Bisphosphonates and RANK-L inhibitors in Myeloma S. Vincent Rajkumar Professor of Medicine Mayo Clinic Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center Rajkumar SV, Dispenzieri A. Abeloff s Clinical Oncology, 4thEdition, 2009
Rajkumar SV Kyle RA and. Cecil Textbook of Medicine, 23nd Edition, 2007 Kyle RA and Rajkumar SV. N Engl J Med 2004;351:1860-73 Pamidronate in Multiple Myeloma Pe ercent of patients* 60 50 40 30 20 10 P=0.016 P=0.016 51% 38% P=NS 37% 31% P=0.005 P=0.005 27% 16% Placebo Pamidronate 90 mg P=0.060 n=392 34% 25% P=NS 9% 9% 0 Any skeletalrelated events All fractures Vertebral fracture Radiation to bone Hypercalcemia *21-month data. Berenson JR et al. J Clin Oncol. 1998;16:593-602.
Zoledronic Acid and Pamidronate Multiple Myeloma Patients with SRE (%) 60 100 46% 44% 40 20 Patients with no event (% %) 80 60 40 20 Zoledronic acid 4 mg Pamidronate 90 mg 0 Pamidronate 90 mg All SREs Zoledronic acid 4 mg 0 0 100 200 300 400 500 Time after start of drug (days) SREs=skeletal-related events. Adapted with permission from Rosen LS et al. Cancer J. 2001;7:377-387. MRC Myeloma IX Analysis Schematic for ZOL vs CLO N = 1,960 Patients with newly diagnosed MM (stage I, II, III) R A N D O M I S A T I O N Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Bisphosphonate treatment continued at least until disease progression Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Endpoints (ZOL vs CLO) Primary: PFS, OS, and Response Secondary: SREs (Time to first SRE, SRE incidence), and Safety Morgan G. Lancet 2010 6
MRC Myeloma IX ZOL Significantly Reduced SREs vs CLO a in the Overall Population ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P =.0004) % Patients with an SRE, 40 30 20 10 0 CLO ZOL 35.3% 27.0% Patients at risk, n ZOL CLO 0 981 979 6 12 18 24 30 36 42 Time from randomisation, months 663 629 506 465 390 337 284 256 201 173 138 112 97 74 Morgan G. Lancet 2010 7 Zoledronic Acid and Survival Morgan G. Lancet 2010; 376: 1989 1999
Zoledronic Acid and Survival Bone Disease No Bone disease Morgan G. Blood 2012 Rajkumar SV. 2010
Bisphosphonates and Renal Dysfunction Pamidronate: Focal collapsing segmental glomerulosclerosis Azotemia often preceded by albuminuria Zoledronic acid: Tubular dysfunction (interstitial nephritis, etc) Renal failure; albuminuria is less likely Subtrochanteric fractures There is a reported risk of subtrochanteric fractures in patients who are on long term bisphosphonates that physicians should be aware of Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011
msmart.org msmart: Consensus Statement Indications for bisphosphonates Osteolytic Lesions Osteopenic/osteoporotic but no lytic lesions: Obtain DXA scan at baseline and use DXA Z-score for comparison to controls. If osteopenia or osteoporosis is out of proportion to age, treat as myeloma related with intravenous bisphosphonates as in myeloma patients with lytic lesions. Otherwise treat with schedules used for general osteoporosis. Bisphosphonates are not recommended for patients with smoldering MM Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011 msmart.org Choice of bisphosphonate Either Pamidronate or Zoledronic Acid Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011
msmart.org Dose of bisphosphonate Pamidronate 90 mg standard dose If ESRD on HD, work with nephrologist No evidence for dose reduction by age/weight Zoledronic Acid Dose reduce according to renal dosing guidelines supplied by manufacturer Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011 msmart.org Duration of bisphosphonate therapy Patients should receive infusions of bisphosphonates monthly for 1 year, and then every 3 months for 2nd year After 2 years: If stable disease or better, discontinue and follow general osteoporosis guidelines If less than stable, continue monthly dosing With relapse, return to monthly dosing and restart as above Z MARK study Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011
Role of DXA scan and bone markers msmart.org Role of DXA: Only in subjects with no evidence of lytic disease Repeat at 2 years Role of Bone Turnover Markers No current role for risk stratification or for following treatment Lacy MQ et al. Mayo Clin Proc 2006;81:1047-53. v3: Jan 2011 www.msmart.org Calcium and Vitamin D Supplementation in Myeloma Measure baseline 25-hydroxy Vit D3 levels in all patients with myeloma Vit D deficiency is very common in elderly Patients on routine bisphosphonates need to maintain adequate Vit D and Ca intake v1. Oct 2007
www.msmart.org Recommendation for patients with Vit D deficiency and/or for patients on bisphosphonates v1. Oct 2007 Vit D Vit D3 (cholecalciferol) 50,000 IU once a month or 1000 IU once a day until sufficient Or Vit D2 (ergocalciferol) 100,000 IU once a month until sufficient Calcium carbonate: 2 tabs per day Myeloma Microenvironment & Bone Disease Osteoblasts Myeloma cells RANKL DKK1, sfrp-2 RANKL RANKL OPG (-) RANKL RANK BMSCs Osteoclast precursor Activated osteoclasts Terpos & Dimopoulos. (Modified) Bone resorption Bone matrix
RANKL: Action Mainly Through NF B & c-fos in Osteoclasts Terpos E. Schett et al. Nat Clin Pract Rheumatol 2005;1:47-54 The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease OPG RANKL Prevents Promotes Adapted from Roodman. N Engl J Med. 2004;350:1655. Increased Osteoclastic Activity and Decreased OPG May Lead to Increased Bone Destruction
Denosumab High Affinity Human monoclonal antibody that t binds RANKL Specific: does not bind to TNF, TNF, TRAIL, or CD40L Inhibits formation and activation of osteoclasts Roodman D. Denosumab in MM 3 RCTs comparing denosumab (120 mg SQ q4 weeks) to zoledronic acid. Trial 20050244 enrolled 1,776 patients; 10% (n= 180) higher for denosumab vs zoledronic acid, HR 2.26 [1.13, 4.50] ONJ: 1.8% of denosumab and 1.3% of zoledronic acid. AEs: fatigue, hypophosphatemia, nausea Trials in MM ongoing (NCT01345019) FDA approval 2010; J Clin Oncol. 2011 Mar 20;29(9):1125-32.