1. Slideset on: Terpos E, Morgan G, Dimopoulos MA, et al. International myeloma working group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31:2347-2357. New Guidelines for Treatment of MM-Related Bone Disease This program is supported by educational grants from

2. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease  Recommendations released by IMWG –Derived from a comprehensive review of all available literature –Represent international expert consensus regarding management of MM-related bone disease  Guideline development process –All IMWG panel members reviewed evidence published through August 2012 on treatment of MM-related bone disease –Additional recommendations based on expert consensus proposed when limited published clinical data available –Established criteria used to assign levels of evidence (levels I-V) and grades of recommendations (grades A-D) –All panel members could critique levels of evidence and grading, and guidelines not finalized until consensus reached by all authors Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.

3. Recommendations Regarding Appropriate Use of BPs in MM

4. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations According to Clinical Characteristics Grade A BPs should be initiated in MM patients with detectable bone lesions receiving conventional radiography who require antimyeloma therapy Grade B BPs should be initiated in MM patients without detectable bone lesions receiving conventional radiography who require antimyeloma therapy Grade ABPs should be initiated in MM patients with osteoporosis Grade CBPs should be initiated in MM patients with osteopenia Grade C BPs are recommended for patients with low- and intermediate-risk asymptomatic MM if osteoporosis is identified by DXA Grade D, Panel Consensus Consider dosing BPs as for symptomatic MM in patients with high-risk asymptomatic MM, or if one cannot differentiate between MM-related vs age-related bone loss, especially in patients with abnormal MRIs Grade C BPs are recommended for treatment of osteoporosis in MGUS; use same doses as for other patients with osteoporosis Grade B Consider DXA scan for patients with MGUS given their reported increase in SREs compared with age- matched controls Grade C, Panel Consensus BPs are not indicated for patients with a solitary lytic lesion and no evidence of osteoporosis; BPs should be administered as for osteoporosis patients if osteoporosis is present; treat with monthly IV BPs if multiple lesions are present on MRI, as these are indicative of MM bone disease Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.

5. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Choice of BPs Terpos E, et al. J Clin Oncol. 2013;31:2347-2357. Grade A IV zoledronic acid and pamidronate are recommended for preventing SREs in patients with active MM; efficacy of the 2 agents is comparable Grade A IV zoledronic acid is recommended over oral clodronate because it is significantly more efficacious at preventing SREs Grade A IV zoledronic acid is recommended over oral clodronate in patients with newly diagnosed MM and bone disease given its potential antimyeloma effects and survival benefits Grade B Patients with MM who are ineligible from transplantation may derive clinical benefit from IV zoledronic acid in combination with antimyeloma therapy Grade B IV zoledronic acid, IV pamidronate, or oral clodronate can be used to control bone pain associated with myeloma bone disease Grade BIV pamidronate 30 mg and 90 mg have shown comparable efficacy for preventing SREs CommentIbandronate ineffective in MM for reducing SREs or improving bone pain

6. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Route of Administration Terpos E, et al. J Clin Oncol. 2013;31:2347-2357. Grade AIV BP administration is preferred Grade D Home IV infusion or oral administration may be considered if hospital care is not feasible

7. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Treatment Duration Terpos E, et al. J Clin Oncol. 2013;31:2347-2357. Grade AAdminister IV BPs at 3- to 4-wk intervals to patients with active MM Grade B Continue IV zoledronic acid until disease progression in patients not achieving CR or VGPR; IV zoledronic acid should be resumed if relapse occurs Grade D IV pamidronate may be continued in patients with active disease at physician’s discretion; IV pamidronate should be resumed if relapse occurs Grade D, Panel Consensus Optimal BP treatment duration for patients with CR or VGPR unclear; BPs should be administered for 12-24 mos, then at physician’s discretion Grade D, Panel Consensus Discontinuation of IV zoledronic acid or pamidronate may be considered after 1-2 yrs in patients who have achieved CR or VGPR so as to prevent ONJ with extended therapy Comment Strict adherence to BP dosing schedules is required to effectively reduce and delay SREs

8. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Adverse Events Panel Consensus Clinicians should ask patients about AE-related symptoms and monitor for development of more serious complications; patients should be instructed on how to recognize AEs and importance of early reporting Grade ACalcium and vitamin D supplementation to maintain calcium homeostasis Grade A Use calcium supplementation with caution in patients with renal insufficiency; monitor creatinine clearance, serum electrolytes, and urinary albumin in all patients receiving BPs Grade C, Panel Consensus Adopt preventive strategies to avoid ONJ, including comprehensive dental examination and education about optimal dental hygiene Grade C, Panel Consensus Treat existing dental conditions before initiating BPs Grade C Avoid unnecessary invasive dental procedures in patients receiving BPs; monitor dental health at least annually during BP treatment Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.

9. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Adverse Events Grade D, Panel Consensus Both a physician and dentist should monitor patients’ ongoing dental health Grade CManage dental problems conservatively, if possible Grade D If invasive dental procedures are necessary during BP treatment, temporarily suspend BPs Panel Consensus Stop BPs 90 days before and after invasive dental procedures (eg, tooth extraction, dental implants, jaw surgery); do not discontinue BPs for routine dental procedures, including root canals Grade CTreatment of ONJ includes BP discontinuation until healing occurs Grade D Decide to restart BPs on individual basis until results of prospective long- term studies available Grade D Weigh pros and cons of continued BP treatment, especially in relapsed/refractory MM setting Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.

10. Recommendations Regarding Management of MM-Related Bone Disease With Other Treatment Modalities

11. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Recommendations on Other Treatment Modalities  Kyphoplasty and vertebroplasty  Radiation therapy Terpos E, et al. J Clin Oncol. 2013;31:2347-2357. Grade A Consider balloon kyphoplasty for symptomatic vertebral compression fractures, especially in patients with impaired quality of life due to painful vertebral compression fractures CommentRole of vertebroplasty in MM unclear given lack of randomized trials Comment Low-dose radiation (≤ 30 Gy) can be used to palliate uncontrolled pain, impending pathologic fracture, or impending spinal cord compression Grade C Consider upfront external beam radiation therapy for patients with plasmacytoma, extramedullary masses, and spinal cord compression Comment Use radiation judiciously and sparingly in accord with patient’s presentation, need for urgent response, treatment history, and previous response; single fractions increasingly preferred to fractionated treatment

12. Summary

13. inPractice.com New Guidelines for Treatment of MM-Related Bone Disease Summary of Key IMWG Recommendations for Use of BPs in MM FactorRecommendation Patient population  Newly diagnosed patients with MM who require antimyeloma treatment (regardless of bone status) Administration  IV Duration/ frequency  Monthly during initial therapy and ongoing in patients who are not in remission  After 2 yrs, discontinue if CR/VGPR; continue if ≤ PR Monitoring  Monthly creatinine clearance Choice of agent  Zoledronic acid (first option)  Pamidronate (second option)  Clodronate (only in patients who cannot come to hospital, those with severe disabilities, and those with contraindications to zoledronic acid and pamidronate) Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.

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