Bone progression in multiple myeloma: Benefit of zoledronic acid for patients achieving at least Very Good Partial Response and prognostic value of bone turnover markers.

INTRODUCTION

Bone destruction is a common feature of multiple myeloma (MM) 1 and is associated with significant morbidity, 2 frequently leading to permanent disability, also in patients of working age. 3 Early initiation of monthly zoledronic acid (ZOL) reduces the risk of developing progressive bone disease (PBD) in MM. 4 , 5 , 6 Consequently, ZOL represents an important supportive therapy in MM, and its initiation is recommended for all patients with active myeloma. 7 However, the optimal duration of ZOL therapy is not clearly established. Current guidelines recommend at least 12 and up to 48 months of treatment. 7 , 8

In the Magnolia study, newly diagnosed MM patients were randomized after 2 years of ZOL treatment to discontinue treatment or to continue ZOL for a total of 4 years. We observed significantly lower rates of PBD in the prolonged treatment group 9 ; however, subgroup analyses according to International Myeloma Working Group (IMWG) response categories were not performed.

Bisphosphonates, including ZOL, are not without adverse effects. Medication‐related osteonecrosis of the jaw (MRONJ) occurs in 2.6%–4% of MM patients treated with bisphosphonates. 5 , 6 Risk factors for MRONJ include prolonged treatment duration, higher bisphosphonate potency, poor dental health prior to therapy initiation and dental extractions performed after treatment commencement. 10 , 11 Additionally, ZOL may impair renal function and cause hypocalcaemia. In cases of renal dysfunction, denosumab is often used as an alternative; however, it carries a similar risk of hypocalcaemia and MRONJ. 12 , 13

Given these potential toxicities, ZOL therapy ideally should be reserved for patients most likely to benefit, though identifying such patients remains challenging. Previous IMWG guidelines suggested that MM patients who have received at least 1 year of ZOL and achieved very good partial response (VGPR) or better may have a diminished need for continued bone‐protective therapy, allowing for treatment interval extension or discontinuation. 7 These recommendations were based on subanalyses of the Myeloma IX study, 14 the improved depth of response achieved with newer MM therapies, and studies exploring extended ZOL dosing intervals. 7 , 15 However, in the newer the European hematology association (EHA)/European Myeloma Network (EMN) guidelines, at least 12 and up to 48 months are recommended for patients achieving at least VGPR. 8

Some studies have reported very low rates of skeletal complications even in patients not receiving bone‐protective therapy, 16 , 17 which is consistent with the concept that reduced disease burden lowers the risk of PBD.

Bone turnover markers are small molecules released into the bloodstream during bone resorption and bone formation, respectively; their levels reflect bone formation and bone resorption activity. 18 , 19 There may be threshold levels of these markers below or above which bone‐protective therapy safely can be withheld, or conversely, levels indicating the need for treatment re‐initiation. Bone formation activity can be assessed by measuring bone‐specific alkaline phosphatase (BAP) and procollagen type I N‐terminal propeptide (PINP). 20 , 21 Bone resorption can be evaluated using C‐terminal cross‐linked telopeptide of type I collagen (CTX) and tartrate‐resistant acid phosphatase isoform 5b (TRAcP). CTX is a marker of type I collagen degradation and increases with bone resorption 20 , 21 , 22 while TRAcP is released during bone breakdown reflecting osteoclastic activity. 20 , 23

In addition, combining anabolic and catabolic markers may enhance predictive accuracy. For example, a prior study demonstrated the prognostic value of the CTX/BAP ratio. 20

In this study, we sought to determine whether specific subgroups of patients with MM could safely omit ZOL treatment on the basis of treatment response or measurements of bone turnover markers. We therefore examined whether patients achieving a VGPR or better continue to derive benefit from ZOL beyond 2 years of therapy. In addition, we investigated whether bone turnover markers could identify patients at increased risk of PBD, independent of disease response status.

MATERIALS AND METHODS (INCLUDING STATISTICAL APPROACH)

This study utilized data from the Magnolia trial (EudraCT number 2014‐002494‐12). The principal outcomes of the trial have been reported previously. 9

The Magnolia trial enrolled 193 newly diagnosed, treatment‐requiring multiple myeloma (MM) patients who received monthly ZOL for 2 years. Thereafter, participants were randomized either to continue monthly ZOL for an additional 2 years or to enter a 2‐year observation phase.

The present study examined two overlapping subpopulations from the Magnolia trial: Participants who at randomization had achieved VGPR or better according to the IMWG Uniform Response Criteria with their most recent treatment regimen ( n = 150; Table 1 ). All patients randomized to observation after 2 years of initial ZOL therapy ( n = 94; Table S1 ).

Baseline characteristics of the study groups are presented in Tables 1 and 2 . All participants were monitored for PBD at monthly clinic visits and myeloma bone imaging every 6 months or when clinically indicated. PBD was defined as a ≥25% increase in existing osteolytic lesions, the appearance of new osteolytic lesions (≥10 mm in diameter), new fractures or lesions requiring radiotherapy or surgery. Progressive disease (PD) was monitored monthly using serum M‐protein, free light kappa and free lambda chains, ionized calcium and renal markers. MRONJ was assessed by oral examination every 3 months; suspected cases were referred to oral surgeons for confirmation and management.

Substudy 1

Patients were classified according to their IMWG response status at the latest treatment before randomization (year 2). Only patients who had achieved VGPR or better were included. Hazard ratios (HRs) for PBD, MRONJ, overall survival (OS) and progression‐free survival (PFS) were estimated using Cox regression to account for variable follow‐up times. Time to event was defined as the interval from randomization to the relevant outcome or censored at the end of study. To avoid bias, patients in the treatment group were censored at the time of PBD, as those in the observation group were withdrawn from the study upon PBD.

Substudy 2

Fasting blood samples were obtained at baseline, 6 months, 12 months, at randomization (after 24 months) and monthly thereafter up to 48 months and stored at −80°C until analysis. Samples collected at baseline, 6 months, 12 months, at randomization and every third month thereafter were analysed. In patients with PD or PBD, markers were measured monthly for up to 3 months before the end‐point. The bone turnover markers investigated were CTX, P1NP, TRAcP and BAP.

Laboratory analyses

All bone turnover biomarker measurements were carried out at the Department of Biochemistry and Immunology, Lillebaelt Hospital, accredited by the Danish Accreditation Fund according to the ISO 15189 standard.

For standard serum (S‐), the blood was allowed to clot at room temperature for 30 min prior to centrifugation at 3000 g for 10 min, whereas for plasma (P‐) samples were centrifuged at 3000 g within 2 h. Samples were aliquoted in 0.0005 L Sarstedt polypropylene tubes and stored at −80°C until analysis. Technicians were not aware of treatment allocation.

Measurement of fasting plasma P1NP and CTX was both performed by validated routine methods (Cobas e602 analyzer, Roche Diagnostics, Denmark). The lower limit of quantification (LOQ) for P1NP and CTX was 10 and 0.05 μg/L, respectively, and the interassay coefficients of variation (CV) on two levels for both methods were 10% or lower.

Levels of TRAcP and BAP were analysed in serum using commercially available Electrochemiluminescence Immunoassay (ECLIA) assays, according to the manufacturer's instructions (ImmunoDiagnostic Systems Holdings PLC, East Boldon, UK). Limit of quantification (LOQ) i for Trap5b and BAP were 0.9 U/L and 0.1 μg/L, respectively, and the interassay CVs on three levels for both methods were 10% or lower.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Regional Committees on Health Research Ethics for Southern Denmark (EPN S‐20140138) and for Norway (EPN REK 2015/626). All patients who are included gave written consent to participation.

Statistical analysis

For each post‐ZOL bone marker measurement (from month 25 onwards), the proportion of PBD events within 6 months of sampling was calculated. For bone resorption markers (CTX and TRAcP), thresholds were determined to assess associations between elevated levels and subsequent PBD risk using the chi‐squared test. A similar approach was applied to bone formation markers (PINP and BAP) and to ratios of bone formation to bone resorption markers, evaluating whether lower ratios were associated with increased PBD risk. Measurements with less than 6 months of follow‐up were excluded.

To assess longitudinal changes in bone marker levels during and after ZOL therapy, mean values were calculated for months 0 (baseline), 6, 25 (after 2 years of treatment) and every 3 months thereafter. As not all participants completed the full study duration, comparisons were performed using unpaired t ‐tests between baseline and months 25 and 46.

All statistical analyses were performed using GraphPad Prism 10.2.1 (Dotmatics, USA) and StataBE 18 (StataCorp LLC, Texas, USA). Categorical variables were compared using chi‐squared or Fisher's exact test. Continuous variables were compared using unpaired t ‐tests.

Time‐to‐event outcomes, including PBD, MRONJ, PFS and OS, were analysed using the Cox proportional hazards model. HRs with 95% confidence intervals (CIs) were reported. The proportional hazards assumption was verified by inspection of log–log survival plots and found to be satisfied.

Kaplan–Meier survival curves were generated for visual comparison of time‐to‐event outcomes.

RESULTS

Sub study 1

Of the 193 participants randomized, 150 (78%) had achieved at least a VGPR at their latest treatment following the initial 2 years of ZOL therapy. Of these, 77 patients were randomized to continue ZOL treatment and 73 to observation. Baseline characteristics were comparable and are shown in Table 1 .

During follow‐up, PBD occurred in 17 of the 73 patients in the observation group and in 7 of the 77 patients in the continued ZOL group. Causes of PBD can be seen in Table 2 . Cox regression analysis demonstrated a significantly lower risk of PBD in the continued treatment group (HR 0.40; 95% CI 0.16–0.92; p = 0.031; Figure 1A ). The number needed to treat (NNT) to prevent one case of PBD was 7.5, similar to that previously reported for the overall study population irrespective of remission depth. 9 No significant differences were observed between groups in risk of PD, OS or MRONJ (Figure 1B–D ). A subgroup analysis was conducted among patients who had achieved a complete response (CR) prior to randomization ( n = 69). In this subgroup, patients continuing ZOL had a lower HR for PBD (HR 0.47; 95% CI 0.12–1.83); however, the difference was not statistically significant ( p = 0.278), likely reflecting limited power in this smaller cohort. No significant differences were observed for PD, OS or MRONJ in this subgroup (Figure S1 ). Of patients with no prior bone disease at diagnosis achieving VGPR at latest treatment before randomization ( n = 24), three experienced PBD during the study.

Substudy 2

For the bone marker study, a total of 94 patients were randomized to observation without further ZOL treatment and were included in the bone marker substudy. Across these participants, 682 fasting blood samples were analysed for CTX (μg/L), P1NP (μg/L), BAP (μg/L) and TRAcP (U/L). The haemolytic index was also assessed, and eight samples were excluded due to elevated indices that could affect assay results. The 94 patients delivered a total of 470 samples were patients had at least 6 months of follow‐up and these samples were included in analyses of PBD risk within 6 months of measurement. Of these, two samples of CTX, one BAP, two P1NP and one TRAcP were unsuccessful.

High levels of bone resorption markers were associated with an increased risk of PBD within 6 months. Samples with CTX ≥0.30 μg/L had a 28.6% risk of PBD within 6 months, compared with <5% for CTX <0.10 μg/L. When comparing samples with CTX ≥0.30 μg/L versus <0.30 μg/L, a significantly higher rate of PBD was observed (28.6% vs. 6.1%; p < 0.001). TRACP5b showed a similar but less pronounced pattern, with samples ≥4 U/L versus <4 U/L associated with 15.2% versus 6.1% 6‐month PBD risk respectively ( p = 0.026; Figure 2 ). Although elevated resorption markers were associated with PBD, this finding applied to only a minority of samples (CTX: 14/468; TRACP5b: 46/469). Bone formation markers (BAP and P1NP) were not predictive of PBD risk (Figure 2 ), and combining formation and resorption markers as ratios did not improve predictive value (data not shown). A significant relation between markedly elevated resorption markers and changes in level of M‐spike/light chains was not found.

Longitudinally, all four bone markers declined after initiation of ZOL therapy and gradually increased after discontinuation without returning to baseline levels during the study period (Figure 3 ). No significant differences in bone marker levels were observed between patients who subsequently developed PD without PBD, those with PBD or those who remained without disease progression at study end. This applied to both individual markers and ratios of bone formation to bone resorption markers (Figure S1 ).

DISCUSSION

The 2021 IMWG guidelines 7 and the 2025 EHA/EMN guidelines 8 differ in their recommendations regarding ZOL treatment. The IMWG recommends monthly treatment for at least 12 months, after which patients achieving at least VGPR may consider reducing treatment frequency to every 3 months, extending intervals to every 6–12 months according to osteoporosis guidelines or discontinuing treatment. This recommendation is based on a subgroup analysis from the Myeloma IX trial. 14

In contrast, the EHA/EMN guidelines, 8 incorporating data from the Magnolia study, 9 recommend treatment for at least 12 months and up to 48 months, while acknowledging that the optimal duration for patients achieving VGPR or CR remains uncertain.

In this study, for patients achieving at least VGPR after 2 years of monthly ZOL treatment, the risk of PBD remained significantly higher in those randomized to observation compared with those continuing ZOL. The magnitude of benefit was similar to that observed in the overall Magnolia study population, which included patients across all response categories. 9 However as a secondary analysis not planned in advance the risk of type 1 error must be noted. Overall, these findings indicate that discontinuation of ZOL based on achievement of VGPR or better may not be justified. On the contrary, this study suggests continued treatment for up to 48 months. It remains possible that patients attaining even deeper responses, such as CR, or patients with VGPR and without bone disease at diagnosis have less benefit of continued ZOL. Of the 14 patients with PBD who had achieved VGPR, three (21%) patients had no prior bone disease. This suggests that even patients without prior bone disease are at risk of PBD even in VGPR. To clarify the magnitude of benefit of ZOL in patients with >CR or VGPR without bone disease, a larger study is needed. While MRONJ was not significantly different, cases were only found in the ZOL treatment group suggesting that there may still be increased risk that this study did not have the power to identify.

In this study, most patients were treated with proteasome inhibitors and 63.6%/69.8% received autologous haematopoietic stem cell transplant. It is possible that with new induction regimens achieving high CR rates and/or high Minimal residual disease (MRD) negativity rates that ZOL treatments become less relevant over time. As such, new studies similar to this one might continuously be considered as treatments improve to avoid overtreatment based on older data.

Higher levels of bone resorption marker, CTX and TRAcP, were associated with an increased short‐term risk of PBD. However, no threshold low level of bone resorption marker values was identified to ensure no risk of PBD. Moreover, markedly elevated values were observed in only a minority of patients. Consequently, while these findings demonstrate a biological association, their application in clinical decision‐making seems to be limited. In the Z‐MARK study, the bone resorption marker N‐terminal telopeptide (NTX) was used in combination with clinical assessment of PBD to guide ZOL dosing frequency. 15 A similar approach incorporating CTX or TRAcP could be explored with CTX seeming more promising. For patients in whom ZOL is discontinued, serial monitoring of CTX might help identify subjects with an increased risk of developing PBD and enable timely re‐initiation of bisphosphonate therapy. Although the optimal measurement regimen has not yet been established, quarterly assessment of bone markers, as implemented in this study, may be a practical and justifiable strategy.

The optimal dosing interval and duration of ZOL therapy in multiple myeloma remain uncertain and have recently been reviewed elsewhere where we argued that 12‐week intervals after 12‐month treatment. 24 Early bisphosphonate studies used 4‐week regimens, 25 , 26 , 27 establishing the current standard of monthly administration. In patients with solid tumours and bone metastases, extending the dosing interval to every 3 months has been shown to be non‐inferior 28 , 29 , 30 and similar results have been reported in trials including myeloma patients. 31 , 32 Our findings show that bone turnover markers decline substantially with ZOL treatment and increase only gradually following discontinuation, supporting a prolonged anti‐resorptive effect. Although these data should be interpreted cautiously, they support the biological rationale for evaluating extended dosing intervals in myeloma, potentially improving convenience and reducing cumulative toxicity without compromising skeletal protection.

CONCLUSION

In this secondary analysis of Magnolia data, continuation of ZOL beyond 2 years was associated with a reduced risk of progressive bone disease in patients who had achieved VGPR or better at their latest treatment. In this study population, for patients not receiving ZOL, markedly elevated levels of the bone resorption markers TRAcP and CTX were associated with a significantly higher risk of PBD within 6 months. Further studies are needed to investigate if monitoring these markers and considering re‐initiation of ZOL in such cases may help prevent skeletal progression in multiple myeloma.

AUTHOR CONTRIBUTIONS

Michael Tveden Gundesen: Writing – original draft; writing – review and editing; formal analysis; data curation; methodology; investigation. Annette Juul Vangsted: Writing – review and editing; conceptualization; methodology; data curation. Einar Haukås: Conceptualization; methodology; data curation; writing – review and editing. Bo Amdi Jensen: Conceptualization; methodology; data curation. Jonna Skov Madsen: Data curation; resources; writing – review and editing. Carsten Helleberg: Conceptualization; methodology; writing – review and editing; data curation. Niels Abildgaard: Conceptualization; methodology; data curation; writing – review and editing. Dorte Aalund Olsen: Writing – review and editing; resources; data curation. Trine Silkjær: Conceptualization; methodology; data curation; writing – review and editing. Aneta Alexandra Nielsen: Data curation; resources; writing – review and editing. Elena Manuela Teodorescu: Conceptualization; methodology; data curation. Jon Thor Asmussen: Conceptualization; methodology; data curation. Tobias Schmidt Slørdahl: Conceptualization; methodology; data curation; writing – review and editing. Hareth Nahi: Conceptualization; methodology; writing – review and editing. Kent Søe: Conceptualization; methodology. Fredrik Schjesvold: Conceptualization; methodology; investigation; data curation; supervision; writing – review and editing. Anders Waage: Conceptualization; methodology; writing – review and editing; data curation. Thomas Lund: Project administration; supervision; conceptualization; methodology; writing – review and editing; writing – original draft; investigation; funding acquisition; validation; visualization; software; data curation; resources; formal analysis.

FUNDING INFORMATION

Funding was provided by Danish Cancer Union, the Nordic Cancer Union and Nordic Myeloma Study Group.

CONFLICT OF INTEREST STATEMENT

Hareth Nahi is partly employed by Pfizer global oncology research and development, New York. The authors have no other conflicts of interest to disclose.

DECLARATION OF AI USE

The authors used ChatGPT (OpenAI) only to improve the language, grammar and clarity of the manuscript. No new content or scientific meaning was generated by the AI, and none of the scientific ideas, interpretations, results or conclusions were influenced or created by the AI tool. All substantive content remains the exclusive responsibility of the authors.

Supporting information

Figure S1. Comparison of bone marker levels in myeloma patients with and without progressive disease and/or progressive bone disease.

Figure S2. PBD‐free survival, OS, PD and MRONJ for patients achieving at least CR at latest treatment after 2‐year ZOL treatment.

Table S1. Baseline characteristics of patients stopping ZOL after 2‐year treatment.

ACKNOWLEDGEMENTS

The authors thank all patients participating in the Magnolia study and to the Danish Cancer Union, the Nordic Cancer Union and Nordic Myeloma Study Group for supporting the Magnolia study. Finally, the author thank all participating study centres in Denmark and Norway.

DATA AVAILABILITY STATEMENT

Data are available upon request.

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