Zoledronic Acid May Improve Survival Compared to Pamidronate in Patients with MM and High BALP Levels: Univariate and Multivariate Models of Hazard Ratios.

Abstract In untreated patients with multiple myeloma, elevated bone-specific alkaline phosphatase (BALP) levels have shown a significant association with bone pain, bone lesions, and pathologic fractures, and have been correlated with reduced survival (Fonseca R, et al. Br J Haemotol.2000;109:24–29). Zoledronic acid reduces the risk of skeletal morbidity and levels of biochemical markers of bone metabolism in patients with bone lesions from multiple myeloma. Zoledronic acid has also demonstrated antimyeloma effects in preclinical studies in vitro and in vivo using mice bearing human or mouse myeloma. Therefore, it is possible that zoledronic acid may not only prevent skeletal complications but also increase survival in patients with multiple myeloma. We conducted a retrospective exploratory analysis of patients with multiple myeloma and bone lesions as part of a large, randomized, controlled trial comparing infusions of zoledronic acid 4 mg and pamidronate 90 mg to assess the effect of zoledronic acid on survival based on baseline bone marker levels. In the overall population of patients with multiple myeloma (N=353), survival was comparable between groups. The subset of multiple myeloma patients who had information on baseline BALP levels were examined in these analyses (n=212; 4 mg zoledronic acid [n=109] or 90 mg pamidronate [n=103]). Patients received treatment for up to 24 months with a final assessment at 25 months. Risk of death was assessed in univariate and multivariate models using Cox regression methodology. Factors included in the multivariate analyses were prior skeletal-related events and baseline ECOG performance status. Among patients who had a baseline BALP assessment, zoledronic acid significantly increased the 25-month overall survival compared with pamidronate (76% versus 63%; P=.026). In the univariate and multivariate analyses, zoledronic acid significantly reduced the risk of death by approximately 42% compared with pamidronate (P=.03 for both). The subset of patients was then retrospectively stratified by baseline BALP levels according to the following criteria: low BALP (<146 U/L) and high BALP (≥146 U/L). Among patients who had low baseline BALP (n=123), 25-month survival was similar for both treatment groups. Although zoledronic acid reduced the risk of death in this subset by approximately 30% compared with pamidronate in the univariate and multivariate analyses, the between-group differences were not statistically significant (P>.2 for both). In contrast, among patients with high baseline BALP (n=89), zoledronic acid significantly improved survival compared with pamidronate (82% versus 53%; P=.041). Zoledronic acid significantly reduced the risk of death in this subset by approximately 56% compared with pamidronate in both the univariate and multivariate analyses (P<.05 for both). These exploratory analyses suggest that, in addition to its established benefits in preventing skeletal complications, zoledronic acid may improve survival compared with pamidronate in patients with multiple myeloma who have high BALP levels. Prospective trials are needed to investigate the improved survival in this subset; the high-BALP subset may have higher statistical power to distinguish between the 2 bisphosphonates (higher event rate), or these patients may still have coupled bone metabolism and better recovery after response to antiresorptive therapy.

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Natural History of Skeletal-Related Events in Patients with Multiple Myeloma: Exploratory Analysis Based on Prior History of Skeletal Complications.

Blood ◽

10.1182/blood.v104.11.4928.4928 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4928-4928

Author(s):

Mohamad A. Hussein ◽

Mary Kaminski ◽

Lee Rosen ◽

David Gordon ◽

Ming Zheng

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Exploratory Analysis ◽

Study Entry ◽

Bone Lesions ◽

Acid Versus ◽

Increased Risk ◽

Skeletal Complications ◽

History Of ◽

Skeletal Related Events

Abstract Background: We previously reported the long-term efficacy and safety of 4 mg zoledronic acid compared with 90 mg pamidronate in patients with bone lesions from breast cancer or multiple myeloma (Rosen et al. Cancer. 2003;98:1735–1744). Bone lesions result in an increased risk of developing skeletal-related events (SREs), including pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia of malignancy. It has also been suggested anecdotally that patients who have experienced a prior SRE may be at increased risk for future SREs, but no data exist to support this hypothesis. We report here the results of a retrospective exploratory analysis to assess whether patients with a history of SREs before study entry had a higher incidence of on-study SREs and to assess the clinical benefit of zoledronic acid compared with pamidronate in advanced multiple myeloma patients based on SRE history. Methods: The subset of multiple myeloma patients treated with zoledronic acid (4 mg) or pamidronate (90 mg) every 3 to 4 weeks was retrospectively stratified according to history of SREs before study entry. A total of 353 patients with multiple myeloma were randomized 1:1 to zoledronic acid or pamidronate for 12 months, and 138 patients elected to continue blinded treatment for an additional year. Results: Before study entry, 284 (~80%) patients had experienced at least 1 SRE and these patients were more likely to develop an SRE on study than patients without a history of SREs (time to first SRE hazard ratio = 2.22; P <.0001). Across treatment groups, 56% of these patients had at least 1 SRE on study (after 25 months) versus only 35% patients with no SRE before study entry. Additionally, patients with an SRE before study entry had a shorter median time to first on-study SRE (median, 293 days for zoledronic acid and 218 days for pamidronate) compared with patients who had no prior SRE (median, 504 days for zoledronic acid and not reached for pamidronate). Among patients with an SRE before study entry, the zoledronic acid group had a decreased percentage of patients with an on-study SRE compared with the pamidronate group (53% for zoledronic acid versus 59% for pamidronate; P =.291). Zoledronic acid also delayed time to first SRE by 75 days compared with pamidronate (median 293 days for zoledronic acid versus 218 days for pamidronate; P =.679). Conclusions: This exploratory analysis indicates that multiple myeloma patients with a history of SREs are at significantly higher risk of developing subsequent skeletal complications. Early intervention for prevention of SREs may provide considerable clinical benefit to these patients.

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Pamidronate Reduces Skeletal Morbidity in Women With Advanced Breast Cancer and Lytic Bone Lesions: A Randomized, Placebo-Controlled Trial

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.3.846 ◽

1999 ◽

Vol 17 (3) ◽

pp. 846-846 ◽

Cited By ~ 444

Author(s):

Richard L. Theriault ◽

Allan Lipton ◽

Gabriel N. Hortobagyi ◽

Richard Leff ◽

Stefan Glück ◽

...

Keyword(s):

Breast Cancer ◽

Hormonal Therapy ◽

Intravenous Infusion ◽

Bone Lesion ◽

Morbidity Rate ◽

Bone Lesions ◽

Skeletal Complication ◽

Pathologic Fractures ◽

Bone Response ◽

Skeletal Complications

PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated. CONCLUSION: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.

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Prognostic Significance of Biochemical Markers of Bone Metabolism in Patients with Bone Lesions from Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v106.11.5015.5015 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5015-5015

Author(s):

Richard J. Cook ◽

Robert E. Coleman ◽

Pierre Major ◽

Allan Lipton ◽

Janet E. Brown ◽

...

Keyword(s):

Bone Metabolism ◽

Biochemical Markers ◽

Univariate Analysis ◽

Pathologic Fracture ◽

Bone Marker ◽

Phase Iii ◽

Bone Lesions ◽

Pathologic Fractures ◽

Increased Risk ◽

Risk Ratios

Abstract BACKGROUND: Biochemical markers of bone metabolism are useful indicators of bone turnover in pts with malignant bone disease. Elevated N-telopeptide (NTX) levels were correlated with increased risks of skeletal-related events (SREs), disease progression, and death in pts with primary bone lesions from MM (Coleman RE, et al. J Clin Oncol. 2005). The prognostic value of other markers (eg, pyridinoline [PYD] and deoxypyridinoline [DXP]) in pts with MM is unknown. METHODS: This study investigated the association between NTX, PYD, DXP, and bone alkaline phosphatase (BAP) levels and risk of SRE or pathologic fracture in pts with MM who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001). Cut-off values for low, moderate, and high marker levels were based on prior reports and the investigators’ experience with bone marker data. Both univariate and multivariate analyses were performed and risk ratios were derived for pts with elevated levels of each bone marker relative to pts with low marker levels. RESULTS: By univariate analysis, moderate (50 to 100 nmol/mmol creatinine) and high (> 100 nmol/mmol creatinine) NTX levels corresponded with significantly increased risks of any SRE, onset of first SRE, or pathologic fracture. Elevated levels of PYD corresponded with a significantly increased risk of SREs, the onset of SREs, and pathologic fracture. Although there were some significant correlations, the association between DXP and BAP levels and risk of skeletal morbidity was inconsistent (Table). In multivariate models, only NTX and DXP were significant, and NTX had a stronger effect. Risk Ratios By Univariate Analysis for SRE Compared With the Respective SRE Pathologic fracture Any Onset (1st) Any Onset (1st) NTX ≤ (vs 50 nmol/mmol creatinine) > 50 – 100 2.26 (.003) 2.76 (.012) 2.98 (< .001) 3.78 (.001) > 100 4.01 (.001) 6.80 (< .001) 5.35 (< .001) 8.87 (< .001) DXP ≤ (vs 15 nmol/mmol creatinine) > 15 – 30 1.95 (.016) 2.14 (.015) 2.30 (< .001) 2.29 (.009) > 30 1.89 (.041) 3.58 (.006) 1.74 (.134) 2.88 (.046) PYD ≤ (vs 62 nmol/mmol creatinine) > 62 1.89 (.009) 2.06 (.006) 1.74 (.028) 1.97 (.017) BAP ≤ (vs 146 U/L) > 146 1.48 (.103) 1.89 (.042) 1.69 (.042) 1.86 (.063) CONCLUSIONS: Elevated baseline PYD, DXP, and BAP levels are significant predictors of an increased risk of some SREs and may therefore have clinical value. Elevated NTX levels are a consistent significant predictor of an increased risk of SREs and pathologic fractures. NTX levels may therefore aid in identifying patients at risk for skeletal complications.

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Zoledronic Acid Extends Survival in Lung Cancer&Multiple Myeloma Patients with High Levels of Bone Metabolism

Oncology Times ◽

10.1097/01.cot.0000295028.03666.62 ◽

2006 ◽

Vol 28 (16) ◽

pp. 37

Author(s):

Mark L. Fuerst

Keyword(s):

Lung Cancer ◽

Multiple Myeloma ◽

Zoledronic Acid ◽

Bone Metabolism ◽

Cancer Multiple

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Prognosis and Therapeutic Response Transfer Learning Model for Multiple Myeloma

Blood ◽

10.1182/blood-2021-152566 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1883-1883

Author(s):

Jerome Voegeli ◽

Dana Moreno ◽

Maxim Kryukov ◽

Gregory Mathez ◽

Remy Petremand ◽

...

Keyword(s):

Neural Networks ◽

Multiple Myeloma ◽

Transfer Learning ◽

Real World ◽

Cox Regression ◽

Conflicts Of Interest ◽

Full Range ◽

Hospital Setting ◽

Bone Lesions ◽

Therapeutic Effects

Abstract The combination of clinical knowledge (applicable for a majority of patients, published in the form of review articles), real world evidence (describing more nuanced outcomes for small cohorts) and innovative artificial intelligence algorithms opens potent avenues to re-examine clinical findings and uncover new biomarkers for the prognosis / prediction of therapeutic responses--in a manner that can directly be incorporated in clinical decision support tools. In this work, neural networks are first developed to reproduce clinical guidelines with >95% accuracy. After mastering the complex knowledge that is generally expected from human doctors, a transfer learning technique was used to sift through de-identified longitudinal data of 9267 patients with multiple myeloma-related conditions at the Vanderbilt University Medical Center using progression free survival (PFS) to quantify therapeutic outcomes. The "precision medicine neural networks" obtained as a result can be compared with conventional and less portable survival model algorithms, using Shapley values to explain prediction differences. Testing a first hypothesis that "lytic bone lesions are a prognostic factor for poor PFS", a study involving 1530 patients confirmed that the median PFS of 54 ± 6 months (684 censored patients showing progression) in the presence of bone lesions is significantly lower than the 107 ± 40 months (90 censored patients) in the absence of lesions. Keeping only 179 patients for which a full range of cytogenetic factors are available and using a Cox regression & Random Survival Forests that provide the best fit of the data, we confirmed previous findings for high-risk trisomies 1 and 7, monosomy 13, deletion 12p and translocation t(11;14)(q13;q32). We furthermore uncovered new additional adverse factors del6q, 2+, 21-, 16- to formulate a model that achieves a statistically significant concordance of 0.72 ± 0.07. Comparing therapeutic effects for patients in a real-world hospital setting with clinical trials, we found that lenalidomide + bortezomib + dexamethasone used in a first-line therapy resulted in lower median PFS of 17-47 months than the 39-52 months published in the SWOG S0777 trial, most likely because comorbidities contributed to shortening the PFS in real-world settings. We conclude with an analysis of concrete examples where therapeutic recommendations differ from guidelines, explaining the reason with statistically significant cohorts observed in the data. Disclosures No relevant conflicts of interest to declare.

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Prognostic variables and clinical staging in multiple myeloma

Blood ◽

10.1182/blood.v74.5.1774.1774 ◽

1989 ◽

Vol 74 (5) ◽

pp. 1774-1780 ◽

Cited By ~ 32

Author(s):

M Cavo ◽

P Galieni ◽

E Zuffa ◽

M Baccarani ◽

M Gobbi ◽

...

Keyword(s):

Multiple Myeloma ◽

Platelet Count ◽

Median Survival ◽

Multivariate Regression ◽

Clinical Staging ◽

Survival Duration ◽

Bone Lesions ◽

Risk Of Death ◽

Dominant Feature ◽

Lytic Bone Lesions

Abstract To evaluate the most important factors in the prognosis and staging of multiple myeloma (MM), the presenting clinical features of 163 previously untreated patients with MM were correlated with survival duration using univariate and multivariate regression analyses. The univariate proportional hazard analysis ranked the parameters in the following order of importance: platelet count, hemoglobin level (Hb), tumor cell mass stage, lytic bone lesions, creatinine, and age. When the individual contribution of each variable was assessed by multivariate regression analysis, platelet count was confirmed to be the dominant feature for prognosis and clinical stage provided additional information. The introduction of platelet count could then be used to improve the reliability of the Durie and Salmon staging, by allowing to separate the high-risk group (stages II and III) into a smaller subgroup (22%) of thrombocytopenic patients (less than 150 x 10(9) platelets/L) whose risk of death was actually very high (median survival, 9 months) and a larger subgroup (46%) of patients with normal platelet count and intermediate or standard risk (median survival, 48 months). This simple change in the prognostic system gave rise to markedly different survival curves also after the exclusion of patients with renal failure and applied successfully to both old and young patients (greater than and less than 50 years, respectively). Finally, platelet count, Hb, and lytic bone lesions could be combined simply to stratify patients with normal renal function into three risk groups: (1) low (39% of cases; median survival, 79 months), (2) intermediate (53% of cases; median survival, 48 months), and (3) high (8% of cases; median survival, 19 months).

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Metastatic Bone Disease in Patients with Solid Tumors–-Burden of Bone Disease and the Role of Zoledronic Acid

Clinical Medicine Therapeutics ◽

10.4137/cmt.s1958 ◽

2009 ◽

Vol 1 ◽

pp. CMT.S1958

Author(s):

Vera Hirsh

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Metastases ◽

Bone Disease ◽

Large Scale ◽

Comparative Trial ◽

Palliative Radiotherapy ◽

Bone Lesions ◽

Pathologic Fractures

Bisphosphonates have become an integral component of the therapeutic repertoire for cancer patients at risk for skeletal-related events (SREs) such as pathologic fractures, bone pain requiring palliative radiotherapy, the need for orthopedic surgery, spinal cord compression, and hypercalcemia of malignancy because of bone metastases. Administered via monthly 15-minute infusion of up to 4 mg (depending on creatinine clearance rate), zoledronic acid (ZOL) has been approved for preventing SREs in patients with bone metastases from any solid tumor or bone lesions from multiple myeloma. Although there have been limited head-to-head comparison trials between bisphosphonates, ZOL displayed benefits beyond pamidronate in a large-scale comparative trial in patients with bone metastases from breast cancer. Monitoring of serum creatinine levels and oral health is important to ensure safety and comfort during treatment. In addition to the established benefits of bisphosphonates in the advanced cancer setting, there is a strong preclinical rationale and emerging clinical evidence that ZOL has antitumor activities and can delay metastasis in patients with early breast cancer. Studies are underway in patients with other tumor types, and the role of bisphosphonates is likely to evolve.

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Efficacy of zoledronic acid versus placebo on biochemical markers of bone metabolism in patients with breast cancer metastatic to bone

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10559 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10559-10559

Author(s):

N. Kohno ◽

K. Aogi ◽

H. Minami ◽

S. Takashima

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Metastases ◽

Bone Metabolism ◽

Biochemical Markers ◽

Breast Cancer Patients ◽

Clinical Complications ◽

Study Results ◽

Skeletal Complications ◽

Sensitive Marker

10559 Background: Zoledronic acid reduces the levels of bone markers and the risk of skeletal complications in patients with bone metastases. Recently, a correlation between the levels of biochemical markers of bone metabolism and the risk of clinical complications (ie, skeletal complications, disease progression, and death) in patients with bone metastases has been reported. The effect of zoledronic acid on bone marker levels was assessed in patients with bone metastases from breast cancer in a multicenter randomized trial conducted in Japan. Methods: Women with bone metastases secondary to breast cancer (N = 228) were randomized to 4 mg zoledronic acid (n = 114) or placebo (n = 114) every 4 weeks for 1 year. Levels of urinary N-telopeptide (NTX), a sensitive marker of bone resorption, were measured at baseline and regularly throughout the study. Results: The table shows that zoledronic acid reduced NTX levels in patients compared with placebo. Patients treated with zoledronic acid had a mean decrease of 61% from baseline NTX levels at week 2. This decrease was maintained throughout the study in this treatment group and was 54% at week 52. In contrast, patients in the placebo group had a mean increase of 27% from baseline NTX levels at week 2, and levels of NTX continued to increase during the study, reaching 146% above baseline at week 52. Conclusions: This analysis shows that treatment with zoledronic acid reduced NTX levels in patients with bone metastases from breast cancer compared with placebo. These results are consistent with published reports in patients with prostate or lung cancer and are consistent with the significant reduction in skeletal morbidity observed in this trial in breast cancer patients. Zoledronic acid demonstrated a 39% reduction in skeletal morbidity in this patient population. [Table: see text] No significant financial relationships to disclose.

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Renal impairment in multiple myeloma patients following zoledronic acid or ibandronate treatment

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.17501 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 17501-17501

Author(s):

L. Antràs ◽

M. Smith ◽

M. Neary ◽

J. Green ◽

N. Wintfeld ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Renal Impairment ◽

Cox Model ◽

Randomized Study ◽

Phase Iii ◽

Event Analysis ◽

Phase Iii Trials ◽

Skeletal Complications ◽

Renal Safety

17501 Background: Although bisphosphonates prevent skeletal complications, agents differ with respect to renal safety. Ibandronate (IB) is a single-nitrogen, noncyclic bisphosphonate that has shown a renal safety profile comparable to placebo in phase III trials. This retrospective study aimed to compare renal impairment rates in multiple myeloma (MM) patients treated with IB or zoledronic acid (ZO). Methods: Medical records in a German oncology clinic (Praxisklinik für Hämatologie und Onkologie Koblenz, Koblenz, Germany) from May 2001 to December 2005 were retrospectively reviewed. Creatinine measurements were analyzed from baseline (before ZO or IB treatment) to last evaluation for each patient. Renal impairment was defined as (1) a serum creatinine (SCr) increase of ≥0.5 mg/dL or ≥1.0 mg/dL from baseline values of <1.4 mg/dL or ≥1.4 mg/dL, respectively, or (2) a ≥25% decrease in glomerular filtration rate (GFR; abbreviated MDRD formula) from baseline. Patients treated sequentially with both ZO and IB were included as separate observations. Andersen-Gill extension of the Cox model was used for multiple-event analysis. Results: In 84 MM patients, 69 received ZO and 40 received IB, with 25 patients receiving both drugs. Compared with IB, the ZO group had a significantly better baseline renal function (mean SCr 1.01 vs 1.34, p = 0.007; mean GFR 75.9 vs 57.3, p = 0.0002). Data analysis showed that ZO treatment increased the relative risk (RR) of renal impairment by ∼3-fold compared with IB (renal impairment rates: ZO 39.1% vs IB 10.8%, RR = 3.6, p = 0.002 [SCr]; 62.3% vs 24.3%, RR = 2.6, p = 0.0002 [GFR]). The incidence rate of renal impairment was higher for ZO than IB (SCr: 1.14 vs 0.48 events per person-year, p = 0.169; GFR: 2.65 vs 0.87 events per person-year, p = 0.007). Multiple-event analysis found significantly higher hazards ratios for ZO over IB (SCr = 5.3; GFR = 2.7; both p < 0.0001). Conclusions: In this retrospective review, MM patients were significantly more likely to experience renal impairment with ZO than with IB. A prospective randomized study is warranted for further validation. [Table: see text]

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