Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw

The Medical Research Council Myeloma IX trial: the impact on treatment paradigms*

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease

The monoclonal antibody nBT062 conjugated to maytansinoids has potent and selective cytotoxicity against CD138 positive multiple myeloma cells _in vitro_ and _in vivo_

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives _in vitro_ and _in vivo_. These agents significantly inhibited growth of CD138-positive MM cell lines and primary tumor cells from MM patients, without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2/M cell cycle arrest followed by apoptosis associated with cleavage of PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth _in vivo_ in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM

International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease

El propósito del estudio fue crear un subgrupo dentro del Grupo Internacional de Trabajo sobre el Mieloma para desarrollar recomendaciones prácticas en el tratamiento de la enfermedad ósea relacionada con el mieloma múltiple (MM). Para ello, un panel interdisciplinario de expertos clínicos en MM y mieloma óseo desarrolló recomendaciones basadas en datos publicados hasta agosto de 2012. Se utilizó el consenso de expertos para proponer recomendaciones adicionales en si-tuaciones en las que no había suficientes datos publicados. Los niveles de evidencia y los gra-dos de las recomendaciones fueron asignados y aprobados por los miembros del panel. Las re-comendaciones fueron: 1) Se deben considerar los bifosfonatos (BP) en todos los pacientes con MM que reciben tratamiento antimieloma de primera línea, independientemente de la presencia de lesiones óseas osteolíticas en la radiografía convencional. Sin embargo, se desconoce si la PA ofrece alguna ventaja en pacientes sin enfermedad ósea evaluados por resonancia magnéti-ca o tomografía por emisión de positrones/tomografía computarizada. 2) Se recomienda el ácido zoledrónico (ZOL) o el pamidronato (PAM) por vía intravenosa (IV) para prevenir eventos relacio-nados con el esqueleto en pacientes con MM. Se prefiere el ZOL sobre el clodronato oral en pa-cientes recién diagnosticados con MM debido a sus posibles efectos antimieloma y beneficios para la supervivencia. 3) Los BP deben administrarse cada 3 a 4 semanas por vía intravenosa durante el tratamiento inicial. ZOL o PAM se deben continuar en pacientes con enfermedad acti-va y se deben reanudar después de la recaída de la enfermedad, si se suspende en pacientes que logran una respuesta completa o parcial muy buena. 4) Los BP son bien tolerados, pero se deben instituir estrategias preventivas para evitar la toxicidad renal o la osteonecrosis de la man-díbula. Se debe considerar la cifoplastia para las fracturas vertebrales sintomáticas por compre-sión. 5) La radioterapia de dosis baja se puede usar para paliar el dolor no controlado, la fractura patológica inminente o la compresión de la médula espinal. Se debe buscar una consulta ortopé-dica para fracturas de huesos largos, compresión de la médula espinal e inestabilidad de la co-lumna vertebral. Ramón García-Sanz fue un participante relevante en el consenso, representando al grupo espa-ñol GEM/PETHEMA. Se trata de la publicación de las discusiones de un grupo de consenso para establecer las recomendaciones del tratamiento de la enfermedad ósea en Mieloma Múltiple. To-dos los autores participaron con el mismo nivel de compromiso, bajo la coordinación del Dr. Ter-pos y el impulso del Dr. Roodman. Fue la principal referencia actual para el tratamiento de la enfermedad ósea en los pacientes con mieloma múltiple, utilizada por casi todos los especialistas de hematología a la hora de tratar pa-cientes con esta rara enfermedad.[EN]The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.International Myeloma Society International Myeloma Working GroupInternational Myeloma Working Grou

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

SummaryNovel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876’s mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets

Targeting IL-17A in Multiple Myeloma: A Potential Novel Therapeutic Approach in Myeloma

We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell–differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report here, that MM cells express IL-17A. We also observed that IL-17A knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease

Panobinostat and Multiple Myeloma in 2018

FDA and EMA approval of panobinostat offers an additional therapeutic option for multiple myeloma; however, adoption of panobinostat has been limited by its adverse event profile. Trials are ongoing to optimize the dosing of panobinostat and to identify its best partners, in order to fully realize the potential of this drug class

Role of the RANK/RANKL Pathway in Multiple Myeloma

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma

Case 9-2008 A 65-Year-Old Woman with a Nonhealing Ulcer of the Jaw

A 65-year-old woman was seen in the oral surgery clinic because of a nonhealing ulcer of the mandible at the site of a tooth that had been extracted 3 years earlier. The patient had multiple myeloma and had been treated with intravenous bisphosphonates for 6 years. Examination disclosed red, raised soft tissue in the right mandible, with mucosal ulceration and exposed bone. A diagnostic procedure was performed. A 65-year-old woman had a nonhealing ulcer of the mandible at the site of a tooth that had been extracted 3 years earlier. The patient had multiple myeloma and had been treated with intravenous bisphosphonates for 6 years. Presentation of Case Dr. Steven E. Smullin (Oral and Maxillofacial Surgery): A 65-year-old woman was seen in the oral surgery clinic of this hospital because of a nonhealing ulcer of the mandible. Three years earlier, the patient had been referred to the oral and maxillofacial surgery clinic for evaluation and extraction of three teeth: the mandibular right cuspid and first bicuspid and the mandibular left second bicuspid. Dental extractions were performed on an outpatient basis with local anesthesia. The right mandibular teeth were extracted nonsurgically; the mandibular left second bicuspid required a surgical extraction with flap elevation and bone removal. . .