Factors Associated with Elevation of Alkaline Phosphatase after First-Line Chemotherapy in Newly Diagnosed Multiple Myeloma By Japan Medical Data Center Claim Database
Authors: Murai Junpei , Nakamura Shingen , Okamoto Yasunobu , Hori Taiki , Yuasa Tomoyuki , Aihara Ken-Ichi , Takishita Makoto , Harada Takeshi , Matsuoka Ken-ichi 
Published: December 2024

Background: Multiple myeloma (MM) is characterized by bone destruction, anemia, and renal disorder with paraproteinemia. Particularly, bone lesions are caused by an imbalance between osteoclastogenesis and osteoblastogenesis due to various factors and cell interactions within the microenvironment, which strongly suppresses bone formation. While some cases experience acute and sustained elevation of alkaline phosphatase (ALP) with bone re-mineralization during early treatment, the frequency and associated factors underlying this phenomenon remain unclear.
Aim: This study aimed to clarify the clinical course of ALP levels and identify the factors associated with its increase in patients with MM.
Method: We retrospectively collected and analyzed data from the anonymized Japan Medical Database Center on patients who received chemotherapy between April 2014 to November 2022. “ALP increase” was defined as doubling of the initial measurement to over 500 U/L within 150 days of treatment initiation. Patients with follow-ups of &lt;90 days and AST or ALT ≥200 IU/L were excluded. Logistic regression analysis evaluated the associations between ALP increase and age, sex, laboratory results, treatment effects, and administered drugs. Prognosis was analyzed using the log-rank test.
Result: A total of 683 patients with newly diagnosed MM (NDMM) and 621 patients with relapsed and refractory MM (RRMM) were enrolled. The median age for both groups was 74 years (67-80), with a median follow-up of 939 days (483-1535) in the NDMM group and 1043 days (582-1640) in the RRMM group. In the NDMM group, IgG and IgA type MM were most common (306 and 110 patients, respectively) with the following median results at diagnosis: ALP of 206 U/L (140-280), hemoglobin of 9.9 g/dL (8.5-11.5), corrected Ca of 9.6 mg/dl (9.2-10.1), and IgG of 4409 mg/dl (2723-6109). Regarding treatment, 415 (60.9%) received bortezomib-based therapies, 113 (16.6%) received daratumumab-based therapies, 173 (25.7%) received denosumab, and 358 (45.2%) received zoledronic acid. Moreover, ALP increase was observed in 73 patients (12.2%), achieving maximum ALP at a median of 41 days (28-68) after treatment initiation, with a 3.94±2.41-fold increase. In RRMM, only 30 patients (4.8%) demonstrated ALP increase. Although 78 deaths were observed in this group, the presence or absence of ALP increase did not significantly affect overall survival (p=0.5). Logistic analysis revealed that pre-treatment hemoglobin (odds ratio [OR]: 0.849, 95% confidence interval [CI]: 0.754-0.955, per 1g/dL increase; p=0.0066) and corrected Ca concentration (OR: 1.220, 95% CI: 1.030-1.440, per 1mg/dL increase; p =0.0228) were significantly associated with ALP increase. Furthermore, administration of zoledronic acid (OR: 1.580, 95% CI: 1.120-2.220; p=0.0087) and achieving a very good partial response (VGPR) within 6 months (OR: 2.010, 95% CI: 1.180-3.420; p=0.0103) were identified as treatment factors in ALP increase.
Conclusion: The study suggests that addressing factors contributing to anemia may be crucial in inducing bone formation in addition to rapid reduction of MM burden and bone resorption.