CancerPhase 3NCT01345019
Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma
A Phase 3 study testing Denosumab, Zoledronic acid and Denosumab (for the open-label treatment phase) in people with Cancer and Hematologic Malignancies, run by Amgen at 309 sites in 29 countries.
Trial summary
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cancer, Hematologic Malignancies, Multiple Myeloma
- What is being tested?
- Denosumab, Zoledronic acid and Denosumab (for the open-label treatment phase)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,718 participants
- Where
- 309 sitesin 29 countries
- Study dates
- 17 May 2012to 29 Mar 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented evidence of multiple myeloma (per local assessment):
- Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and
- Monoclonal protein present in the serum and/or urine
- Radiographic (X-ray, or computer tomography [CT]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging [MRI])
- Plan to receive or is receiving primary frontline anti-myeloma therapies
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
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- Age ≥ 18 years
- Adequate organ function, as defined by the following criteria (per central or local laboratory values):
- Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN)
- Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN
- Serum total bilirubin ≤ 2.0 x ULN
- Creatinine clearance ≥ 30 mL/min
- Serum calcium or albumin-adjusted serum calcium 2.0 mmol/L (8.0 mg/dL) and 2.9 mmol/L (11.5 mg/dL)
- Written informed consent before any study-specific procedure is performed
Who cannot join
- Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Plasma cell leukemia
- More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]).
- Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization)
- Prior administration of denosumab
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- Use of oral bisphosphonates with a cumulative exposure of more than 1 year
- More than 1 previous dose of IV bisphosphonate administration
- Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
- Active dental or jaw condition which requires oral surgery, including tooth extraction
- Non-healed dental/oral surgery, including tooth extraction
- Planned invasive dental procedures
- Evidence of any of the following conditions per subject self-report or medical chart review:
- Any prior invasive malignancy within 5 years before randomization
- Any non-invasive malignancy not treated with curative intent or with knownactive disease within 5 years before randomization
- Major surgery or significant traumatic injury occurring within 4 weeks before randomization
- Active infection with Hepatitis B virus or Hepatitis C virus
- Known infection with human immunodeficiency virus (HIV)
- Active infection requiring IV anti-infective therapy
- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after end of treatment
- Female subject of child bearing potential is not willing to use highly effective contraception during treatment and for 5 months after the end of treatment (see section 6.3)
- Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D)
- Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication)
- Subject will not be available for follow-up assessment
- Any major medical or psychiatric disorder that in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Trial locations and contacts
309 sites in 29 countries.
309 sites in 29 countries
United States79 sites
Research Site
Aberdeen, South Dakota, 57401
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Ames, Iowa, 50010
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Anaheim, California, 92801
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Anderson, Indiana, 46016
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Baltimore, Maryland, 21204
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Baltimore, Maryland, 21229
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Baltimore, Maryland, 21237
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Bethesda, Maryland, 20817
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Billings, Montana, 59101
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Bismarck, North Dakota, 58501
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Boston, Massachusetts, 02114
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Boston, Massachusetts, 02215
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Boynton Beach, Florida, 33426
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Boynton Beach, Florida, 33435
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Campbell, California, 95008
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Charleston, South Carolina, 29406
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Charleston, South Carolina, 29414
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Chicago, Illinois, 60612
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Christiansburg, Virginia, 24073
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Columbus, Georgia, 31904
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Danvers, Massachusetts, 01923
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Detroit, Michigan, 48201
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Encinitas, California, 92024
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Fairhaven, Massachusetts, 02719
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Fayetteville, Arkansas, 72703
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Fayetteville, North Carolina, 28304
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Fort Wayne, Indiana, 46845
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Fresno, California, 93720
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Goldsboro, North Carolina, 27534
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Greenville, South Carolina, 29615
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Hackensack, New Jersey, 07601
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Hershey, Pennsylvania, 17033
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High Point, North Carolina, 27262
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Houston, Texas, 77030
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Indianapolis, Indiana, 46202
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Iowa City, Iowa, 52242
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Jackson, Mississippi, 39216
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Jacksonville, Florida, 32256
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Joliet, Illinois, 60435
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Lake Success, New York, 11042
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Lansing, Michigan, 48910
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Lincoln, Nebraska, 68506
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Lubbock, Texas, 79415
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Maywood, Illinois, 60153
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Memphis, Tennessee, 38120
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Minocqua, Wisconsin, 54548
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Morgantown, West Virginia, 26506
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New Orleans, Louisiana, 70121
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New York, New York, 10021
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Niles, Illinois, 60714
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North Las Vegas, Nevada, 89086
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Oklahoma City, Oklahoma, 73120-8345
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Omaha, Nebraska, 68198
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Paducah, Kentucky, 42003
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Philadelphia, Pennsylvania, 19106
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Philadelphia, Pennsylvania, 19140
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Philadelphia, Pennsylvania, 19141
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Pleasant Hill, California, 94523
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Rapid City, South Dakota, 57701
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Rochester, New York, 14621
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Salt Lake City, Utah, 84106
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Santa Barbara, California, 93105
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Santa Maria, California, 93454
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Savannah, Georgia, 31405
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Scarborough, Maine, 04074
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Sioux Falls, South Dakota, 57105
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Skokie, Illinois, 60076
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Skokie, Illinois, 60077
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Spokane, Washington, 99208
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Springfield, Missouri, 65806
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Stamford, Connecticut, 06902
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Tacoma, Washington, 98405
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Tucson, Arizona, 85704
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Washington D.C., District of Columbia, 20007
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Washington D.C., District of Columbia, 20010
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Watertown, South Dakota, 57201
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Wauwatosa, Wisconsin, 53226
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West Reading, Pennsylvania, 19611
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Westminster, Maryland, 21157
France25 sites
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Amiens, 80054
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Avignon, 84902
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Créteil, 94010
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Le Kremlin-Bicêtre, 94270
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Le Mans, 72000
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Le Mans, 72037
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Lille, 59037
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Lyon Cédex 3, 69437
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Marseille, 13273
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Marseille, 13385
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Nantes, 44035
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Nice, 06202
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Paris, 75010
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Paris, 75013
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Paris, 75015
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Paris, 75571
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Paris, 75679
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Pessac, 33604
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Pierre-Bénite, 69495
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Pontoise, 95301
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Reims, 51056
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Rouen, 76038
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Saint-Quentin, 02321
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Strasbourg, 67000
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Villefranche-sur-Saône, 69400
Italy21 sites
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Ancona, 60126
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Bari, 70124
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Brescia, 25125
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Busto Arsizio, 21052
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Catania, 95124
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Florence, 50134
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Genova, 16132
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Messina, 98125
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Milan, 20153
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Naples, 80131
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Naples, 80136
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Novara, 28100
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Palermo, 90146
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Pescara, 65124
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Pisa, 56127
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Roma, 00144
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Roma, 00161
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Rozzano MI, 20089
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Torino, 10126
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Udine, 33100
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Vimercate MB, 20871
Japan18 sites
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Akita, Akita, 010-8543
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Fukuoka, Fukuoka, 814-0180
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Fukuyama-shi, Hiroshima, 720-0001
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Gifu, Gifu, 501-1194
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Kamogawa-shi, Chiba, 296-8602
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Kawagoe-shi, Saitama, 350-8550
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Kobe, Hyōgo, 650-0047
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Kumamoto, Kumamoto, 860-0008
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Kyoto, Kyoto, 603-8151
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Maebashi, Gunma, 371-8511
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Nagoya, Aichi-ken, 457-8510
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Ogaki-shi, Gifu, 503-8502
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Okayama, Okayama-ken, 701-1192
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Shibukawa-shi, Gunma, 377-8511
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Shibuya-ku, Tokyo, 150-8935
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Shinjuku-ku, Tokyo, 162-8655
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Tokushima, Tokushima, 770-8503
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Toyama, Toyama, 930-8550
Canada17 sites
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Barrie, Ontario, L4M 6M2
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Burnaby, British Columbia, V5G 2X6
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Laval, Quebec, H7M 3L9
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Moncton, New Brunswick, E1C 6Z8
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Montreal, Quebec, H1T 2M4
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Montreal, Quebec, H4J 1C5
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Newmarket, Ontario, L3Y 2P9
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Québec, Quebec, G1R 2J6
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Sault Ste. Marie, Ontario, P6B 0A8
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St. John's, Newfoundland and Labrador, A1B 3V6
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Toronto, Ontario, M2K 1E1
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Toronto, Ontario, M3M 0B2
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Toronto, Ontario, M5B 1W8
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Toronto, Ontario, M6R 1B5
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Trois-Rivières, Quebec, G8Z 3R9
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Windsor, Ontario, N8W 2X3
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Winnipeg, Manitoba, R3E 0V9
Russia14 sites
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Dzerzhinsk, 606019
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Moscow, 115478
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Nizhny Novgorod, 603126
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Novosibirsk, 630051
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Penza, 440071
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Petrozavodsk, 185019
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Saint Petersburg, 193312
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Saint Petersburg, 197022
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Saint Petersburg, 197110
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Saint Petersburg, 198205
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Samara, 443099
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Saratov, 410012
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Volgograd, 400138
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Yekaterinburg, 620102
South Korea11 sites
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Anyang, 431-070
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Busan, 602-739
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Daegu, 700-721
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Daejeon, 301-721
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Gwangju, 519-763
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Incheon, 405-760
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Seoul, 110-744
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Seoul, 120-752
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Seoul, 135-710
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Seoul, 137-701
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Seoul, 158-710
Spain11 sites
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Badalona, Catalonia, 08916
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Barcelona, Catalonia, 08036
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Donostia / San Sebastian, Basque Country, 20014
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Madrid, 28006
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Madrid, 28034
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Ourense, Galicia, 32005
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Palma de Mallorca, Balearic Islands, 07198
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Salamanca, Castille and León, 37007
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Seville, Andalusia, 41013
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Valencia, Valencia, 46017
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Valencia, Valencia, 46026
Australia10 sites
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Clayton, Victoria, 3168
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Douglas, Queensland, 4814
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Epping, Victoria, 3076
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Hobart, Tasmania, 7000
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Liverpool, New South Wales, 2170
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Malvern, Victoria, 3144
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Parkville, Victoria, 3050
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Prahran, Victoria, 3181
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South Brisbane, Queensland, 4101
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Tweed Heads, New South Wales, 2485
Germany9 sites
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Bonn, 53127
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Chemnitz, 09113
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Cologne, 50924
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Essen, 45239
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Hamburg, 20246
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Kassel, 34125
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Leipzig, 04103
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Münster, 48149
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Regensburg, 93049
Austria7 sites
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Graz, 8036
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Innsbruck, 6020
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Krems, 3500
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Salzburg, 5020
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Vienna, 1090
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Vienna, 1140
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Wels, 4600
Bulgaria7 sites
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Pleven, 5800
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Plovdiv, 4002
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Sofia, 1407
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Sofia, 1431
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Sofia, 1606
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Sofia, 1756
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Varna, 9010
Greece7 sites
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Athens, 11525
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Athens, 11527
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Athens, 11528
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Heraklion, 71110
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Pátrai, 26500
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Piraeus, 18537
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Thessaloniki, 57010
Hungary7 sites
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Budapest, 1083
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Budapest, 1097
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Debrecen, 4032
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Győr, 9024
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Gyula, 5700
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Kaposvár, 7400
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Szeged, 6725
Poland7 sites
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Legnica, 59-220
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Lublin, 20-081
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Słupsk, 76-200
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Torun, 87-100
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Warsaw, 02-097
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Warsaw, 02-776
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Wroclaw, 53-439
Taiwan7 sites
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Changhua, 50006
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Kaohsiung City, 83301
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Taichung, 40447
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Taichung, 407
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Tainan, 70403
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Taipei, 10002
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Taoyuan, 33305
Ukraine7 sites
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Cherkasy, 18009
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Dnipropetrovsk, 49102
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Ivano-Frankivsk, 76008
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Khmelnitskiy, 29000
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Kyiv, 04107
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Lviv, 79031
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Poltava, 36024
United Kingdom6 sites
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Harrow, HA1 3UJ
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Inverness, IV2 3UJ
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Leeds, LS9 7TF
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London, NW3 2QG
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London, SW17 0RE
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Oxford, OX3 7LJ
Czechia5 sites
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Brno, 625 00
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Ostrava-Poruba, 708 52
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Pilsen, 304 60
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Prague, 100 34
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Prague, 128 08
Ireland5 sites
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Dublin, 24
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Dublin, 7
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Dublin, 8
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Limerick
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Tullamore
Portugal5 sites
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Braga, 4710-243
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Coimbra, 3000-075
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Lisbon, 1169-050
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Matosinhos Municipality, 4464-513
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Porto, 4200-072
Turkey (Türkiye)5 sites
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Adana, 01330
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Ankara, 06100
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Ankara, 06500
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Istanbul, 34452
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Izmir, 35340
Malaysia4 sites
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Ampang, 68000
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George Town, Pulau Pinang, 10990
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Ipoh, Perak, 30990
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Kuching, Sarawak, 93586
Singapore3 sites
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Singapore, 119228
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Singapore, 169856
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Singapore, 308433
Slovakia3 sites
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Bratislava, 851 07
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Nitra, 950 01
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Nové Zámky, 940 34
Switzerland3 sites
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Chur, 7000
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Zurich, 8032
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Zurich, 8038
New Zealand2 sites
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Christchurch, 8011
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Grafton, Auckland, 1023
About this study
Official title: A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.
- Conditions
- Cancer, Hematologic Malignancies, Multiple Myeloma, Oncology, Bone Metastases, Multiple Myeloma Bone Lesions
- Being tested
- Denosumab, Zoledronic acid, Placebo to Denosumab, Placebo to zoledronic acid, Denosumab (for the open-label treatment phase)
- Keywords
- zoledronic acid, hematologic malignancies, SRE, skeletal-related event, blood cancer, lytic bone lesions, bone metastases, myeloma, fractures, spinal cord compression, radiation to bone, surgery to bone, bisphosphonates, Neoplasms, Plasma Cell, Paraproteinemias, Neoplasms, Neoplasm Metastasis, Bone Neoplasms, Bone Marrow Diseases, Blood Protein Disorders
- Medical subject headings
- Neoplasms, Hematologic Neoplasms, Multiple Myeloma, Neoplasms, Plasma Cell, Fractures, Bone, Spinal Cord Compression, Paraproteinemias, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DenosumabDrug
Also called XGEVA®, AMG 162
Administered by subcutaneous injection once every 4 weeks.
Zoledronic acidDrug
Also called Zometa®
Administered by intravenous infusion over 15 minutes once every 4 weeks
Placebo to DenosumabDrug
Administered by subcutaneous injection once every 4 weeks.
Placebo to zoledronic acidDrug
Administered by intravenous infusion over 15 minutes once every 4 weeks
Denosumab (for the open-label treatment phase)Drug
Also called XGEVA®, AMG 162
Administered by subcutaneous injection once every 4 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Zoledronic acid | Active comparator | Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) Receives: Drug: Zoledronic acid; Drug: Placebo to Denosumab; Drug: Denosumab (for the open-label treatment phase) |
| Denosumab | Experimental | Denosumab 120 mg subcutaniously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) Receives: Drug: Denosumab; Drug: Placebo to zoledronic acid; Drug: Denosumab (for the open-label treatment phase) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to First On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Percentage of Participants With an On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported.
Secondary outcomes (5)
Time to First On-study Skeletal Related Event - Superiority Analysis
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.
A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.
A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Overall Survival
Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first.
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Percentage of Participants Who Died
Measured: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Apr 2011 (estimated)
- Study start17 May 2012
- Primary completion19 Jul 2016
- Study completion29 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for CancerStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,718 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Daiichi Sankyo
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01345019
- Sponsor's protocol ID
- 20090482
- Other IDs
- 2010-020454-34
- Status last verified
- Nov 2022
- First submitted
- 28 Apr 2011
- Last updated
- 8 Nov 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Publications
Raje N, Roodman GD, Willenbacher W, Shimizu K, Garcia-Sanz R, Terpos E, Kennedy L, Sabatelli L, Intorcia M, Hechmati G. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America. J Med Econ. 2018 May;21(5):525-536. doi: 10.1080/13696998.2018.1445634. Epub 2018 Mar 5.
PubMed 29480139Raje N, Terpos E, Willenbacher W, Shimizu K, Garcia-Sanz R, Durie B, Legiec W, Krejci M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. Epub 2018 Feb 9.
PubMed 29429912Huang SY, Yoon SS, Shimizu K, Chng WJ, Chang CS, Wong RS, Gao S, Wang Y, Gordon SW, Glennane A, Min CK. Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis. Adv Ther. 2020 Jul;37(7):3404-3416. doi: 10.1007/s12325-020-01395-x. Epub 2020 Jun 10.
PubMed 32524500Terpos E, Raje N, Croucher P, Garcia-Sanz R, Leleu X, Pasteiner W, Wang Y, Glennane A, Canon J, Pawlyn C. Denosumab compared with zoledronic acid on PFS in multiple myeloma: exploratory results of an international phase 3 study. Blood Adv. 2021 Feb 9;5(3):725-736. doi: 10.1182/bloodadvances.2020002378.
PubMed 33560384
Study at a glance
From the registry record, last updated by the sponsor on 8 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma
- ClinicalTrials.gov ID
- NCT01345019
- Acronym / sponsor ID
- 20090482
- Conditions
- Cancer, Hematologic Malignancies, Multiple Myeloma, Oncology, Bone Metastases, Multiple Myeloma Bone Lesions
- Keywords
- zoledronic acid, hematologic malignancies, SRE, skeletal-related event, blood cancer, lytic bone lesions, bone metastases, myeloma
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,718 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Collaborators
- Daiichi Sankyo
- Study start
- 17 May 2012 (actual)
- Primary completion
- 19 Jul 2016 (actual)
- Study completion
- 29 Mar 2019 (actual)
- First posted
- 29 Apr 2011 (estimated)
- Results
- Posted 7 Mar 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Zoledronic acid | Active comparator | Drug: Zoledronic acid, Drug: Placebo to Denosumab, Drug: Denosumab (for the open-label treatment phase)Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) |
| Denosumab | Experimental | Drug: Denosumab, Drug: Placebo to zoledronic acid, Drug: Denosumab (for the open-label treatment phase)Denosumab 120 mg subcutaniously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Documented evidence of multiple myeloma (per local assessment):
- Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and
- Monoclonal protein present in the serum and/or urine
- Radiographic (X-ray, or computer tomography [CT]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging [MRI])
- Plan to receive or is receiving primary frontline anti-myeloma therapies
Key exclusion criteria (25 listed)
- Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Plasma cell leukemia
- More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]).
- Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DenosumabAlso: XGEVA®, AMG 162Administered by subcutaneous injection once every 4 weeks. | Drug | Denosumab |
| Zoledronic acidAlso: Zometa®Administered by intravenous infusion over 15 minutes once every 4 weeks | Drug | Zoledronic acid |
| Placebo to DenosumabAdministered by subcutaneous injection once every 4 weeks. | Drug | Zoledronic acid |
| Placebo to zoledronic acidAdministered by intravenous infusion over 15 minutes once every 4 weeks | Drug | Denosumab |
| Denosumab (for the open-label treatment phase)Also: XGEVA®, AMG 162Administered by subcutaneous injection once every 4 weeks. | Drug | Denosumab, Zoledronic acid |
Primary outcome
Time to First On-study Skeletal Related Event
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
Percentage of Participants With an On-study Skeletal Related Event
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported.
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
5 secondary outcomes
Time to First On-study Skeletal Related Event - Superiority Analysis
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Overall Survival
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Percentage of Participants Who Died
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Nov 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 29480139Raje N, Roodman GD, Willenbacher W, Shimizu K, Garcia-Sanz R, Terpos E, Kennedy L, Sabatelli L, Intorcia M, Hechmati G. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America. J Med Econ. 2018 May;21(5):525-536. doi: 10.1080/13696998.2018.1445634. Epub 2018 Mar 5.
- Background: PubMed 29429912Raje N, Terpos E, Willenbacher W, Shimizu K, Garcia-Sanz R, Durie B, Legiec W, Krejci M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. Epub 2018 Feb 9.
- Background: PubMed 32524500Huang SY, Yoon SS, Shimizu K, Chng WJ, Chang CS, Wong RS, Gao S, Wang Y, Gordon SW, Glennane A, Min CK. Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis. Adv Ther. 2020 Jul;37(7):3404-3416. doi: 10.1007/s12325-020-01395-x. Epub 2020 Jun 10.
- Background: PubMed 33560384Terpos E, Raje N, Croucher P, Garcia-Sanz R, Leleu X, Pasteiner W, Wang Y, Glennane A, Canon J, Pawlyn C. Denosumab compared with zoledronic acid on PFS in multiple myeloma: exploratory results of an international phase 3 study. Blood Adv. 2021 Feb 9;5(3):725-736. doi: 10.1182/bloodadvances.2020002378.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
309 sites in 29 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Denosumab, Zoledronic acid and Denosumab (for the open-label treatment phase) in people with Cancer and Hematologic Malignancies, run by Amgen at 309 sites in 29 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 309 sites in United States, France, Italy, Japan, Canada and 24 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Mar 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to First On-study Skeletal Related Event (time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01345019, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Nov 2022; AzTrials last refreshed its copy on 8 Nov 2026.