Does zoledronic acid (ZOL) reduce skeletal-related events (SREs) and improve progression-free survival (PFS) in patients (Pts) with multiple myeloma (MM) with or without bone disease? MRC myeloma IX study results.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 8010-8010 ◽  
Author(s):  
K. Boyd ◽  
G. Morgan ◽  
F. Davies ◽  
P. Wu ◽  
W. Gregory ◽  
...  
Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2402-2402 ◽  
Author(s):  
Shaji Kumar ◽  
Emily Blood ◽  
Martin M. Oken ◽  
Philip R. Greipp

Abstract Background: Syndecan-1 (CD138) is a heparan sulfate bearing proteoglycan found on various epithelial cells as well as on B lineage cells depending on its stage of development. Syndecan-1 (CD138) is abundantly expressed by plasma cells, especially myeloma cells. The extra cellular domain along with the heparan sulfate side chains can be cleaved off the cell surface and can be detected in the serum as soluble syndecan. Syndecan possibly plays a multifunctional role in the biology of myeloma. It has been shown to be an independent prognostic factor in patients with multiple myeloma. It has also been shown to promote myeloma cell growth through different mechanisms. Its expression has also been suggested to correlate with bone disease in MM. Methods: In this study we studied serum levels of soluble syndecan in newly diagnosed MM patients enrolled in the Eastern Cooperative Oncology Group (ECOG) E9486 and its associated correlative laboratory clinical trial E9487. We evaluated the prognostic value of syndecan in MM and its relationship to other known prognostic factors for this disease. In addition, syndecan levels were correlated with clinical and laboratory markers of bone disease. Results: A total of 501 patients were studied and the median serum syndecan-1 was 158 ng/mL. Syndecan levels correlated positively with other prognostic factors and markers of tumor burden such as β2-microglobulin (correlation coefficient 0.3; P <0.00001), labeling index (0.25; <0.0001), creatinine (0.23; <0.0001), soluble IL6 receptor (0.3; <0.0001), BM plasma cell percentage (0.16; <0.0006), and disease stage (P=0.0007). Significant differences in the overall and progression free survival was found between two groups of patient separated using the median value as cut-off. The High syndecan group had a median overall survival of 36.3 months compared to 49.3 months for the low syndecan group (P < 0.0001). Similarly, the high syndecan group had progression free survival of 25.4 months compared to 33.5 months for the low syndecan group (P < 0.0001). In a proportional hazards model including syndecan-1 as well as labeling index, β2M, Platelet count, IL-6R, syndecan-1 retained its prognostic value for overall survival (HR 1.3, P = 0.021). Syndecan levels were correlated with various bone markers including C-terminal telopeptide of type I collagen (ICTP), osteocalcin (OC), C-terminal type I procollagen (PICP), bone-specific alkaline phosphatase (BAP), and tartrate resistant alkaline phosphatase (TRAP) and were found to correlate only with ICTP (0.25, P < 0.0001). No correlation was found between clinical markers of bone disease including presence of lytic lesions, osteoporosis and pathologic fractures on X-rays or bone pain. Conclusion: In this large study, we once again confirm the prognostic value of serum syndecan-1 levels in large group of patients with newly diagnosed myeloma. Syndecan-1 level correlates with other disease markers. Syndecan levels also correlated with ICTP, a marker of bone turnover, though no strong correlation was found between syndecan levels and clinical markers of myeloma bone disease. The biological basis of these finding needs further evaluation.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9630-9630
Author(s):  
L. Duck ◽  
M. Delforge ◽  
C. Doyan ◽  
H. Wildiers ◽  
K. MacDonald ◽  
...  

9630 Background: The bisphosphonate (BP) ZOL is frequently used to prevent skeletal-related events (SRE) in cancer pts. However, data are limited on its use beyond 2 years. LOTUZ is among the first studies to examine Rx and outcomes in pts with ZOL Rx for >2y. We report 6-month results. Methods: Prospective (18m), multicenter (50), pharmacoepidemiologic study. Baseline (0m) and 6m data available on 205 pts (of 298 enrolled), all free from osteonecrosis of the jaw (ONJ) at 0m. Prior to ZOL Rx, 27.8% had non-ZOL BP Rx. Mean pre-enrollment BP duration was 42 mo (23–145) with 38 mo (23–80) for ZOL. Results: Mean age: 64 y (38–88); M/F: 29/71%; 67.8% with MBD vs 32.2% MM. 89.3% continued ZOL RX 0–6m; 90% with dose 4mg. From 0–6m, 10 pts (4.8%) developed ONJ (4 with MM, 6 with MBD): 5 mild, 3 moderate, 2 severe (median BP duration: 38.4, 46.5, and 34.8 months, respectively). Five pts with ONJ continued on ZOL RX 0–6m (3 mild, 2 moderate). 4/10 pts with ONJ had baseline dental conditions or procedures, 8/10 at 6m (only 1/10 at neither). SREs and pain levels remained constant 0–6m compared to 6m prior to baseline (see Table ). Conclusions: Beyond 2y, 90% of pts were continued on ZOL. SREs did not increase, but ONJ was diagnosed in 10/205 pts 0–6m, of which 5 were on ZOL RX beyond 24m. Long-term data are needed to better understand the risk/benefit of long-term ZOL Rx. [Table: see text] [Table: see text]


Author(s):  
Nutrisia Aquariushinta Sayuti ◽  
Tri Murti Andayani ◽  
Dwi Endarti ◽  
Kartika Widayati

Zoledronic acid and ibandronic acid are listed in the Indonesian national formulary to prevent skeletal-related events (SRE) in patients diagnosed with bone metastasis in multiple myeloma (MM), with limited evidence to compare their effectiveness. This study aimed to investigate the effectiveness and safety of zoledronic acid and ibandronic acid in delaying SRE. The method was the retrospective, with data obtained from the multicenter study for MM patients with bone metastasis (aged over 18 years), based on medical records between January 2016 and December 2018. Patients were assigned to zoledronic acid and ibandronic acid groups. The clinical outcome was the next SRE which consists of vertebral/bone fracture, spinal cord compression leading to the need for surgery or radiation, and adverse event (AE) due to 2 years of drugs usage. Result of this research was made up of a total of seventy (70) patients with  40  in the zoledronic acid group, and 30 in ibandronic acid. At median treatment duration of 8 months (range: 2 – 24 month), SRE incident in zoledronic acid and ibandronic acid were 20.0 % and 23.3 % respectively. Furthermore, their mean SRE free survival times were 21 months [95% confidence interval (CI) 19 - 23 months], and 19 months [95% CI, 16 – 22 months], respectively. Also, their time intervals were not significantly different (p>0.05). The osteonecrosis of the jaw (ONJ) was AE which occurred more in zoledronic acid than ibandronic acid. The conclusion was zoledronic acid tends to delay SRE time compared to ibandronic acid, although more ONJ occur.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4978-4978 ◽  
Author(s):  
Heather McDonagh ◽  
William Falk ◽  
Anissa Bingman ◽  
Susan Geyer ◽  
Don M. Benson ◽  
...  

Abstract Abstract 4978 Introduction: Testosterone (T) is important for maintenance of bone mineral density and muscle mass, stimulation of erythropoiesis, energy level, mood, and libido. Androgen deprivation therapy, i. e. near-complete hypogonadism, for prostate cancer is associated with type 2 diabetes, myocardial infarction, and overall mortality. In a study of male cancer patients with prostate and germ cell tumors, the prevalence of low T was 48–78% with opioid use, obesity, and being Caucasian as statistically significant covariates. Obesity increases T in women, with an associated increased breast cancer risk, and lowers T in men while raising estradiol levels. As fatigue and depression are common in multiple myeloma, we conducted a review of T in myeloma patients. None of the published literature has looked for an association between free testosterone and either characteristics of disease biology or concrete endpoints such as age of diagnosis, performance status, progression free survival, or overall survival. Methods: We retrospectively reviewed consecutive patients with plasma cell dyscrasias referred to Ohio State University that signed consent for the IRB-approved Ohio Myeloma Registry (www. ohiomyeloma. org). 343 patients were initially identified with either a total or free testosterone level available for evaluation, 171 patients with active myeloma. Results: 168 patients had a diagnosis of active myeloma and low or normal T – 44/171 (25%) were receiving opiates, 29/171 (17%) were taking anti-depressants, and 135/171 (79%) were male. 37/171 (22%) had type 2 diabetes and 92/171 (54%) had hypertension. The BMI median was 28. 9 (range 16. 9–53. 1) with 32 (19%) patients normal, 48 (28%) overweight, and 60 (35%) obese. The median time from diagnosis to T assessment was 49 days. In the entire cohort, the median free testosterone was 4. 17 (range 0. 11–16. 17) with 45 (26%) patients below the normal range, 123 (72%) within normal limits, and 3 (2%) with high T. In the subset of male patients (n=135), the median age was 61 y. o. (range 18–80). We designated two groups of male patients – 44 with low T and 91 with normal T. When comparing the two groups across hemoglobin, creatinine, calcium, stage, BMI, renal insufficiency, and anemia, there were no statistically significant differences. There was a difference between the presence or absence of lytic bone disease (p<0. 036) – less detectable bone disease on skeletal survey in the normal testosterone group. The median PFS in the low free T group was 23 months (16 events) and 35 months in the normal T group (27 events), p<0. 28. If we repeated this analysis but included women, the median PFS in the low free T group was 23 months compared to 35 months in the normal T group (p<0. 39). If we expand to include patients that had total as well as free testosterone, the median PFS was 24 months compared to 34 months with normal T (p<0. 23) (see figure). Conclusions: With approximately 30% of the cohort with severe hypogonadism (free testosterone below normal range) in a population predisposed to fractures, anemia, and depression, increased awareness of the prevalence of this diagnosis may change supportive care options for a population that often has a poor quality of life. There is a trend towards shorter PFS in patients with low free T. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Vol 5 (3) ◽  
pp. 725-736 ◽  
Author(s):  
Evangelos Terpos ◽  
Noopur Raje ◽  
Peter Croucher ◽  
Ramon Garcia-Sanz ◽  
Xavier Leleu ◽  
...  

Abstract An exploratory end point from a recent trial in patients with newly diagnosed multiple myeloma showed that median progression-free survival (PFS) was increased by 10.7 months with denosumab vs zoledronic acid. We performed additional analyses to identify factors that may have contributed to the favorable PFS with denosumab. Ad hoc analyses were performed for patients intending to undergo autologous stem cell transplantation (ASCT; ASCT intent), not intending to undergo ASCT (ASCT no intent), and intent-to-treat according to age (&lt;70 or ≥70 years) and baseline renal function (≤60 mL/min or &gt;60 mL/min creatinine clearance [CrCl]). Of 1718 patients, 930 (54.1%) were in the ASCT-intent subgroup, and 788 (45.9%) were in the ASCT-no-intent subgroup. In the ASCT-intent subgroup, frontline triplet (median PFS, not estimable vs 35.7 months; hazard ratio [HR] [95% confidence interval (CI)], 0.65 [0.47-0.90]; descriptive P = .009) or bortezomib-only (median PFS, not estimable vs not estimable; HR [95% CI], 0.61 [0.39–0.95]; descriptive P = .029) induction regimens demonstrated the strongest PFS benefit favoring denosumab vs zoledronic acid. In the ASCT-no-intent subgroup, no benefit with denosumab vs zoledronic acid was observed. PFS favored denosumab vs zoledronic acid in patients with CrCl &gt;60 mL/min and in patients &lt;70 years old, but no difference was observed in patients with CrCl ≤60 mL/min or patients ≥70 years old. The PFS difference observed with denosumab is one of the notable benefits reported in newly diagnosed multiple myeloma and was most pronounced in patients intending to undergo ASCT and those who received proteasome inhibitor (PI)−based triplet regimens. This study was registered at www.clinicaltrials.gov as #NCT01345019.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2967-2967
Author(s):  
Ramón García-Sanz ◽  
Albert Oriol ◽  
Javier De La Rubia ◽  
Luis Palomera ◽  
Paz Ribas ◽  
...  

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.


2021 ◽  
pp. 107815522199603
Author(s):  
Christina Billias ◽  
Megan Langer ◽  
Sorana Ursu ◽  
Rebecca Schorr

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.


2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Matthew A. Wall ◽  
Serdar Turkarslan ◽  
Wei-Ju Wu ◽  
Samuel A. Danziger ◽  
David J. Reiss ◽  
...  

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.


2016 ◽  
Vol 44 (6) ◽  
pp. 1462-1473 ◽  
Author(s):  
Wan-jun Sun ◽  
Jia-jia Zhang ◽  
Na An ◽  
Men Shen ◽  
Zhong-xia Huang ◽  
...  

Objectives To investigate the clinical characteristics, survival and prognosis of patients with multiple myeloma (MM) and head extramedullary plasmacytoma (EMP). Methods Forty MM patients were enrolled in the study (18 men, 22 women; median age, 55 years). Results Median overall survival (OS) and progression-free survival (PFS) were 24 (5–78) months and 17 (2–36) months, respectively. The 2-, 3- and 5-year OS rates were 51%, 20% and 7%, respectively. The 2-year PFS was 15%. Median OS and PFS in patients administered velcade were 26 (18–50) and 22.5 (5–78) months, compared with 20 (10–30) and 13.5 (2–36) months in patients without velcade, respectively. Median OS was 23.5 (5–50) months in patients with EMP at MM diagnosis ( n = 25) and 36 (22–78) months in patients with head EMP diagnosed during the disease course ( n = 15). Sixteen MM patients had EMP invasion of the head only and 24 had invasion at multiple sites. Median OS was 25 (22–78) months in patients with EMP of the head only and 22 (5–78) months in patients with EMP invasion at multiple sites. Conclusion MM patients with head EMP show a more aggressive disease course and shorter OS and PFS. The prognosis of these patients is poor, especially in patients with head EMP at MM diagnosis, though combined chemotherapy and radiotherapy may prolong survival.


Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.


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