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

Blood ◽  
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.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3589-3589 ◽  
Author(s):  
James R. Berenson ◽  
Meletios A. Dimopoulos ◽  
Yin-Miao Chen
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Metabolism ◽  
Cox Regression ◽  
Multivariate Analyses ◽  
Bone Lesions ◽  
Multivariate Models ◽  
Risk Of Death ◽  
Pathologic Fractures ◽  
Skeletal Complications

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.

scholarly journals Use of Bone-Modifying Agents in Myeloma and Bone Metastases: How Recent Dosing Interval Studies Have Affected Our Practice

2018 ◽  
Vol 14 (8) ◽  
pp. 457-464 ◽  
Author(s):  
Erica Campagnaro ◽  
Melissa A. Reimers ◽  
Angel Qin ◽  
Ajjai S. Alva ◽  
Bryan J. Schneider ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Myeloma ◽  
Metastatic Breast Cancer ◽  
Zoledronic Acid ◽  
Metastatic Breast ◽  
Bone Lesions ◽  
Dosing Interval ◽  
Skeletal Related Events ◽  
Dosing Intervals

The management of bone lesions from advanced solid tumors and multiple myeloma typically includes use of a bone-modifying agent to reduce the risk of skeletal-related events. Recent data demonstrate that when using zoledronic acid to reduce the risk of skeletal-related events in metastatic breast cancer, metastatic prostate cancer, and multiple myeloma, the dosing interval of zoledronic acid may be extended from every 4 weeks to every 12 weeks. The ASCO guidelines on the role of bone-modifying agents in metastatic breast cancer and multiple myeloma address zoledronic acid dosing intervals. Herein, we discuss how new data on dosing of bone-modifying agents influence our clinical practice.

Predictors for Skeletal-Related Events in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1482-1482
Author(s):  
Evangelos Terpos ◽  
Richard Cook ◽  
Robert Coleman ◽  
Allan Lipton ◽  
James Berenson
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Pathologic Fracture ◽  
Bone Lesions ◽  
Narcotic Analgesics ◽  
Lower Weight ◽  
Skeletal Related Events ◽  
Reduced Time ◽  
Significant Covariates

Abstract Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P &lt; .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

Analysis of Zoledronic ACID Therapy for Patients with Multiple Myeloma with Asymptomatic Biochemical Relaps.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2967-2967
Author(s):  
Ramón García-Sanz ◽  
Albert Oriol ◽  
Javier De La Rubia ◽  
Luis Palomera ◽  
Paz Ribas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Disease ◽  
Interim Analysis ◽  
Response Rate ◽  
Bone Lesions ◽  
Biochemical Relapse ◽  
Acid Therapy ◽  
Number Of Patients ◽  
Skeletal Related Events

Abstract Abstract 2967 Zoledronic Acid (ZOL) has demonstrated up to half a year improvement in survival of multiple myeloma patients. This conjoins with prior experimental studies to support a potential anti-myeloma effect for bisphosphonates. However, the in vivo effect can be confounded with the concomitant use of chemotherapy and new drugs, as well as with competing risks that emerge from the beneficial effect of bisphosphonates on the skeletal related events and its relationship with survival. Accordingly, the real anti-tumor effect of ZOL remains to be elucidated in clinical practice, for example in patients free of the disturbing effect of chemotherapy. New therapies provide an 80–90% response rate in MM, although most patients ultimately relapse. During relapse, many patients show an initial re-positivization or re-growth of the M-component (biochemical relapse) that is usually not accompanied by clinical symptoms. The usual decision at this point is not to treat such patients. Thus, these asymptomatic patients represent a perfect group to explore the antitumor benefit of ZOL in the absence of any other cytotoxic therapy. Aim: To analyze the anti-tumor effect of ZOL in the absence of any other cytotoxic drug in MM patients under asymptomatic biochemical relapse. Primary end-point was Symptomatic Progression Free Survival (sPFS). Secondary evaluation variables were response rate, skeletal related events and time to next chemotherapy. Patients and methods: 192 patients are calculated to be recruited in a randomized, prospective, open label phase IV trial in which a group of patients receive ZOL (4 mg iv./4 wk, 12 doses) and Best Supportive Care (BSC) and the rest only BSC. All patients are monitorized every 4 wk. Results: This is an interim analysis corresponding to the first 93 patients included in the trial: 49 treated with ZOL and 44 without ZOL. Asymptomatic Biochemical Relapse was confirmed in all patients who had a median age of 68 yr (40–87) and a male female distribution of 50/43. M-component distribution was IgG (69%), IgA (29%) and only light chain (2%). Relapse had presented after 1, 2 or 33 lines of therapy in 67%, 22% and 11% of cases, respectively. Prior treatment had always included transplant (65%), bortezomib (33%), IMiDs (33%), or a combination of them. Lytic bone lesions were present in 66% of patients and one or two skeletal related events (SRE) had presented prior to the inclusion in the trial in 31% of cases. FISH/cytogenetics was abnormal in 49% of cases: t(11;14) 18%, Rb deletion (alone) 16%, del(p53) 9%, t(4;14) 6% and t(14;x) 4%. After randomization, both groups of patients were well balanced in terms of prognostic features, prior response, and time from diagnosis and relapse to the inclusion in the trial. 25 patients have completed the program and four terminated before completion due to patient refusal (n=2) and development of other diseases (n=2). 31 patients are still ongoing and 38 have progressed before 12 mo of treatment, with a median sPFS of 287 days (9.4 months) with similar results between the two arms (271 vs. 308 days for patients receiving or not receiving ZA, respectively; 12-month projected sPFS was 47% vs. 42%, respectively). Interestingly, patients not treated with ZOL progressed with more advanced bone disease (8 cases of new bone lesions or re-growth of prior lesions, 1 spinal cord compression, and 2 cases of hypercalcemia) vs. patients treated with ZOL (two cases re-growth of bone lesions, p<0.01). By contrast, patients treated with ZOL progressed more frequently with decrease o Hb level below 10 g/dL (13 vs. 8 cases). There were 7 SRE that presented only in the group of patients treated without ZOL (p=0.005) Conclusions: Zoledronic Acid therapy in MM with asymptomatic relapse seems to reduce the risk of progression with symptomatic bone disease and SREs. The possible antitumor effect of Zoledronic Acid alone in biochemical relapses cannot be elucidated yet. This interim analysis supports the continuation of the trial to reach a higher number of patients and longer follow-up. Disclosures: García-Sanz: Novartis Oncology: Grant Support Other. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria.

Risk of renal failure associated with IV bisphosphonate use in patients with multiple myeloma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8104-8104
Author(s):  
A. T. Joyce ◽  
D. J. Harrison ◽  
S. Jun ◽  
A. L. Feliu ◽  
M. Anthony
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Incidence Rate ◽  
Regular Monitoring ◽  
Increased Risk ◽  
Lytic Lesions ◽  
History Of ◽  
Skeletal Related Events ◽  
Rate Ratios ◽  
Incident Cases

8104 Background: IV Bisphosphonates including zoledronic acid (ZA) and pamidroniate are frequently used to delay time to skeletal related events in patients with multiple myeloma. The risk of renal toxicity with these agents is well known and regular monitoring of kidney function is required. Despite regular monitoring of creatinine, patients taking IV bisphosphonates may experience decreased renal functioning and renal failure. The purpose of this study was to determine the relative risk of renal failure in patients with multiple myeloma treated with ZA or pamidronate relative to patients whose lytic lesions remained untreated with medications. Methods: Commercially insured adults newly diagnosed with multiple myeloma 7/1/2002–6/2006 were identified using ICD-9 codes within the PHARMetrics Integrated Outcomes Database. Patients were stratified based on evidence of IV bisphosphonate use (treated) or no such evidence (untreated) following initial qualifying diagnosis. For treated patients, the date of first administration of an IV bisphosphonate was the patient's index date. Treated patients were matched to untreated patients based on use of radiation therapy or chemotherapy, year of cancer diagnosis, and health plan enrollment duration.The incidence rate (IR) for renal failure defined using ICD-9 codes was based on number of incident cases identified among the total person-years at risk and expressed as a rate per patient year. IRs and incidence rate ratios (IRR) (comparing the treated to untreated cohorts), with corresponding 95% confidence intervals are reported. Results: Treated (n=401) and untreated (n=431) patients were similar with respect to age (mean 56 years in both cohorts), but treated patients were more likely to be female (54% vs. 47%; p = 0.04) and less likely to have a history of anemia (48% vs. 51%; p=0.002). IV bisphosphonate use was associated with an 8.5% incidence of developing renal failure per patient year versus 4.9% in the untreated cohort (IRR 1.72; 95% CI 1.22–2.42). The risk was similar whether patients were treated with ZA or pamidronate. Conclusions: IV bisphosphonate use was associated with a significantly increased risk (72%) of developing renal failure in patients with multiple myeloma. No significant financial relationships to disclose.

Safety and efficacy of bone-modifying agents among multiple myeloma patients: A retrospective cohort study

2021 ◽  
pp. 107815522199603
Author(s):  
Christina Billias ◽  
Megan Langer ◽  
Sorana Ursu ◽  
Rebecca Schorr
Keyword(s):  
Multiple Myeloma ◽  
Cohort Study ◽  
Zoledronic Acid ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Osteonecrosis Of The Jaw ◽  
Safety And Efficacy ◽  
Modifying Agent ◽  
Skeletal Related Events ◽  
Agent Group

Objective To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. Methods This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. Results A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172–1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. Conclusion Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.

Sign in / Sign up

Export Citation Format

Share Document