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  • Staurosporine Current ASCO recommendations suggest initiatin

    2019-05-15

    Current ASCO recommendations suggest Staurosporine initiating bisphosphonate therapy in myeloma when there is evidence of bone involvement [124]. The optimal duration and frequency of bisphosphonate therapy for myeloma are not well understood and are currently being studied. All randomized, placebo-controlled trials of bisphosphonate use in MM to date have given bisphosphonates for a maximum of two years, thus two years is the treatment duration currently recommended by ASCO and the European myeloma network (EMN). Consensus statements recommend treating patients monthly for 2 years and then considering discontinuation of therapy at that time if the patient is in remission or at plateau phase of disease [124], or at physician discretion [125]. A subset of patients in the MRC IX trial did receive zoledronic Staurosporine for more than 2 years and had a reduced incidence of SREs and improved overall survival compared with the clodronate treated group [126]. However, it is not known whether this finding is independent of the patients\' response to their anti-myeloma therapy. As discussed in a recent evidence-based review of bisphosphonate use in MM, it is not clear whether patients who achieved complete response (CR) in the MRC IX trial continued to have an advantage with continued zoledronic acid use as compared to those who did not achieve a CR [127]. Patients with mild-moderate renal impairment (CrCl: 30–60mL/min) >3mg/dl) should receive reduced doses of zoledronic acid. No change in the zoledronic acid infusion time is recommended. In these patients, pamidronate should be administered over an extended infusion time (2–4h) [127]. DEXA scans are recommended for consideration for patients with monoclonal gammopathy of undetermined significance and low and intermediate risk smoldering MM, given the increased risk of skeletal-related events in the patients compared with age-matched controls [128,129]. Patients with DEXA scans demonstrating osteoporosis (T score <2) should be treated with bisphosphonates in the same manner as patients with osteoporosis. An emerging complication of bisphosphonate therapy is osteonecrosis of the jaw (ONJ). ONJ has been reported in association with bisphosphonate use in patients with metastastic bone disease as well as benign osteoporosis, although a cause and effect relationship has not been clearly demonstrated. Patients with myeloma have been reported to have the highest incidence of ONJ (1.6–11%; reviewed in [130]) while patients with postmenopausal osteoporosis who are treated with oral bisphosphonates have an incidence of ONJ of 1/10,000–1/100,000 patient treatment years [131]. Bisphosphonate associated ONJ is defined as the presence of the exposed bone in the mandible or maxilla in patients receiving bisphosphonate therapy that does not heal within 8 weeks of appropriate dental management in the absence of local metastatic disease or previous radiation therapy [130]. Clinical examination usually shows an exposed alveolar ridge with evidence of necrotic bone, often with a purulent discharge. The surrounding gums and mucosal tissue are often inflamed and can be painful to the touch [130]. Patients can have single or multiple lesions with the mandible more frequently involved than the maxilla. Most patients have only exposed bone, although fistulae to the maxillary sinus or the skin rarely occur and pathologic fractures of the mandible have been reported [130]. The overwhelming majority of cases reported are case reports or retrospective studies of patients receiving bisphosphonate therapy. A long-term follow-up study of 97 myeloma patients with ONJ followed for at least 3.2 years identified dental extraction, older age and longer survival as risk factors for ONJ [132]. ONJ resolved in 60 of the 97 patients studied, resolved and recurred in 12 of the patients, and did not heal over a 9-month period in 26% of the patients. Dental extraction preceded development of ONJ in 47% of the patients and was more common in patients with a single episode of ONJ than in patients with recurrent or nonhealing ONJ. ONJ recurrence in these patients was associated with reinitiation of bisphosphonate therapy or dental procedures. Patients developing ONJ following dental procedures were less likely to have a recurrence or nonhealing, and although infrequent, recurrence was linked to re-treatment with bisphosphonates in patients with relapsed myeloma.