Bisphosphonates and RANK-L inhibitors in Myeloma

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1 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

Multiple Myeloma Pe ercent of patients* 60 50

$skeletalrelated events All fractures Vertebral$

2 Rajkumar SV Kyle RA and. Cecil Textbook of Medicine, 23nd Edition, 2007 Kyle RA and Rajkumar SV. N Engl J Med 2004;351: Pamidronate in Multiple Myeloma Pe ercent of patients* P=0.016 P= % 38% P=NS 37% 31% P=0.005 P= % 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:

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

3 Zoledronic Acid and Pamidronate Multiple Myeloma Patients with SRE (%) % 44% Patients with no event (% %) Zoledronic acid 4 mg Pamidronate 90 mg 0 Pamidronate 90 mg All SREs Zoledronic acid 4 mg Time after start of drug (days) SREs=skeletal-related events. Adapted with permission from Rosen LS et al. Cancer J. 2001;7: 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

4 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, CLO ZOL 35.3% 27.0% Patients at risk, n ZOL CLO Time from randomisation, months Morgan G. Lancet Zoledronic Acid and Survival Morgan G. Lancet 2010; 376:

5 Zoledronic Acid and Survival Bone Disease No Bone disease Morgan G. Blood 2012 Rajkumar SV. 2010

6 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: v3: Jan 2011

7 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: v3: Jan 2011 msmart.org Choice of bisphosphonate Either Pamidronate or Zoledronic Acid Lacy MQ et al. Mayo Clin Proc 2006;81: v3: Jan 2011

8 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: 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: v3: Jan 2011

9 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: v3: Jan 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

10 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

Nat Clin Pract Rheumatol 2005;1:47-54 The

11 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

12 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 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 (NCT ) FDA approval 2010; J Clin Oncol Mar 20;29(9):

Bone Health in Patients with Multiple Myeloma

Bone Health in Patients with Multiple Myeloma Amrita Y. Krishnan, MD Director Judy and Bernard Briskin Myeloma Center City of Hope Comprehensive Cancer Center Bone Health Bisphosphonates in Space Bone