Treatment Of Myeloma Bone Disease Research Articles

Prevention and Treatment of Myeloma Bone Disease

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal-related events (SREs) that cause significant morbidity. Bone destruction in myeloma is due to an increased activity of osteoclasts coupled with suppressed bone formation by osteoblasts. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease. Zoledronic acid and pamidronate have shown similar efficacy in reducing SREs in a randomized study in the conventional chemotherapy era. However, in a recent study (the Myeloma-IX trial of the UK Medical Research Council, MRC), zoledronic acid was found to be superior to clodronate in reducing SREs, but also it produced a survival advantage of approximately 10months in patients with bone disease at baseline. During recent years, novel agents targeting bone have been used in myeloma. This review focuses on the established therapy of myeloma bone disease and also on recent advances in treatment that take advantage of the better understanding of the pathophysiology of bone disease.

Loss of CYR61 in Myeloma Microenvironment Is Associated with Poor Survival

Abstract 1813Previously, we used gene expression profiling (GEP) on whole-bone biopsies (BX) and plasma cells (PCs) of newly diagnosed multiple myeloma (MM) patients and age-matched controls to identify 62 non-PC-related genes that were significantly differentially expressed in bone biopsies of MM. CYR61/CCN1 was the most significantly overexpressed gene in BX in subsets of MGUS and MM patients. We hypothesize that alteration of the microenvironment may be central to the conversion of MGUS to MM and that abnormal expression of CYR61 may precede this conversion. CYR61 has been shown to promote proliferation, migration, adhesion and angiogenesis and is expressed in many cell types. Within the bone, CYR61 is induced during osteoblast differentiation by endothelin-1, (Clines et al., 2007) and by Wnt3a (Si et al., 2006). CYR61 also inhibits the formation of multinucleate osteoclasts in vitro (Crockett et al., 2007). To investigate the role of CYR61 in MM pathogenesis CYR61 protein production in MM was analyzed in sera of 192 newly diagnosed myeloma patients by ELISA. In agreement with that observed by GEP, CYR61 is significantly elevated in a subset of MM patients (144/192) at diagnosis compared with healthy donors (p < 0.001). In Total Therapy 3 (TT3) patients low CYR61 (< 500 pg/ml) is associated with poor overall survival (p < 0.05) compared with levels greater than 500 pg/ml. CYR61 levels were also significantly elevated in MGUS, Waldenstrom’s macroglobulinemia and smoldering/indolent myeloma compared with healthy donors (p < 0.001). Patient samples were grouped into the 8 GEP-defined MM molecular subtypes (Zhan et al., 2006) and CYR61 levels were significantly different from healthy donors in all subtypes with the exception of MY that typically is associated with a better prognosis. Analysis of CYR61 levels in TT3 patients 48h post-Velcade (Vel) revealed an inverse correlation between change in CYR61 levels post-Vel and 80-gene risk in TT3a patients (p < 0.01). Likewise, the change in CYR61 levels from diagnosis to remission is also inversely correlated with risk (p < 0.01). To better understand the mechanism by which loss of CYR61 might negatively affect risk we examined the GEP from MM Bx and CD138-selected plasma cells to compare gene signatures in patients with low CYR61 (Q1) and high CYR61 (Q4). Those genes that exhibited ≥ 2-fold difference were investigated further. Patients with low CYR61 differentially expressed 179 probesets in MMBX including elevated SFRP2 (4.1-fold), a Wnt inhibitor, and COL2A1 (3.5-fold) which are associated with myeloma bone disease and osteoarthritis, respectively. SFRP2 is also elevated (4.3-fold) in MMPCs (194 probesets elevated) along with TNFSF10 (2.1-fold) indicative of the HY subtype and FGFR3 (2.1-fold) which is elevated in the MS subtype. In patients with high CYR61, many muscle-specific genes were elevated in MM BX and may indicate a predominance of osteocytes. Additionally, BGLAP, whose loss is associated with poor survival in myeloma, is elevated (2-fold) in MM BX (171 probesets) with high CYR61 and EDN1, an activator of CYR61/CCN1, is elevated (2.8-fold) in MM PCs (111 probesets) with high CYR61. The test the effect of CYR61 on cell growth, H929 cells were exposed to rCYR61 which caused a dose- and time-dependent suppression of cell growth and survival. To examine the role of CYR61 in the MM ME, H929 cells transduced with empty vector, wild type CYR61 or CYR61 cDNA with a mutated αvβ3 binding site were injected into implanted bones in SCID-hu mice. CYR61-induced effects on bone have been shown to be mediated by the αvβ3 integrin, presumably through osteoblasts. X-rays of the implanted bone and serum measurement of hIg levels were taken weekly for 5 weeks. Quantitation of change in bone mineral density (BMD) over the course of the experiment showed that CYR61 inhibits osteolysis (p<0.04), whereas CYR61 that is incapable of binding αvβ3 attenuates this effect. These data indicate that the αvβ3 integrin mediates CYR61-induced inhibition of osteolysis in MM. Additionally, quantitation of serum hIg demonstrated that CYR61 significantly reduces MM tumor growth (p<0.04) and this is not effected by mutation of the avb3 binding site. Taken together these data suggest that loss of CYR61 in myeloma may be indicative of a dysfunctional ME and thus serve as a biomarker to monitor the MM ME. Finally, therapeutics that upregulate CCN1 will be tested as a novel treatment for myeloma bone disease. Disclosures:Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.

Ibandronate and Renal Function In Myeloma Patients

AbstractAbstract 5047 Introduction:Treatment of myeloma bone disease with bisphosphonates (BP) is standard of care. However, renal toxicity due to BP treatment tends to be a major problem in myeloma patients, especially. At highest risk are patients with reduced renal function and patients who had switched the BP. Toxicity appears typically after few month of BP treatment.We evaluated the renal safety of ibandronate (IBD) in myeloma patients, who were treated with IBD for myeloma bone disease. The patients were stratified according to pretreatment and kidney function. Methods:In a prospective noninterventional study about safety and efficacy of IBD in breast cancer patients it turned out that myeloma patients were also included unintentionally. Out of 3540 documented patients 105 myeloma patients were identified. The data from these myeloma patients were evaluated separately.The patients were subdivided in 4 groups according to their glomerular filtration rate [GFR]: GFR>90 (1), 60–90 (2), 30–59 (3) and <30 (4) ml/min. Since pretreatment with other BP could be of influence, patients were analysed according to former pretreatment: no BP (I), IBD (II), and other BP (III). The renal function was calculated every month over a period of six month by the MDRD-formula. Results:105 patients were available for evaluation. In 99 patients RF was documented over a minimum of 5 months. The initial RF was (1) n=14, (2) n=36, (3) n=38 and (4) n=17, respectively. At baseline there were no differences in renal function according to their pretreatment. A total number of 692 infusions were documented. The IBD dosage was 6 mg in 90% of all infusions, 4 mg in 3,6%, 3 mg in 2% and 2 mg in 4.4%, respectively. The GFR (mean GFR+/−SD) was stable over time in the groups 1–3 and increased significantly in group 4;The mean changes were similar in all groups irrespectively of the pretreatment. In 9 patients the treatment was terminated prematurely, due to disease progression (n=3), death due to myeloma during study period (n=3). Two patients were lost by follow up and one patient declined further treatment. Discussion:The data of this noninterventional study demonstrate, that there is no evidence for renal toxicity of IBD in myeloma patients in all stages of renal function. Quite in contrary to previous observations with other BP patients with worse kidney function (stage 4) had a significant improvement of GFR over the study period. The reason for this observation remains unclear, because parameters like hypercalcemia or burden of light chains are not recorded in this study.GroupGFR [ml/min] at baseline (mean +/− SD)GFR [ml/min] at last measurement (mean +/− SD)Difference over the time [ml/min]95% confidence interval1110.8 +/− 28.7107.5 +/− 10.6− 3.3−11.2–4.6274.8 +/− 8.776.5 +/− 17.2+ 1.7−3.0–6.6348.3 +/− 10.554.1 +/− 18.7+ 5.50.0–11.2420.5 +/− 6.736.1 +/− 28.8+ 15.61.0–32.9 Disclosures:Off Label Use: Ibandronate is not approved for myeloma bone diease.

Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease

Skeletal-related events (SREs) are common in patients with osteolytic lesions from multiple myeloma (MM), and result in substantial morbidity. We report herein a comprehensive, retrospective, multivariate analysis of prognostic factors for survival and first on-study SRE in MM patients using data from the phase III, randomized study comparing zoledronic acid with pamidronate in MM or breast cancer. Cox regression analyses were used to assess 22 variables for prognostic significance (defined as associations with P<0.05) in patients with bone metabolism marker assessments and complete baseline variable data. Of 510 evaluable MM patients, 282 had complete covariate information and were included in models. Reduced Cox multivariate models identified five significant prognostic factors for first SRE (weight, race, high N-terminal cross-linked telopeptide of type I collagen (NTX), high pain score, and need for narcotic analgesics) and seven for survival (age, SRE history, myeloma subtype, anemia, high lactate dehydrogenase, high NTX, and low albumin levels). High NTX was the only variable associated with elevated risks of both first SRE and death (P< or =0.02 for each). These analyses identified prognostic factors for SREs and survival in patients with MM. Taken together with current staging systems, these factors could further facilitate decision making for optimal treatment of myeloma bone disease, although further prospective assessments are needed.

Renal Safety of Ibandronate in the Treatment of Myeloma Patients.

Abstract 4943 IntroductionTreatment of myeloma bone disease with bisphosphonates is standard of care. But renal toxicity due to bisphosphonate treatment tends to be a major problem in myeloma patients, especially. Patients with reduced kidney function and patients who have switched bisphosphonate drugs are at highest risk. Toxicity appears typically after few months of treatment. In patients with myeloma and impaired renal function with GFR < 30 ml/min no bisphosphonate is approved for treatment of myeloma bone disease in Germany. In breast cancer patients ibandronate dosage should be reduced from 6 to 2 mg in advanced kidney failure (GFR < 30 ml/min).We evaluated safety data about renal function from myeloma patients, who were treated with ibandronate. The patients were stratified according to pre-treatment and kidney function. MethodsIn a prospective non-interventional study (NIS) about safety and efficacy of ibandronate in breast cancer patients it turned out that unintentionally myeloma patients were also included. Out of 3528 documented patients 93 myeloma patients were identified. We evaluated the data from these myeloma patients separately.The myeloma patients were subdivided in 4 groups according to their renal function: GFR > 90 (stage 1), 60 – 90 (stage 2), 30 – 59 (stage 3) and < 30 (stage 4-5) ml/min. Since pre-treatment with or without bisphosphonates could be of influence, patients were analysed according to former pre-treatment: no bisphosphonate (I), ibandronate (II), and other bisphosphonates (III). The kidney function was calculated every month over a period of six months. ResultsNinety-three (93) patients with multiple myeloma were available for evaluation. In 87 patients renal function was documented over a minimum of 5 months. Eleven (11) patients had stage 1, 34 patients had stage 2, 36 patients stage 3 and 12 patients stage 4-5 of renal impairment, respectively. There were no differences in renal function according to their pre-treatment. There were also no differences in the three groups (I-III) regarding the prevalence of diabetes, hypertension and kidney function. A total number of 620 infusions were documented. The ibandronate dosage was 6 mg in 89% of all infusions, 4 mg in 4%, 3 mg in 2% and 2 mg in 5%, respectively. In the subgroups (stages) renal function was stable over time (mean GFR+/-SD ; difference over the time [ml/min]: stage 1: 116,8+/- 20,9; - 3,38; stage 2: 74,7 +/- 8.4; +2,04; stage 3: 46,1 +/- 8,1; +3,7; stage 4-5: 20,4 +/- 7; + 13,37; all changes n. s.), but there was a trend for improved renal function in patients with renal function stage 4-5. The mean changes were similar in all groups irrespectively of the pre-treatment. In 8 patients the treatment was terminated prematurely. Three patients had disease progression, and two patients died due to myeloma during study period. Two patients were lost by follow up and one patient declined further treatment. DiscussionThe data of this non-interventional study suggest that there is no evidence for renal toxicity of ibandronate in myeloma patients in all stages of renal function. This applies also for patients who received higher dosages of ibandronate as recommended. Patients with worse kidney function (stage 4-5) had a trend of improvement of renal function over the study period, however the changes were not significant due to the limited number of patients. There were also no differences in renal function irrespectively of the pre-treatment. DisclosuresBergner:Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ibandronate is not approved for use in myeloma bone disease.

Dasatinib Promotes Osteoprogenitor Differentiation and Inhibition of Osteoclastogenesis: Rationale for Treatment of Myeloma Bone Disease.

Abstract 3834Poster Board III-770 IntroductionMultiple myeloma (MM), an hematological malignancy of terminally differentiated plasma cells, is characterized by the presence of bone disease, caused by increased osteoclast (OC) activity and differentiation as well as a reduction in osteoblast (OB) number and function. Dasatinib (BMS-354825) is an oral multitargeted tyrosin-kinase inhibitor approved for chronic myeloid leukemia which is also under clinical investigation in several other types of tumors. Preclinical data suggests that dasatinib can also be of value in MM based on its effects on myelomatous plasma cells and angiogenesis. In this study, we have further investigated the effects of dasatinib on in vitro OB differentiation and function, as well as on OC formation and resorption activity. Materials and methodsFor studies on OB differentiation and function, human mensenchymal stem cells (hMSC) from bone marrow samples of healthy donors and MM patients were used. Alternatively, the mesenchymal hMSC-TERT, the osteoblast-like (MG-63) and multiple myeloma (MM.1S) cell lines were employed. Dasatinib mechanism of action was investigated by Western blotting, PKH67/Annexin V/7 aminoactinomycin D staining, real time RT-PCR, alkaline phosphatase (ALP) activity and quantitative mineralization assays. Receptor activator of nuclear factor κ B ligand (RANKL) and osteoprotegerin (OPG) levels in conditioned media were measured by ELISA. OCs were generated by culture of peripheral blood mononuclear cells from healthy volunteers in medium containing macrophage colony stimulating factor and RANKL. The effect of dasatinib on osteoclastogenesis was assessed by enumeration of multinucleated (≥3) tartrate resistant acid phosphatase-positive cells, whereas bone resorption was calculated by the resorbed area on calcium-coated slides. ResultsWe found that dasatinib inhibited platelet derived growth factor (PDGF)-stimulated activation of PDGF receptor β (PDGFRβ) and c-Src in hMSC-TERT and MG-63 cell lines, both tyrosin kinases implicated in OB remodelation processes. Inhibition of PDGFRβ and c-Src signalling correlated with diminished proliferation of the same cell lines without affecting cell viavility as assessed by PKH67/Annexin V/7 aminoactinomycin D staining. Also, treatment of human osteoprogenitor cells with low dasatinib concentrations (2 - 5 nM) promoted OB differentiation since ALP activity at day 7 and gene expression levels of bone formation markers (Runx2/Cbfa1, ALP, and COLIA1) at day 7 and 14 in the osteoblastic differentiation process, were elevated; besides, dasatinib also increased mineral nodular formation as per quantification of alizarin red staining. Finally, treatment with dasatinib decreased the RANKL/OPG ratio in conditioned media from co-cultures of MG-63 and MM.1S cell lines. Similar range of dasatinib concentrations markedly inhibited OC formation, both at the initial and late stages of differentiation from hemopoietic progenitor cells. Finally, a significant reduction of OC resorptive activity of a calcium-coated substrate was observed. ConclusionOur results indicate that dasatinib favours both OB differentiation and activity and markedly impairs osteoclastogenesis and OC resorption, thus providing rationale for its use to improve bone lesions in MM patients and other bone pathologies.This work was supported by grants from Ministerio de Ciencia e Innovación - ISCIII (PI081825); Fundación de Investigación Médica Mutua Madrileña AP27262008, and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León 07-09, Consejería Sanidad JCyL-ISCIII. Disclosures:Garzon:Bristol-Myers Squibb Company: Employment.

Pathogenesis and management of myeloma bone disease

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of increased activity of osteoclasts that is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition, including the RANKL/osteoprotegerin pathway, macrophage inflammatory proteins and the wingless type signaling pathway. These molecules also appear to interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma. Currently, bisphosphonates are the mainstay of treatment for myeloma bone disease, although several novel agents appear promising. This review focuses on recent advances in understanding the biology of bone disease in multiple myeloma, diagnosis and recent progress in treatment options.

Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6

Multiple myeloma (MM) is associated with increased activation of osteoclasts, causing enhanced bone degradation and formation of lytic bone lesions. In this study, we observed the inhibitory effect of bortezomib on osteoclasts maturation and function from peripheral blood mononuclear cells (PBMCs) of MM patients, in an attempt to clarify the upstream molecular mechanism of bortezomib on osteoclastogenesis. Osteoclast precursors from PBMCs of eight MM patients were cultured in the presence of receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Administration of 2.5 and 5 nM bortezomib resulted in the reduction of osteoclast differentiation by less formation of osteoclasts and the decreased activity level of TRAP. Osteoclast resorption capacity also decreased, suggesting that bortezomib was able to inhibit the function of osteoclasts. The results of Western-blot and RT-PCR assays suggested that bortezomib inhibited osteoclasts by decreasing TRAF6 production at both protein and mRNA levels. In conclusion, bortezomib acts on osteoclastgenesis at low concentrations by interfering with TRAF6 production, which might prove to be a potential strategy for the treatment of myeloma bone disease.

Skeletal Imaging and Management of Bone Disease

Up to 90% of patients with multiple myeloma develop bone lesions. The lesions are purely osteolytic because of increased osteoclast activity and markedly suppressed or absent osteoblast activity. The "gold standard" for imaging myeloma bone lesions is the metastatic bone survey. However, plain radiographs are relatively insensitive and can only demonstrate lytic disease when 30% of trabecular bone loss has occurred. Technicium-99m bone scanning is not appropriate for evaluating myeloma patients since bone scans underestimate the extent of bone involvement in patients with myeloma. The limited reproducibility of bone surveys have led to the use of computerized tomography (CT) scanning, magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to evaluate the extent of bone disease. CT scans are more sensitive than plain radiographs for detecting small lytic lesions, and MRI scans detect marrow involvement by the tumor. PET scans have been used to detect bone lesions in patients with myeloma, are more sensitive than plain radiographs, and have the same sensitivity as MRIs for detecting bone disease in the spine and pelvis. Treatment of myeloma bone disease involves treatment of the underlying malignancy and its manifestations. Current treatments that will be discussed include bisphosphonate therapy, kyphoplasty, vertebroplasty, radiation therapy, and novel agents to suppress osteoclastic bone resorption. In addition, complications with bisphosphonate therapy will be reviewed, in particular, osteonecrosis of the jaw associated with bisphosphonate therapy. As survival of myeloma patients increases, therapies to prevent the complications of aggressive myeloma bone disease become more important.

Treatment for Myeloma Bone Disease

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.

Biphasic anti-osteoclastic action of intravenous alendronate therapy in multiple myeloma bone disease

Multiple myeloma is a malignancy of plasma cells with osteolytic bone destruction. Bisphosphonates inhibit osteoclast activity and are widely used for the treatment of myeloma bone disease. We analyzed the changes in urinary cross-linked N-telopeptides of collagen (u-NTx) and urinary calcium (u-Ca) after bisphosphonate alendronate therapy in ten patients with myeloma bone disease. In all patients, the levels of u-Ca and u-NTx decreased within a week. After the maximum decrease of u-NTx, u-NTx started increasing in half of the patients. However, this further increase in u-NTx decreased again without any additional therapy. Disease severity and pretreatment u-NTx concentrations did not differ between patients with and without the rebound. Patients who did not have rebound had decreased bone marrow monocytes and decreased serum concentrations of interleukin 18, which is produced by monocytes. Our results suggest that impaired activity of monocytes, which are possible osteoclast precursors, is related to reduced bone destruction in multiple myeloma.

Expression of receptor activator of NF-kappaB ligand (RANKL) mRNA in human multiple myeloma cells.

Increased bone resorption is a hallmark of multiple myeloma and a result of excessive osteoclast activation. Recently, the receptor activator of NF-kappaB ligand (RANKL) was found to be the critical factor for osteoclastogenesis. Studies showed that myeloma cells induce RANKL expression in bone marrow stromal cells, but it remained a controversy whether myeloma cells directly express RANKL. Therefore, we analyzed the expression of RANKL mRNA in freshly isolated CD138 positive plasma cells from patients with multiple myeloma and osteolytic bone lesions, using three different primer pairs against human RANKL. RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease. These findings show that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease.

Bisphosphonates in the treatment of myeloma bone disease

European Journal of HaematologyVolume 70, Issue 4 p. 271-272 Bisphosphonates in the treatment of myeloma bone disease P. Croucher, P. CroucherSearch for more papers by this author P. Croucher, P. CroucherSearch for more papers by this author First published: 26 March 2003 https://doi.org/10.1034/j.1600-0609.2003.11819.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume70, Issue4April 2003Pages 271-272 RelatedInformation

Advances in the biology and treatment of myeloma bone disease

The major clinical manifestations of multiple myeloma are related to the loss of bone. This bone loss often leads to pathologic fractures, spinal cord compression, hypercalcemia, and bone pain. This article reviews the cytokine network involved in myeloma bone disease; describes the signaling cascade involved in osteoclastogenesis and mechanisms of action of novel therapeutic options for myeloma bone disease such as osteoprotegerin, RANK human immunoglobulin fusion protein, the proteasome inhibitor PS-341, and bisphosphonates; and summarizes the latest clinical trial results using oral and intravenous bisphosphonates for bone disease in multiple myeloma. Semin Oncol 29 (suppl 17):11-16. Copyright 2002, Elsevier Science (USA). All rights reserved.

Advances in the biology and treatment of myeloma bone disease.

The major clinical manifestations of multiple myeloma are related to the loss of bone. This bone loss often leads to pathologic fractures, spinal cord compression, hypercalcemia, and bone pain. This article reviews the cytokine network involved in myeloma bone disease; describes the signaling cascade involved in osteoclastogenesis and mechanisms of action of novel therapeutic options for myeloma bone disease such as osteoprotegerin, RANK human immunoglobulin fusion protein, the proteasome inhibitor PS-341, and bisphosphonates; and summarizes the latest clinical trial results using oral and intravenous bisphosphonates for bone disease in multiple myeloma.

Advances in the biology and treatment of myeloma bone disease.

Potential antitumor effects of bisphosphonates are discussed, and trial results of zoledronic acid, a bisphosphonate that recently received FDA approval for the treatment of hypercalcemia of malignancy (HCM), are described. Substitution at two sites on the central carbon in the phosphate-carbon-phosphate backbone has resulted in bisphosphonates increasingly more potent than the first such drug, etidronate disodium. Besides having an antihypercalcemic effect, the nitrogen-containing bisphosphonates pamidronate disodium and zoledronic acid have been shown to have an antitumor effect. Possible mechanisms include inducing apoptosis in tumor cells, inhibiting angiogenesis, and reducing adherence of cancer cells to the bone matrix. Zoledronic acid 4 mg is superior to pamidronate disodium 90 mg in achieving a normal serum calcium concentration, without increased toxicity. Zoledronic acid has a higher response rate, faster onset, and longer duration of action, and is more convenient to administer. Doses of > or = 1.5 mg given every four weeks for three months resulted in sustained reductions in urinary markers of bone resorption. Clinical trial results suggest that zoledronic acid 4 mg is at least as effective as pamidronate disodium 90 mg in preventing skeletal complications of osteolytic disease. Zoledronic acid is superior to pamidronate disodium in treating HCM and more convenient to administer. More research to evaluate its safety and effectiveness at higher doses is needed before its full antitumor potential is realized.

Myeloma bone disease

Bone destruction is a hallmark of myeloma, with 70% to 80% of patients manifesting bone involvement. Destruction is mediated through normal osteoclasts (OCLs), which respond to local osteoclast-activating factors (OAFs) produced by myeloma cells or by other cells in the local microenvironment. OAFs implicated in myeloma bone disease include tumor necrosis factor-beta (TNFβ), RANK ligand (RANKL), interleukin-1 (IL-1), parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and macrophage inflammatory protein-1-alpha (MIP-1α). To date, the leading candidates for OAFs are MIP-1α and RANKL. Adhesive interactions between marrow stromal cells and myeloma cells induce marrow stromal cells to secrete IL-6, a potent myeloma growth/survival factor that may contribute to the bone disease. Evaluation of myeloma bone disease includes plain radiographs, and newer methods, such as magnetic resonance imaging (MRI), positron emission tomography (PET) scans, technetium-99m-sestamibi (Mibi) scanning, and dual-energy x-ray absorptiometry (DEXA) scanning, may provide more complete information. In addition, biochemical markers of bone resorption are being evaluated, although the limited availability of these assays and lack of extensive testing in patients make their routine use premature. Treatment of myeloma bone disease includes radiation therapy, vertebroplasty, surgery, and bisphosphonates. New developments on the pathogenesis and treatment of myeloma bone disease present great opportunities to combat bone disease.

New advances in the biology and treatment of myeloma bone disease

New advances in the biology and treatment of myeloma bone disease

New advances in the biology and treatment of myeloma bone disease

The bisphosphonates provide effective therapy for the skeletal complications of multiple myeloma (MM). Although the earliest bisphosphonates had poor bioavailability and relatively low potency, newer compounds such as pamidronate and zoledronic acid have greater potency. Bisphosphonates block the development of monocytes into osteoclasts and are thought to promote apoptosis of osteoclasts. These agents prevent osteoclasts from moving to the bone surface and seem to inhibit the production of bone-resorbing cytokines such as interleukin-6 (IL.-6) by bone marrow stromal cells. In addition, bisphosphonates seem to have a direct antimyeloma effect by inducing apoptosis of malignant plasma cells. The beneficial effects of pamidronate have been demonstrated in a clinical trial setting. Patients who failed to respond to chemotherapy had a slight prolongation of survival and better performance status and quality of life. Ongoing clinical trials with ibandronate and zoledronic acid indicate the latter is 100 to 1,000 times more potent than pamidronate. Biochemical effects of zoledronic acid continue for as long as 8 weeks after a single administration. In a new trial comparing pamidronate and zoledronic acid, 90% of the patients who received zoledronic acid were normocalcemic, compared with 69% of those who received pamidronate at 10 days. In addition, the time to relapse or development of hypercalcemia was shorter for patients receiving pamidronate compared with zoledronic acid.

LONG‐TERM EFFECTS OF PARENTERAL DICHLOROMETHYLENE BISPHOSPHONATE (CL2MBP) ON BONE DISEASE OF MYELOMA PATIENTS TREATED WITH CHEMOTHERAPY

Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty. In a prospective pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate), in addition to standard chemotherapy, in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/day i.v. for seven days followed by 100 mg/day i.m. for 10 days, administered at a mean interval of 4 months (range 3-6). The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits; these effects were maintained throughout the follow-up. In three hypercalcemic episodes serum calcium became normal after 2-5 days of treatment with Clodronate. No toxic or side effects were noticed. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients (p less than 0.001) in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures (p less than 0.001). Supportive Clodronate therapy contributes significantly in controlling the progression of myeloma bone disease.