Professional Documents
Culture Documents
Faculty
Matthew Raymond Smith, MD, PhD Allan Lipton, MD
Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Professor of Medicine and Oncology Milton S. Hershey Medical Center Penn State Cancer Institute Hershey, Pennsylvania
Noopur Raje, MD
Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Boston, Massachusetts
1. National Cancer Institute. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. 3. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 4. Palumbo A, et al. Blood. 2004;104:3052-3057. 5. Smith W, et al. Semin Oncol. 2004;31(suppl 4):11-15. 6. Lipton A. J Support Oncol. 2004;2:205-213. 7. Tu SM, et al. Cancer Treat Res. 2004;118:23-46.
1,25(OH)2D3
Prevents Promotes
PTHrP
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
* *
10 20 30 40 Patients With SREs (%) 50 60
*9-mo data. Placebo arm of pamidronate randomized trial. Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593602.
60 50
P < .001
Patients (%)
40 30 20 10 0 9
Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593602.
Mos
21
13-month follow-up: zoledronic acid was shown to be effective compared with pamidronate across all clinical endpoints The proportion of patients requiring radiation therapy to bone was significantly lower in the zoledronic acid 4 mg group than in the pamidronate group (15% vs 20%, respectively, P = .031) Zoledronic acid not inferior to pamidronate in reducing the risk of skeletal complications
60 46% 40 44%
20
Pamidronate 90 mg
Zoledronic acid 4 mg
All SREs
Rosen LS, et al. Cancer J. 2001;7:377-387.
Endpoints (zoledronic acid vs clodronate) Primary: PFS, OS, and ORR Secondary: time to first SRE, SRE incidence, and safety
*Dose-adjusted for patients with impaired renal function, per the prescribing information.
MRC Myeloma IX: ZOL SREs* vs CLO Regardless of Bone Lesions at Baseline
Bone Lesions at Baseline
0.5
No Lesions at Baseline
0.5 0.4
CLO ZOL
SREs/Patient
CLO ZOL
Pts at Risk, n
Zoledronic acid 668 415325 250 189 136 100 69 50 35 Clodronate 682 402297 212 164 117 75 50 37 24 18 6 12 4 0
8 7
5 4
0 0
Highlights the importance of treating all patients regardless of skeletal morbidity at presentation Morgan GJ, et al. ASH 2010. Abstract 311. Reprinted with permission. Morgan G, et al. Lancet. 2010;376:1989-1999.
OS
0.842
16%
PFS
0 0.2 0.4
0.883
12%
.0179 1.8 2
Reprinted from The Lancet, 376(9757), Morgan GJ, Davies FE, Gregory WM, et al., First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.989-1999, Copyright 2010, with permission from Elsevier.
uNTx < 50
ZOL 4 mg q12wke
ZOL 4 mg q4wk
*Patient had to receive 4 doses of IV bisphosphonate; last previous IV bisphosphonate dose must have been administered 3 wks before initial zoledronic acid dose on study. nmol/mmol creatinine. Patients will remain on zoledronic acid q 4 wks for remainder of the study. All patients were reminded to take supplemental oral calcium ( 500 mg) and vitamin D ( 400 IU) daily. Dose adjusted for patients with mild to moderate renal impairment at study entry.
Results
SREs by end of Year 1
2 patients receiving zoledronic acid q12wk
Spinal cord compression (1 patient) Radiation therapy to bone x 4 (1 patient)
uNTX
Baseline uNTX
Median: 17 nmol/mmol Cr Range: 7-71 nmol/mmol Cr
Summary of Bisphosphonates in MM
Inhibit bone resorption Pamidronate better than placebo Pamidronate and zoledronic acid equivalent Zoledronic acid has a survival advantage
Denosumab was noninferior to zoledronic acid in delaying time to first on-study SRE (HR: 0.84; 95% CI: 0.71-0.98; P = .0007) Serious adverse events were similar ONJ infrequent and similar (10 vs 11 patients)
Bortezomib/Lenalidomide in MBD
Myeloma cells Lenalidomide
OAFs Bortezomib
OCL precursor
OCL Osteoblasts
Bone
BMP-2
Runx-2
MSCs
Cathepsin K expression
PB2 + +
MLN3807 10 nM MLN3807 10 nM
P < .05
12 10 8 6 4 2 0
P < .05
0.2
10
MLN3807(nM)
This research was originally published in Blood. Vallet S, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. 2007 Nov 15;110(10):3744-52. the American Society of Hematology.
MM Cells
150 100 50 0
P = .08
P = .0001
With MM Cells
B
huIL-6 ng/mL
8 6 4 2 0
This research was originally published in Blood. Fulciniti M, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. 2009;114:371-379. the American Society of Hematology.
Osteoblast
Activin
Activin
Activin receptor type IIA Reduced bone formation Activin decreases bone mineral density and strength
pg/mL
100
pg/mL
Mean 1300
Average Levels of Activin A MM 0-1 OL: 28.62 6.2 pg/mL MM > 1 OL: 112.07 30.4 pg/mL Non-MM: 30.6 7.9 pg/mL
Vallet S, et al. Proc Natl Acad Sci U S A. 2010;107:5124-5129. Copyright 2010 National Academy of Sciences, U.S.A.
ClinicalTrials.gov. NCT00747123.
Results
28 patients had at least 1 previous treatment 13 patients receiving bisphosphonates 75% of patients had Hb increase of 1.5 gm/dL vs 17% of patients receiving placebo Increased BSAP and slightly decreased S-CTX levels among BP-naive patients
68
80
Patients With SREs (%) *24 mos. 21 mos. Placebo arm of pamidronate or zoledronic acid randomized trials.
Coleman RE. Oncologist. 2004;9(suppl 4):14-27.
Patients With Bone Lesions Are at High Risk for Skeletal Complications
60 52 Placebo Arms of Large Randomized Studies
50 40 30 20 10 0
43 33 25 37 34
Multiple myeloma*[3,4] NSCLC + other 21 mos solid tumors[5] 21 mos Cancer Type *21-mo data except for surgical intervention and spinal cord compression, for which only 9-mo data are available.
1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F, et al. AUA 2003. Abstract 1472. 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. 4. Berenson JR, et al. N Engl J Med. 1996;334:488-493. 5. Rosen LS, et al. Cancer. 2004;100:2613-2621.
12.3 26.7
As advances are made in cancer treatment, survival is increasedand with it, the risk of skeletal-related events
1. Rosen LS, et al. Cancer. 2004;100:2613-2621. 2. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 4. Berenson JR, et al. N Engl J Med. 1996;334:488493. 5. Kumar SK, et al. Blood. 2008;111:2516-2520. 6. Saad F, et al. J Natl Cancer Inst. 2004;96:879892. 7. Coleman RE. Cancer. 1997;80(8 suppl):1588-1594.
Zoledronic Acid Significantly Delays Time to First SRE Compared With Placebo
Proportion of Patients With Bone Metastases Without an SRE
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 50
P = .004
100 150 200 250 300 Days After Start of Study Drug
350
400
Kohno N, et al. SABCS 2004. Abstract 3060. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Reprinted with permission.
Multiple Event Analysis Total Breast carcinoma hormonal therapy stratum Breast carcinoma chemotherapy stratum Multiple myeloma stratum
*Patients who entered the extension study in the 4 mg zoledronic acid or pamidronate groups.
Patients with advanced breast cancer and confirmed bone metastases (N = 2046)
Secondary endpoints: time to first on-study SRE (superiority); time to first and subsequent on-study SRE (multiple event analysis) Current or previous IV bisphosphonate administration not permitted
*IV agent dose adjusted for creatinine clearance at baseline and subsequent dosing intervals determined based on serum creatinine levels according to zoledronic acid label. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
0.75
0.50 0.25 KM Estimate of Median Mos Not reached Denosumab 26.4 Zoledronic acid 0 3
829 839
6
676 697
9
584 602
12
498 514
Patients at Risk, n Zoledronic acid 1020 Denosumab 1026 *Adjusted for multiplicity.
15 Mos
427 437
18
296 306
21
191 189
24
94 99
27
29 26
30
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. 2010 American Society of Clinical Oncology. All rights reserved.
1.0
Time to Experiencing Mod or Severe Pain (Worst Pain Score > 4 Pts/Brief Pain Inv)
1.00
Proportion of Subjects
0.75
0.50 0.25
12 Mos
15
18
21
24
27
463 511
318 378
250 312
209 256
172 214
126 159
93 109
56 59
17 27
Disease Progression
Proportion of Subjects Without Disease Progression
1.00 0.75 HR: 1.00 (95% CI: 0.89-1.11; P = .93)
0.50 0.25
6
686 693
9
563 567
12
462 453
15 Mos
370 351
18
240 241
21
148 128
24
65 65
27
17 20
30
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. 2010 American Society of Clinical Oncology. All rights reserved.
Overall Survival
1.00 HR: 0.95 (95% CI: 0.81-1.11; P = .49)
0.75
0.50 0.25
6
897 916
9
834 849
12
757 771
15 Mos
699 690
18
515 511
21
352 336
24
184 177
27
54 57
30
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. 2010 American Society of Clinical Oncology. All rights reserved.
Adverse Events
Adverse Event, % Overall Serious Acute phase reactions (first 3 days) Renal toxicity Zoledronic Acid (n = 1013) 97.2 46.5 27.3 8.5 1.5 1.4 Denosumab (n = 1020) 95.8 44.4 10.4 4.9 0.2 2.0
Overall Serious
ONJ*
*P = .39
64%
51%
34%
27%
Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
BAP (U/L)
400 600 800 1000 1200 1400 NTx (nmol/mmol creatinine) Reproduced and adapted with permission from the American Association for Cancer Research: Cook RJ, et al. Clin Cancer Res. 2006;12:3361-3367. Figure 1B. Normal
Patients on the 8-mg arm reduced to 4 mg because of renal toxicity Primary outcome: proportion of patients having 1 SRE Secondary outcomes: time to first on-study SRE; proportion of patients with SREs, and TTP
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
90 80 70 60 50 40 30 20 10 0 0 Zoledronic acid 4 mg Zoledronic acid 8/4 mg Placebo 90 163 155 149 180 270 360 Days After the Start of Study Drug 113 102 103 92 68 69 70 46 43 450 5 4 1 540 0 0 0
Patients at Risk, n Zol acid 4 mg 214 Zol acid 8/4 mg 221 Placebo 208
Saad F, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468, by permission of Oxford University Press.
Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901)
Primary endpoint SREs: fracture, radiation or surgery to bone, spinal cord compression
Fizazi K, et al. Lancet. 2011;377:813-822.
0.75
0.50
0.25 HR: 0.82 (95% CI: 0.71-0.95; P = .0002 for noninferiority analysis; P = .008 for superiority analysis) 0 3 758 733 6 582 544 9 472 407 12 15 Study Mo 361 299 259 207 18 168 140 21 115 93 24 70 64 27 39 47
Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castrationresistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier
Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier
Results
Denosumab was superior to zoledronic acid
Delay time to first SRE on study Reduce the rate of multiple SREs
Rates of adverse events similar (infection) ONJ infrequent and no statistical difference between arms Hypocalcemia more frequent in denosumab arm
Conclusions
Disease-related skeletal complications are common in men with metastatic prostate cancer Zoledronic acid decreases risk of SREs in men with castrate-resistant disease and bone metastases Denosumab is superior to zoledronic acid for delay in first SREs and rate of SREs in this setting
PSA and PSADT Are Associated With Shorter Bone Metastasis-Free Survival
1.0
PSA < 7.7 ng/mL PSA 7.7-24.0 ng/mL PSA > 24.0 ng/mL
PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos
0.5
3.0
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. 2005 American Society of Clinical Oncology. All rights reserved.
Patients with CRPC and no bone metastases; PSA > 8 or PSADT < 10 mos (N = 1435)
Placebo monthly
Patients at Risk, n Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59
Smith MR, et al. 2011 AUA. Plenary.
Patients at Risk, n Placebo 716 667 565 474 411 368 347 293 242 189 142 130 94 Denosumab 716 683 603 503 441 385 360 308 260 200 160 143 96
Note: Symptomatic bone metastases before or coinciding with imaging diagnosing. Smith MR, et al. 2011 AUA. Plenary.
Study does not control for ADT 1. Some men will develop bone metastases prior to ADT 2. Dramatic variation in duration of response to ADT
Frequency (%)
15 12 9 6 3 0 2.4 Any Fracture Fracture Resulting in Hospitalization 5.2 12.6 +2.8%; P < .001
Percent Change
12-mo data
12-mo data
for 3 yrs
for 3 yrs
ClinicalTrials.gov. NCT00089674.
01 3 6
12
Mos
24
36
Smith MR. N Engl J Med. 2009;361:745-755. Copyright 2009 Massachusetts Medical Society. All rights reserved.
Patients, n
Smith MR. N Engl J Med. 2009;361:745-755. Copyright 2009 Massachusetts Medical Society. All rights reserved.
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