Oh Snap! Denosumab versus Bisphosphonates for Skeletal Related Events in Multiple Myeloma

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1 Oh Snap! Denosumab versus Bisphosphonates for Skeletal Related Events in Multiple Myeloma Pharmacotherapy Grand Rounds Anndee S. Gritte, PharmD PGY1 Pharmacy Practice Resident South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy UT Health San Antonio February 22, 2019 Learning Objectives 1. Describe the basic pathophysiology of multiple myeloma and how skeletal-related events are implicated 2. Identify treatment approaches to preventing skeletal related events in multiple myeloma 3. Evaluate the literature supporting bisphosphonates and denosumab in multiple myeloma 4. Formulate evidence-based recommendations for preventing skeletal related events in multiple myeloma

2 Multiple myeloma I. Definition: malignancy of plasma cells or immunoglobulin-producing B lymphocytes II. Epidemiology 1,2 a. Incidence i. 30,330 cases were diagnosed in the United States in 2016 ii. Primarily a disease of the elderly, 69 years old being the median age of diagnosis iii. Occurs more frequently in men and in African Americans b. Prognosis/Survival i. Incurable ii. 5-year survival ~52.4% iii. Malignancy with a wide spectrum of aggression iv. In its end stages, patients typically relapse rapidly and show broad treatment refractoriness v. Genetic prognostic factors Table 1. Known genetic abnormalities implicated in multiple myeloma 3 Risk Abnormality Low risk Chromosomal trisomies Intermediate risk T(4;14), del13, hypoploidy High Risk T(14;16), t(14;20), or del 17p13 Standard risk Absence of genetic abnormalities listed above c. Risk factors i. Environmental exposures 1. Radiation exposure 2. Chemicals pesticides, aromatic hydrocarbons, petroleum products ii. Genetics no specific genetic abnormalities have been identified as a higher risk for developing multiple myeloma III. Pathophysiology 1-5 a. Multiple myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma cells that are derived from post-germinal center B cells b. Three stages of malignancy development i. Monoclonal gammopathy of undetermined significance (MGUS) 1. No organ or tissue damage present 2. Elevated levels of monoclonal immunoglobulin, not great enough to be considered myeloma 3. Risk of progression is ~1% per year ii. Smoldering multiple myeloma 1. No evidence of clinical manifestations of multiple myeloma 2. Further elevated levels of monoclonal immunoglobulin 3. Risk of progression is 10% the first year and 3% yearly for the next 5 years iii. Active multiple myeloma 1. Presence of clinical manifestations 2. Monoclonal protein in serum or urine 10% 2

3 Figure 1. Abnormalities associated with stages of myeloma 2 c. Influence of the cellular microenvironment i. Interactions between myeloma cells and bone marrow cells, mediated through cell-surface receptors (such as integrins, selectins, and cell-adhesion molecules), increase the tumor growth, survival, migration, and drug resistance ii. Adhesion of myeloma cells to hematopoietic and stromal cells induces the secretion of cytokines, including IL-6, VEGF, insulin-like growth factor 1, TNFs, growth factor β-1, and IL-10 iii. IL-6 produced by bone marrow stem cells and macrophages is a strong mediator of myeloma cell growth, survival, migration, and drug resistance 1. IL-6 is a product of bone marrow stromal cells and acts as a paracrine stimulus for plasma cells 2. Plasma cell adhesion to bone marrow stroma has been shown to increase stromal IL-6 secretion, thus leading to a self-augmenting feedback loop and demonstrating how amplification of IL-6 pathways may be central to plasma cell tumorigenesis 2, 4-6 IV. Signs/symptoms a. Classified as symptomatic or asymptomatic depending on the presence or absence of myeloma related organ or tissue dysfunction i. CRAB Criteria 1. Hypercalcemia a. Adjusted serum calcium 11 mg/dl b. 13% of patients present with hypercalcemia 2. Renal dysfunction a. Serum creatinine > 2mg/dL b % of patients exhibit renal dysfunction 3. Anemia a. Hemoglobin < 10 g/dl b. 73% of patients present with anemia 4. Bone lesions a. 80% of patients have bone lesion including plasmacytoma, fractures, or evidence of osteolytic lesions on imaging b % of patients present with fractures 3

4 b. Other signs/symptoms present i. Monoclonal protein on serum protein electrophoresis (SPEP) or serum free light chain assay 1. Also called M-spike 2. Type of M protein present: IgG > IgA > light chain only ii. Urine protein immunofixation iii. Increased 10% clonal bone marrow plasma cells V. Diagnosis 7-9 a. Diagnosis is based on 10% clonal bone marrow plasma cells and monoclonal protein in serum or urine b. Three staging systems have been developed Table 2. Comparison of multiple myeloma staging systems 7,8,9 Stage Durie-Salmon Criteria International staging system (ISS) Criteria I All of the following: Serum β2- Hemoglobin > 10 g/dl microglobulin < Serum calcium normal or 3.5 mg/l 12 mg/dl Serum albumin Bone imaging normal or 3.5 g/dl solitary bone plasmacytoma only Low M-component production rate Revised international staging system (r-iss) Criteria ISS stage I + no high risk chromosomal abnormalities AND normal lactic acid dehydrogenase (LDH) level II Not Stage I or III Not Stage I or III Not Stage I or III III One or more of the following: Hemoglobin < 8.5 g/dl Serum calcium > 12 mg/dl Advanced lytic bone disease High M-component production rate Serum β2- microglobulin 5.5 mg/l ISS Stage III + either high risk chromosomal abnormality OR high LDH c. Comparison of staging systems 7-14 i. Durie-Salmon Staging System 1. First staging system developed 2. Heavily influenced by lytic lesions on radiographs and, therefore, more observer dependent ii. International staging system (ISS) 1. Major component is albumin which can be heavily influenced by other health factors 2. More reproducible than Durie-Salmon Staging iii. Revised International staging system (r-iss) 1. Improved over ISS by including chromosomal abnormalities and LDH serves as a marker of aggressiveness of plasma cells 2. Only derived from patient in clinical trials with untreated, symptomatic multiple myeloma 3. Subsequent studies done to validate in myeloma patients with both newly diagnosed disease and relapsed disease found r-iss staging to be more closely correlated with patient outcomes 4. Most commonly used for reproducibility 4

5 VI. Treatment of multiple myeloma 15,16 a. Treatment approach depends on whether the patient is a candidate for hematopoietic stem cell transplant (HSCT) Patients who are HSCT candidates Induction therapy HSCT Pt shows treatment response or stable disease Maintenance therapy Patients who are not HSCT candidates Initial treatment based on patient comorbidities Pt shows treatment repsonse or stable disease Maintenance therapy Figure 3. General treatment strategies in newly diagnosed multiple myeloma patients 15 b. See Appendix A for common treatment regimens c. Almost all patients will relapse after initial therapy i. Median time to relapse after HSCT- 4 years ii. Median time to relapse without HSCT- 2.5 years Skeletal related events in multiple myeloma I. What are skeletal related events (SREs)? 17,18 a. SREs include fractures, vertebral compressions, and the need for radiation or surgery to treat bone disease b. Associated with 23-32% increased risk of mortality c % of patients will develop osteolytic lesions during their myeloma course II. Relevance a. Multiple myeloma patients lose bone much more rapidly than age matched controls b. Patient exhibit ~6% more bone loss in the lumbar spine and ~10% more loss at the femoral neck over a 12-month time period c. Myeloma bone disease predominately affects the axial skeleton, which includes the vertebrae, ribs, and sternum d. Associated with decreased quality of life due to severe pain, psychological distress, and loss of autonomy III. Pathogenesis of myeloma bone disease a. Osteoclasts are derived from the monocyte-macrophage lineage i. They degrade the inorganic and organic bone matric by binding tightly to the bone surface and create an acidic microenvironment rich in proteases ii. RANK/RANKL and osteoprotegerin (OPG) are considered key factors in regulating osteoclast differentiation and activity b. Osteoblasts evolve from mesenchymal cells to osteocytes i. Osteoblasts secrete collagen and other extracellular structural/hormonal proteins ii. They mineralize the bone matric, inducing bone formation iii. They ultimately become bone-lining cells, osteocytes c. Multiple myeloma patients have dramatically increased osteoclast activity and proliferation, leading to increased/excessive bone resorption i. Upregulation of osteoclast promoting cytokines: NF-kB ligand (RANKL), IL-1, IL-3, IL-6, chemokine C-C motif ligand 3 (CCL3), and CCL20 ii. Upregulation of osteoblast inhibitors such as DKK1 and sclerostin 5

6 d. Bone lesions are caused by an imbalance in the function of osteoblasts and osteoclasts Figure 2. Influence of cellular microenvironment on multiple myeloma cell differentiation 2 IV. Guideline recommendations for treatment and prevention of SREs in multiple myeloma 16, Table 3. Guideline recommendations for bone-modifying therapy in multiple myeloma Organization Recommendations National Comprehensive All patients receiving primary myeloma therapy should be given bisphosphonates or Cancer Network (NCCN) denosumab Multiple Myeloma Pamidronate and zoledronic acid have shown efficacy (category 1) Guidelines (2018) 15 Denosumab preferred in patients with renal insufficiency (category 2a) American Society of Clinical Oncology (ASCO) Role of Bone Modifying Agents in Multiple Myeloma Update (2018) 21 Multiple myeloma: European Society of Medical Oncology (ESMO) Clinical practice guidelines for diagnosis, treatment and follow-up (2017) 22,23 European Myeloma Network Guidelines For The Management Of Multiple Myeloma-Related Complications (2015) 24 See appendix B for NCCN recommendation category interpretation For patients with active symptomatic MM that requite systemic therapy with or without evidence of lytic destructions, pamidronate or zoledronic acid is recommended. Denosumab has been shown to be noninferior to zoledronic acid for the prevention of SRE and provides an alternative Fewer adverse effects related to renal toxicity have been noted with denosumab compared with zoledronic acid Bone modifying treatment should continue for up to two years Use of pamidronate and zoledronic acid for clinical benefit in the treatment of bone disease in patients with multiple myeloma recommended Denosumab is under investigation All multiple myeloma patients with adequate renal function (CrCl > 30 ml/min) and osteolytic disease should be treated with zoledronic acid or pamidronate in addition to anti-myeloma therapy Treatment duration is two years and then at the physician s discretion Denosumab has not yet been approved for use in MM, currently can be given only in the rare cases of resistant hypercalcemia to bisphosphonates 6

7 International myeloma working group recommendations for the treatment of multiple myeloma bone disease (2013) 25 Bisphosphonates should be considered in all patients with multiple myeloma, with or without evidence of bone lesions Zoledronic acid or pamidronate are preferred bisphosphonates Denosumab not included V. Pharmacotherapy a. Bisphosphonates i. Agents approved for use in multiple myeloma: zoledronic acid (Zometa ) and pamidronate (Aredia ) 26,27 1. Zoledronic acid was approved for use multiple myeloma in 2002 and pamidronate was approved in See Appendix C for complete prescribing,pharmacokinetic information, and cost 19, 20, 28, 29 ii. Mechanism of action 1. Bisphosphonates are absorbed into bone where they are taken up by active osteoclasts 2. Once inside the osteoclasts, they inhibit osteoclast proliferation by interrupting protein synthesis and interaction of osteoclasts at bone-resorption sites 3. Both zoledronic acid and pamidronate are nitrogen-containing bisphosphonates with invitro data showing they may have some additional anti-myeloma activity by inducing myeloma cell apoptosis 20, 26, 27 iii. Adverse Effects 1. Acute phase reactions after first administration a. Flu-like symptoms: fever, fatigue, malaise b. Myalgia, arthralgia, and bone pain 2. Osteonecrosis of the jaw a. Dental procedures must be completed before initiation of therapy b. Ensure maintenance of good oral hygiene c. Avoid invasive oral procedures while on medication 3. Renal toxicity 4. Low energy fractures iv. Select evidence for use in multiple myeloma 1. MRC Myeloma IX Study 30 a. 1,960 patients with newly diagnosed multiple myeloma were randomized to receive zoledronic acid or clodronic acid (oral bisphosphonate) along with their chemotherapy b. Zoledronic acid was found to decrease overall mortality by 16% when compared with clodronic acid c. Zoledronic acid also increased overall survival, progression-free survival d. This study formed the basis for recommending use of bisphosphonates in myeloma 2. Aredia Study Group 31 a. 392 patients with advanced multiple myeloma and evidence of at least one bone lesions were randomized to receive pamidronate or placebo in addition to myeloma therapy b. 24% of pamidronate treated patients experienced skeletal related events, versus 41% of placebo treated patients 7

8 VI. c. Pamidronate also had significant decreases in bone pain and was well-tolerated 3. Extended dosing interval 32 a. Himelstein, et al (2017) found that zoledronic acid given every 12 weeks versus every 4 weeks had similar outcomes with respect to risk of skeletal events b. Study included patients with breast cancer, prostate cancer, and multiple myeloma c. Extending dosing to every 12 weeks decreases healthcare utilization costs and potentially side effects v. Bisphosphonate comparison 1. Neither technically preferred 2. Renal impairment: neither zoledronic acid nor pamidronate are recommended in patients with CrCl < 30mL/min 26,27 a. In patients with intermediate renal function (CrCl 30-60mL/min), zoledronic acid has recommended dosing reductions, but no change in infusion time b. Pamidronate has no dose reduction, but has a recommended extended infusion in CrCl < 30mL/min 3. Efficacy: zoledronic acid and pamidronate have not been studied in head-to-head trials, but meta-analyses reveal a lower SRE incidence rate with zoledronic acid than with pamidronate (1.43 vs 1.64) 33,34 b. Denosumab (Xgeva ) i. See Appendix C for complete prescribing, pharmacokinetic information, and cost 35 ii. Approved for use in multiple myeloma in , 36 iii. Mechanism of action 1. Monoclonal antibody that binds nuclear factor-kappa ligand (RANKL) blocking the interaction between RANKL and RANK, thereby preventing osteoclast formation and function 2. Decreases markers of bone resorption by 85% within 3 days 3. Markers of bone resorption return to baseline within 12 months of discontinuing therapy iv. Adverse effects 35,37 1. Peripheral edema 2. Bone pain, fatigue 3. Hypocalcemia, hypophosphatemia 4. Shortness of breath, upper respiratory tract infection 5. Atypical femur fracture 6. Rebound bone fragility a. Because denosumab is reversible, it is associated with high rates of bone turnover following discontinuation, which can increase risk of fracture b. When used for osteoporosis, an increase in fracture risk was seen after denosumab treatment was discontinued, leading to recommendations of longer treatment duration or follow-up bisphosphonate therapy 7. Osteonecrosis of the jaw Challenges with both therapies a. Renal toxicity and other side effects i. Denosumab is not renally metabolized or excreted; no known renal toxicity ii. Osteonecrosis of the jaw still present with denosumab iii. Denosumab does not show acute phase reactions, but does carry a risk for hypocalcemia 8

9 b. Intravenous (IV) administration with bisphosphonates i. Both bisphosphonates approved for use in multiple myeloma are IV only ii. Denosumab is given subcutaneously c. Denosumab has demonstrated superiority to bisphosphonates in breast cancer and prostate cancer for time to first skeletal related event is this true in multiple myeloma also? Clinical Question Is denosumab superior to bisphosphonates for the prevention of skeletal related events in multiple myeloma? Table 5. Body JJ, Facon T, Coleman R, et al. A study of the biological receptor activator of nuclear factor- kappab ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin cancer res 2006;12(4): Objective: Investigate the safety, pharmacokinetics, and pharmacodynamics of denosumab in patients with multiple myeloma or bone metastases from breast cancer compared to pamidronate Methods Design Randomized, double-blind, double-dummy, active controlled multicenter study conducted at 4 centers in the United States and Europe Population Inclusion Criteria Exclusion Criteria Intervention Women with breast cancer and evidence of lytic or mixed bone metastases -or- multiple myeloma and evidence of lytic bone disease Age 18 years old Ambulatory Disorders of parathyroid or thyroid glands Osteomalacia Rheumatoid arthritis Flares of osteoarthritis or gout Paget s disease Malabsorption syndrome Ascites Long bone fracture within 90 days before dosing SCr > 221 umol/l (2.5 mg/dl) TBili > 43 umol/l (2.5 mg/dl) Adjusted serum Ca 2.62 mmol/l (10.5mg/dL) Chemotherapy within 21 days of randomization Glucocorticoid treatment within 14 days of dosing Two phases: Dose-escalation phase: patients within each disease stratum were randomly assigned in a 3:1 ratio to receive a single dose of either pamidronate 90mg or denosumab 0.1mg/kg. After the safety of this dose of denosumab was confirmed to be safe, the 3:1 randomization was repeated as the dose was escalated in 0.3, 1, and 3mg/kg dose cohorts Parallel-dosing phase: additional patients were enrolled to the denosumab dose cohorts to further explore the dose-response relationship Patients were stratified by disease type Patients received either: Denosumab SQ + IV saline Placebo SQ + pamidronate IV Outcomes Bone metabolism variables- measured using serum and urinary N-telopeptide (NTX) levels Safety of medications Pharmacokinetics Statistical Analysis Data from both study phases were combined for descriptive statistical analysis Data was summarized by disease stratum 9

10 Baseline characteristics Outcomes Multiple myeloma population: Results Characteristic Pamidronate Denosumab Denosumab Denosumab Denosumab (n=5) 0.1 mg/kg 0.3mg/kg 1mg/kg 3mg/kg (n=4) (n=4) (n=3) (n=9) Age Disease duration (y) Skeletal involvement (%) Only presented descriptively, no statistical analysis performed Average dose of denosumab was 1.58 mg/kg Bone turnover markers: Significant reductions in urinary NTX observed in both groups as early as one day after administration Duration of response exhibited dose-dependent effects Two intermediate doses of denosumab exhibited similar effects to the highest dose Transient early reductions in serum calcium were seen Author s conclusions Strengths Safety and tolerability: 5 patients in the breast cancer stratum and 2 patients in the myeloma stratum experiences adverse events while on study therapy, investigators did not consider any to be related to either study drug. Pharmacokinetics: Denosumab exhibited nonlinear, dose-dependent kinetics Half-life was 5X longer and AUC 44X greater at highest denosumab dose compared with lowest dose Denosumab was effective at decreasing bone resorption markers rapidly with a sustained effect in patients with multiple myeloma or breast cancer metastatic to bone. The duration of bone turnover suppression seemed to be much longer with higher doses of denosumab compared with pamidronate Reviewer s Critique Limitations Provided evidence for the safety of denosumab across a wide range of dosing schemes Results were stratified by cancer type Overall Conclusions Small study population Excluded patients receiving chemotherapy or glucocorticoids Descriptive data only Both drugs given only once No reported median dose Denosumab appears to be safe for administration in the multiple myeloma population and effective for suppressing bone turnover markers, which is encouraging for further investigation for the treatment and prevention of skeletal related events in myeloma. The small patient population and low overall rates of adverse events in this study make it difficult to draw conclusions about denosumab s place in therapy. 10

11 Table 6. Henry DH, Costa L, Goldwasser F, et al. Randomized, Double-Blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Onc 2011;29(9): ,40 Objective: Evaluate the efficacy and safety of denosumab compared with zoledronic acid in patients with solid tumors and bone metastases or with osteolytic lesions from myeloma. Methods Design International, phase III, randomized, double-blind, active controlled trial Population Inclusion criteria: Exclusion criteria: Age 18 years old Histologically or cytologically confirmed solid tumors or myeloma Radiographic evidence of at least one bone metastases or osteolytic lesion CrCl 30mL/min Eastern cooperative oncology group (ECOG) 2 Breast or prostate solid tumors Prior treatment with IV bisphosphonates Planned radiation or surgery to bone Unhealed dental/oral surgery Intervention Patients randomly assigned 1:1 to either: o Denosumab 120mg SQ with IV placebo every 4 weeks o Zoledronic acid 4mg IV with SQ placebo every 4 weeks Zoledronic acid dose adjustments for renal dysfunction allowed Assignments were stratified by malignancy, previous SRE, and systemic anticancer therapy at enrollment (receiving or not) Myeloma enrollment was limited to 10% of the total population Outcomes Primary outcome: time to first on-study SRE, comparing ZA vs denosumab for noninferiority Secondary outcomes (evaluated only if met noninferiority): Superiority of denosumab compared with zoledronic acid for time to first on-study SRE Time to first and subsequent SRE Treatment emergent adverse events and serious adverse events Changes in laboratory values Incidence of anti-denosumab antibodies Exploratory outcomes: Bone turnover markers Overall survival Overall disease progression Statistical Planned sample size was 1690 patients, assuming HR of 0.9, 745 patients with at least one SRE Analysis would provide sufficient power to detect non-inferiority based on a synthesis approach o Synthesis approach: designed to demonstrate that denosumab preserves 50% of the effect of zoledronic acid Intention to treat analysis looking at time to first SRE analyzed using Cox model Secondary efficacy endpoints were tested only if the null hypothesis of the primary endpoint was rejected Hochberg approach was used to adjust for multiple secondary end points Incidence rates for adverse effects were evaluated for any patient receiving at least one dose of investigational product 11

12 Results Baseline characteristics Characteristic Denosumab (n=886) Zoledronic acid (n=890) Median age 60 (18-89) 61 (22-87) Malignancy Non-small cell lung cancer 39% 40% (NSCLC) Multiple myeloma 10% 10% Other 51% 50% Prior bisphosphonate therapy 3% 3% Prior antineoplastic therapy 96% 96% Outcomes Outcome Hazard Ratio 95% CI P value Time to first on study SRE Overall survival Disease Progression Myeloma-specific outcomes Time to first on study SRE Overall survival Author s conclusions Strengths Outcome Denosumab (n=886) Zoledronic acid (n=890) P-Value Median time to first on-study SRE 20.6 months 16.3 months 0.06 Adverse effects (%) Hypocalcemia 10.5% 5.8% - Grade 3 or 4 2.3% 1% - ONJ incidence at 3 years 1.1% 1.3% - Acute phase reactions 6.9% 14.5% - No patients developed anti-denosumab antibodies Renal dose adjustment required in 17.3% of patients in the zoledronic acid arm Denosumab was noninferior to zoledronic acid in delaying or preventing SRE across a broad range of tumor types with denosumab showing a trend toward superiority for time to first on-study SRE Reviewer s Critique Limitations Evaluated malignancies other than myeloma, only 10% of the population was myeloma Very low rates of patients remaining on study at primary analysis cutoff date- less than half of discontinuations were death Median time on study was very short (~7 months) Only included patients with evidence of osteolytic lesions Large patient population Overall cohorts well matched International nature ensures wide variety of patients Overall Conclusions Denosumab was effective at preventing skeletal related events in the study population, which included myeloma patients. Further investigation is warranted for the trend towards decrease in overall survival found with myeloma patients. 12

13 Table 7. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study. Lancet Oncol 2018;19: Objective: To assess the efficacy and safety of subcutaneous denosumab compared with intravenous zoledronic acid in symptomatic patients with newly diagnosed myeloma. Methods Design Double-blind, double-dummy, randomized active controlled, phase 3 study done in 259 centers in 29 countries Population Inclusion Criteria Exclusion criteria Intervention Outcomes Statistical Analysis Age 18 years old Newly diagnosed multiple myeloma At least one documented lytic bone lesion based on imaging Adequate performance status (ECOG 0-2) Adequate organ function, including a CrCl 30mL/min Plasma cell leukemia More than one previous dose of IV bisphosphonate Non-healed dental or oral surgery Additional in protocol Patients were randomized to receive one of the following, along with investigator s choice first-lime myeloma therapy SQ denosumab 120 mg + IV placebo every 4 weeks IV zoledronic acid 4 mg + SQ placebo every 4 weeks Denosumab dose adjustments were not allowed Zoledronic acid adjustments allowed per package insert at baseline Skeletal surveys were obtained at baseline and every 12 weeks to assess fractures and spinal cord compression Patients were randomly assigned 1:1 using a fixed, stratified, permuted, block randomization, with a block size of four, to either denosumab or zoledronic acid Randomization was stratified by intent to undergo autologous transplant, antimyeloma therapy (novel vs non-novel), international staging system stage, previous skeletal related event, and region (Japan vs other) Primary outcome: non-inferiority of denosumab versus zoledronic acid with respect time to first onstudy skeletal related event Secondary outcomes: Superiority of denosumab versus zoledronic acid for time to first skeletal related event Overall survival Progression-free survival, as an exploratory endpoint Safety endpoints: treatment emergent adverse events, serious adverse events, changes in laboratory values, emergence of anti-denosumab antibodies Anticipated HR of denosumab to zoledronic acid would be 0.95 or less To achieve 85% power to rule out non-inferiority at a one-sided 2.5% significance level, 404 first, on-study events were needed o Because of the relatively low number of events that occurred, the research protocol had to be amended to increase the patient sample size by 180 patients Assumed 45-month enrollment and 25% mortality rate per year estimated 1700 patients needed 13

14 Baseline characteristics Results Characteristic Denosumab (n=859) Zoledronic Acid (n=859) Mean Age (IQR) 63 (29-91) 63 (31-89) ISS stage at Diagnosis (%) I 272 (32%) 275 (32%) II 307 (36%) 326 (38%) III 257 (30%) 232 (27%) Previous SRE (%) 567 (66%) 577 (67%) Median creatinine clearance (IQR) 77mL/min (58-100) 77mL/min (59-103) Previous bisphosphonate use only reported as 2% of overall study population 27% of study population had creatinine clearance of 60 ml/min or lower Outcomes Outcome Denosumab (n=859) Zoledronic Acid (n=859) P-Value First on-study skeletal related 44% 45% event Overall Survival 49.5 months Not Estimable 0.41 Progression free survival 46.1 months 35.4 months Adverse effects, number (%) Study related grade 3 44 (5%) 49 (6%) - Renal toxicity 85 (10%) 146 (17%) - Adverse events associated with 30/233 (13%) 58/220 (26%) - renal function in patients with known renal dysfunction Hypocalcemia- any grade 144 (17%) 106 (12%) - ONJ- any grade 35 (4%) 24 (3%) - Author s conclusions Time to first on-study SRE: HR=0.98 (95% CI ), P-value % of study population remained on treatment through the primary analysis cutoff 31% discontinued the study drug before the cut off; primary reason being death Post hoc analysis done at 15 months: showed that denosumab was superior for time to first skeletal related event- statistical analysis not provided One patient in zoledronic acid group had sudden cardiac death that was deemed to be treatmentrelated, no other treatment-related death Denosumab was non-inferior to zoledronic acid for the prevention of skeletal related events in patents with multiple myeloma Since most skeletal-related events occurred within the first 3 months of the study, patient exposure to antiresorptive therapies during this time might not have been sufficient for treatment differentiation Reviewer s Critique Limitations Strength s Large patient population Risk-stratification ensured study groups were well matched Overall Conclusions Did not include patients with more severe renal dysfunction (CrCl < 30mL/min) High rates of on-study discontinuation (variety of reasons) Denosumab was shown to be non-inferior to zoledronic acid for delaying skeletal related events in multiple myeloma patients The previous trend towards decrease in overall survival present in previous studies was not present in this study Denosumab showed a significantly lower rate of renal outcomes than zoledronic acid 14

15 36, 42 Pharmacoeconomic argument I. An argument for denosumab: Raje, et al (2018) performed a cost effectiveness analysis for denosumab when used in multiple myeloma to prevent SREs in the US 42 a. Incremental cost of denosumab: $26,329 b. Incremental quality-adjusted life years (QALY): $107,939 per QALY gained c. Net difference in cost of therapy found to be ~$62,500 d. Study argues that when administration costs, costs of preventable SREs, and costs of renal toxicity are accounted for, this is when the value to denosumab makes up for the increase in cost e. Of note: based on cost of zoledronic acid given every 3-4 weeks f. Concludes that denosumab is cost effective based on a willingness to pay threshold of $150,000 per QALY gained II. Differences in progression-free survival have not been proven III. Differences in drug costs are about $24,000 at 4-week dosing a. No data for 12-week denosumab administration b. 12-week administration of bisphosphonates versus 4-week dosing of denosumab will further exacerbate the cost difference IV. Rates of adverse events have proven similar V. Rebound bone deterioration seen with denosumab might necessitate post-treatment bisphosphonate use Conclusions and recommendations 1. Patients with multiple myeloma are at increased risk for developing skeletal related events due to the pathophysiology and manifestation of the disease 2. Bone-preserving therapy is imperative to prevent skeletal complications 3. Available agents to treat and prevent skeletal related events in the multiple myeloma population include bisphosphonates and denosumab 4. Based on the studies reviewed, denosumab can be used to treat and prevent skeletal related events in multiple myeloma a. Denosumab might be safer than bisphosphonates with respects to some of the adverse effects between the two agents, especially renal toxicity b. It has not demonstrated superiority against bisphosphonates for preventing SREs or overall survival and it remains significantly more costly than bisphosphonates 5. Consider the use of denosumab for patients with severe renal dysfunction, especially CrCl < 30mL/min or in patients whose renal function fluctuates widely 6. Areas for future exploration: a. Treatment of patients without evidence of skeletal lesions at presentation b. Denosumab rebound fragility in patients with multiple myeloma c. Duration of therapy in multiple myeloma no consensus on length of therapy d. Denosumab versus zoledronic acid given every 12 weeks e. Overall survival with bisphosphonates and denosumab 15

16 Appendices Appendix A. Recommended initial treatment strategies for newly diagnosed multiple myeloma 16 Multiple Myeloma treatment regimens For transplant candidates Bortezomib, lenalidomide, dexamethasone Bortezomib, cyclophosphamide, dexamethasone Bortezomib, doxorubicin, dexamethasone Bortezomib, dexamethasone *Doublet regimens may be used in elderly or frail patients Bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide For non-transplant candidates Bortezomib, lenalidomide, dexamethasone Lenalidomide, low-dose dexamethasone Daratumumab, bortezomib, melphalan, prednisone Maintenance therapies Lenalidomide Bortezomib Abbreviation VRD CyBorD VAD VD VTD-PACE VRD Appendix B. NCCN categories of evidence and consensus 16 Category Interpretation 1 Based upon a high level of evidence, there is uniform NCCN consensus that the intervention is appropriate 2a Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate 2b Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate 16

17 Appendix C. Approved medications for treating and preventing skeletal related events in multiple myeloma 16,20,26,27,35 Agent Dose Dose Adjustments PK/PD Price per dose Zoledronic Acid Pamidronate 4mg IV every 3-4 weeks or every 12 weeks Given over at least 15 minutes 90mg IV every 4 weeks Given over 4 hours Denosumab Dose: 120mg SQ every 4 weeks Renal dose adjustments CrCl > 60 ml/min: no adjustment CrCl ml/min: 3.5 mg CrCl ml/min: 3.3 mg CrCl ml/min: 3 mg CrCl < 30 ml/min: not recommended In patients with severe renal impairment (CrCl<30mL/min): give dose over 4-6 hours or consider dose reduction No renal/hepatic dose adjustments recommended Monitor patients with severe impairment for increased risk of hypocalcemia -Binds to bone -Primarily eliminated intact by the kidney -Not metabolized -T ½ : 146 hours $53.64 $ T ½ ~25 days $1, References 1. Rao KV, Pick AM. Multiple Myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill. URL: Accessed December 06, Palumbo A, Anderson, K. Multiple Myeloma. N Engl J Med. 2011; 364: Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2008;23(1): Bouvard B, at al. Monoclonal gammopathy of undetermined significance, multiple myeloma, and osteoporosis. Joint Bone Spine. 2010; 77: Naymagon L, Abdul-Hay, M. Novel agents in the treatment of multiple myeloma: a review about the future. Journal of hematology and oncology. 2016;9(52). 6. Hameed A, Brady JJ, Dowling P, Clynes M, O'Gorman P. Bone disease in multiple myeloma: pathophysiology and management. Cancer Growth Metastasis. 2014;7: Durie BGM, Salmon SE. A clinical staging system for multiple myeloma: correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 1975;36: Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26): Greipp PR, San Miguel J, Durie BGM, Crowley JJ, barlogie B, Blade J, et al. International Staging System for Multiple Myeloma. J clin onc. 2005;23(15) Hari PN, Zhang MJ, Roy V, et al. Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia. 2009;23(8): Scott E, Hari P, Kumar S, Fraser R, Davila O, Nieto Y, Mark TM, Kumar SK, Gasparetto CJ, D Souza A. A Comparison between 3 Staging Systems in Multiple Myeloma Using the Center for International Blood and Marrow Transplant Research (CIBMTR) Database. Blood. 2017:130(suppl1): Tandon N, Rajkumar SV, LaPlant B, et al. Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma. Blood Cancer J. 2017;7(2):e Kastritis E, Terpos E, Roussou M, et al. Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma. Haematologica. 2017;102(3): Durie BGM. The role of anatomic and functional staging in myeloma: description of Durie/Salmon plus staging system. European Journal of Cancer. 2006;42(11): Rajkumar SV, Harousseau JL. Next Generation multiple myeloma treatment: a pharmacoeconomic perspective. Blood. 2016;128:

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