytic bone lesions, distinguishing it from other cancers with bone involvement. This occurs because myeloma causes predominantly osteoclastic (bone-destroying) activity without corresponding osteoblastic (bone-forming) activity, and ALP is primarily a marker of bone formation 1, 2.

The Pathophysiology Behind Low ALP in Myeloma

• Multiple myeloma causes bone destruction through increased osteoclastic activity that occurs near myeloma cells, but critically, this is not accompanied by a comparable increase in bone formation because osteoblasts are functionally exhausted 2
• Since ALP is a marker of osteoblastic activity and bone formation, the suppressed osteoblast function in myeloma results in normal or low ALP levels despite extensive lytic bone disease 2
• This contrasts sharply with solid tumors metastatic to bone, where ALP is typically elevated 1

Clinical Significance as a Diagnostic Discriminator

A landmark 2021 study of 901 patients (440 with myeloma, 461 with solid cancers) demonstrated that ALP values in multiple myeloma patients remained predominantly normal despite bone lesions, while patients with solid cancers and bone metastases had elevated ALP 1. This difference was independent of:

• Disease stage 1
• Number of bone lesions 1
• Type of bone lesions 1

The study concluded that normal or low ALP in the presence of bone lesions should prompt investigation for myeloma, including serum and urine protein electrophoresis, followed by bone marrow aspirate if a monoclonal component is detected 1.

Important Caveats and Exceptions

When ALP May Rise in Myeloma

• High baseline bone-specific ALP (≥146 U/L) is actually a poor prognostic marker in myeloma patients, associated with worse survival 3
• ALP can increase during successful treatment with certain agents:
  • Bortezomib therapy causes ALP elevation in responding patients (complete and partial responders) within three cycles, reflecting osteoblastic reactivation 4
  • Carfilzomib treatment shows ALP increases of >15 U/L by Cycle 2 Day 1 in patients achieving very good partial response or better 5
  • These treatment-related increases represent restoration of bone formation and are positive prognostic indicators 4, 5

Bone Markers in Myeloma

• Markers of bone resorption (NTX, CTX, ICTP) are elevated in myeloma and correlate with extent of bone disease and survival 2
• Bone formation markers like bone-specific alkaline phosphatase (BALP) have produced conflicting results but correlate with bone pain, lytic lesions, and fractures in some studies 2
• However, routine use of biochemical bone markers for monitoring is not recommended due to lack of prospective validation studies 3

Practical Clinical Algorithm

When encountering a patient with bone lesions:

1. Check ALP level alongside imaging findings

2. If ALP is normal or low with lytic lesions present: High suspicion for multiple myeloma

   • Order serum protein electrophoresis with immunofixation 1
   • Order urine protein electrophoresis with immunofixation 1
   • Order serum free light chain assay 6
   • If monoclonal protein detected, proceed to bone marrow biopsy 1

3. If ALP is elevated with bone lesions: More consistent with solid tumor metastases, though does not exclude myeloma with high baseline BALP 1, 3

4. During myeloma treatment: Rising ALP may indicate therapeutic response and osteoblastic reactivation, particularly with proteasome inhibitors 4, 5