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.

Zoledronic acid (ZOL) treatment (Rx) of ≥2 years in patients (pts) with metastatic bone disease (MBD) or multiple myeloma (MM): Six-month results from the LOTUZ study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9630-9630
Author(s):  
L. Duck ◽  
M. Delforge ◽  
C. Doyan ◽  
H. Wildiers ◽  
K. MacDonald ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Disease ◽  
Osteonecrosis Of The Jaw ◽  
Metastatic Bone Disease ◽  
Skeletal Related Events ◽  
Dental Conditions ◽  
Term Data

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]

scholarly journals Retrospective Analysis of the Relationship between Time to Anti-Resorptive Therapy and Incidence of Skeletal Related Events in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Kelly Hughes ◽  
Abdullateef O Abdulkareem ◽  
Niketa Raj ◽  
Adam Barsouk ◽  
Tingting Zhan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Sample Size ◽  
Retrospective Analysis ◽  
Bone Disease ◽  
Area Deprivation ◽  
Bone Lesions ◽  
Newly Diagnosed ◽  
Time To Initiation ◽  
Skeletal Related Events ◽  
The Relationship

Background Multiple Myeloma (MM) is a plasma cell neoplasm causing a proliferation of monoclonal immunoglobulins that causes end organ damage in the form of hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. Specifically, patients with MM are at risk for developing significant bone disease eventually leading to development of skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that the use of anti-resorptive agents (i.e. Bisphosphonates, Denosumab) lead to fewer bony lesions, less severe bone disease, and fewer SREs. However, while anti-resorptive therapy is recommended for all MM patients undergoing treatment, it is common for initiation of anti-resorptive therapy to be delayed due to the need for dental clearance, clinician preference, or relative contraindications to the medications. Current studies show that this therapy is overall underutilized, likely for similar reasons. However, the effect on SRE with regards to time to initiation of anti-resorptive agent has not been well studied. Herein, we conducted a retrospective analysis to determine if time to anti-resorptive agent has an effect on incidence of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify and analyze data of patients with newly diagnosed Multiple Myeloma from July 1st, 2016 until June 30th, 2019 to determine whether time to anti-resorptive therapy affects the incidence of SRE. Patients previously treated with bisphosphonates, and patients not treated with anti-resorptive therapy were excluded. The study's primary endpoint was probability of developing SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, sex, age, ISS stage at diagnosis, Area Deprivation Index (ADI), and prior SRE present at diagnosis was analyzed by multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: Three hundred and seventy-five patients with newly diagnosed multiple myeloma patients were identified. In total, 237 patients were included in the final analysis. Demographic information is detailed in the table provided. Of these, 208 patients (88%) used bisphosphonates and 29 (12%) used a RANK ligand inhibitor as their anti-resorptive agent. The median time to therapy was 55 days (IQR 135 days). One hundred twenty four (55%) patients had an SRE present at diagnosis. Forty-one (15.2%) patients developed a new SRE after initiation of anti-resorptive therapy. The model showed that patients who had a delay to anti-resorptive therapy of 31 days or greater had a higher risk of developing SRE after diagnosis (HR 2.49, 95% CI 0.95-6.55, p=0.064). In addition, when comparing ISS II to ISS I, patients with ISS II disease had a higher risk of developing SRE (HR 2.78, 95% CI 1.02-7.57, p=0.045). Conclusions: Patients with longer delays to anti-resorptive therapy had higher risk of developing SRE after diagnosis, however the difference was not statistically significant. One explanation for this may be that starting anti-resorptive therapy at any time point may be more important than time it takes to start therapy in the setting of effective anti-myeloma treatment. However, the rate of SRE in this study was lower than initially predicted based on previous studies, and therefore, our sample size may have been too small to detect a significant outcome related to time to initiation of anti-resorptive agents. Ongoing efforts to increase the sample size through multi-institutional initiatives are underway. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy.

Osteonecrosis of the Jaw (ONJ) in Patients with Multiple Myeloma, Receiving Bisphosphonate Therapy, Is Independent of Renal Function: Single Institute Experience of an Emerging Clinical Problem.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5129-5129
Author(s):  
Rami Manochakian ◽  
Jean-Gabriel Coignet ◽  
Swaminathan Padmanabhan ◽  
Maureen Sullivan ◽  
Kena C. Miller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Zoledronic Acid ◽  
Creatinine Level ◽  
Clinical Problem ◽  
Bisphosphonate Therapy ◽  
Stage Iii ◽  
Bone Lesions ◽  
Duration Of Treatment ◽  
Number Of Patients

Abstract Introduction: Use of bisphosphonate (zoledronic acid and pamidronate) for prevention of pathological fractures is standard of care in multiple myeloma (MM) patients with osteolytic bone lesions. While clinical trials have investigated effectiveness of these agents for up to 2 years of use, clinical practice has incorporated their use indefinitely. With improvement in survival through availability of novel agents in MM patients, the use of bisphosphonate therapy has also prolonged. Recent reports unveiled a new side effect of Bisphosphonate therapy i.e., ONJ, characterized by necrosis of the jawbone with antecedent subluxation or loss of the teeth and ulceration of the gum mucosa. The underlying etiology remains elusive, and in the absence of effective remedy ONJ has raised significant concerns upon the duration of treatment with Bisphosphonate. We investigated the magnitude of this problem among MM patients receiving Biphosphonate therapy at our institute. Methods: We conducted a retrospective review of all patients diagnosed with MM at our institute since 2001 who received bisphosphonate treatment and developed ONJ. Clinical characteristics, prior treatments and renal function prior to development of ONJ were evaluated. Results: Records of 20 pts who developed ONJ were reviewed. The median age of these pts was 57 (range 45–69). Among these, 9 were males, 11 were females. All pts (100%) had stage III MM. 11 patients (55%) received 2 or more antimyeloma treatment. 14 pts (70%) were on Zoledronic acid, 5 pts (25%) were on Pamidronate, and 1 pt (5%) was first on Zoledronic acid then switched to Pamidronate. Out of those 20 patients, 19 (95%) had normal renal function prior to and after development of ONJ, with Creatinine level range of (0.5–1). Only 1 patient (5%) had decreased renal function prior to development of ONJ, with Creatinine level of 6.6 Conclusion: Although the number of patients reported are small, experience at our center with ONJ in MM patients who were on Bisphosphonate failed to show any association with renal function. Interestingly all patients who developed ONJ were stage III MM. There are currently no established guidelines for prevention or treatment of this disorder.

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.

scholarly journals The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

2021 ◽  
Author(s):  
Houfu Leng ◽  
Hanlin Zhang ◽  
Linsen Li ◽  
Shuhao Zhang ◽  
Yanping Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Disease ◽  
Drug Dose ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Plasma Membrane Fluidity ◽  
Autophagic Degradation ◽  
High Doses

AbstractMultiple myeloma (MM) is a fatal hematological malignancy, where the majority of patients are diagnosed with, or develop, destructive and debilitating osteolytic bone lesions. Current treatments for MM bone disease such as the bisphosphonate zoledronic acid can result in deleterious side effects at high doses. In this study, eliglustat, an FDA approved glycosphingolipid inhibitor, was shown to reduce MM bone disease in preclinical models of MM. Mechanistically, eliglustat alters the lipid composition and plasma membrane fluidity and acts as an autophagy flux inhibitor in bone-resorbing osteoclasts (OC). Autophagic degradation of the signaling molecule TRAF3 is key step in OC differentiation; this was prevented by eliglustat in OC precursors. In addition, eliglustat works depend on TRAF3 in vivo. Furthermore, the combination of eliglustat and zoledronic acid was found to have an additive effect to reduce MM bone disease, suggesting the potential for combination therapies that would allow for drug dose reductions. Taken together, this project identifies a novel mechanism in which glycosphingolipid inhibition reduces osteoclastogenesis via autophagy and highlights the translational potential of eliglustat for the treatment of bone loss disorders such as MM.One Sentence SummaryTranslational use of eliglustat as an autophagy inhibitor to limit bone lesions in multiple myeloma.

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.

Defining a Murine Model To Study Bone Disease in Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3518-3518
Author(s):  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Zhenxin Shen ◽  
Nipun Patel ◽  
Robert Fajardo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Disease ◽  
Volume Fraction ◽  
Bone Volume ◽  
Human Bone ◽  
Bone Lesions ◽  
Bone Volume Fraction ◽  
Bone Chip

Abstract Multiple Myeloma (MM) is associated with significant skeletal changes including ospeoporosis and bone lesions in more than 80% of patients. Bone resorption is caused by an enhanced osteoclast number and activation. However, molecular and cellular basis for these effects are not completely understood. Here we describe a model that allows us to evaluate in vivo, the relationship and interactions between MM cells and cellular elements of bone formation and resorption. In this model, the BM stroma and IL-6-dependent human MM cell line (INA-6) was injected in a human bone chip implanted into SCID mice. Bone chip in the control mice were injected with media alone. At different time points (days 1, 7 and 30) following injection, myelomatous and control bone chips were retrieved, fixed in paraformaldehyde and evaluated by micro-computed tomography (μCT) and histological examinations for effects of MM cells on bone compartment. The μCT is a non-invasive quantitative imaging method that can asses the degree and extent of bone disease as well as quantify changes in bone structure, that may reflect the effect of interaction between MM cells and bone elements. Additionally, we have measured the levels of human osteocalcin in murine serum to reflect the remodelling of human bone in mice. We have observed that only at day 30 after the MM cell injections, lesions in myelomatous bone is observed in mice; while no significant changes in the matched control bones are seen. By 3-D histomorphometric parameters, calculated from μCT (bone volume fraction= bone volume/total volume), the quantitative measurement confirmed that at day 30, a decreased bone volume fraction (314) was observed in bones with MM compared with normal bones (394), due to reduction of bone density in the trabecular bone. Moreover histological examination of the same bones revealed a significant increase in number of multinucleated TRAP-expressing osteoclasts in mice engrafted with MM versus control (52 versus 8 per field, p= 0.011). Also compared to serum from control mice, animals with bone containing myeloma cells had significantly elevated markers of bone remodelling. To confirm the validity of this model to study effect of MM cells on bone as well as to show its utility for evaluation of novel agents active in MM bone disease, we treated mice with Zoledronic acid at 0,6 mg/kg, weekly for 2 months. As evaluated by μCT, X-rays and TRAP staining Zoledronic acid was able to significantly inhibit the development of bone lesions in treated mice compared to untreated mice. Additionally, , we also observed that Zoledronic acid was also able to retard the MM tumor growth as measured by human IL-6sR released by INA-6 cells in mice sera corroborating its reported anti-MM activity. This model therefore provides a reproducible and predictable in vivo system to study biology of bone disease in MM and to identify and evaluate therapeutic targets and agents targeting MM bone disease.

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.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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