Study Description

This is a randomized (participants will be assigned by chance to study treatments), open-label (all participants and study personnel will know the identity of the study treatments), active-controlled (none of the study treatments are placebo), parallel-group (both treatment arms will run at the same time), multicenter study. In this study, daratumumab, lenalidomide, and low-dose dexamethasone (DRd) will be compared with lenalidomide and low dose dexamethasone (Rd) in participants with relapsed or refractory multiple myeloma. Participants will be randomized in a 1:1 ratio to receive either DRd or Rd. The study will include a Screening Phase, a Treatment Phase (involving treatment cycles of approximately 28 days in length), and a Follow-up Phase. The Treatment Phase will extend from the administration of the first dose of study medication until disease progression or unacceptable toxicity. Participants will also discontinue study treatment if: they become pregnant; have their dose held for more than 28 days (or if 3 consecutive planned doses of daratumumab are missed for reasons other than toxicity); or for safety reasons (for example, adverse event). The Follow-up Phase will begin at the end of treatment and will continue until death, loss to follow-up, consent withdrawal for study participation, or the final overall survival (OS) analysis, whichever occurs first. Eligible participants from Rd group who have had sponsor confirmed disease progression will be offered the option for treatment with daratumumab monotherapy (of 28 days cycle). The primary endpoint will be progression-free survival (PFS). Analysis of the primary endpoint was performed at a pre-specified point determined by PFS events with a clinical cutoff of March 7, 2016 when 169 events of death or progression had occurred. The end of study is anticipated at approximately 6 years after the last participant is randomized. Blood and urine samples will be obtained at time points during the study, together with bone marrow aspirates/biopsies and skeletal surveys. Participant safety will be assessed throughout the study.

Condition or Disease	Intervention/Treatment
Multiple Myeloma	Drug: Daratumumab Drug: Lenalidomide Drug: Dexamethasone

Study Design

Study Type	Interventional
Actual Enrollment	569 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Official Title	Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed or Refractory Multiple Myeloma
Study Start Date	May 23, 2014
Actual Primary Completion Date	March 7, 2016
Anticipated Study Completion Date	November 29, 2024

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
Daratumumab + lenalidomide + dexamethasone During each 28-day treatment cycle, participants will receive daratumumab, lenalidomide, and dexamethasone.	Drug: Daratumumab Daratumumab 16mg/kg will be administered as an intravenous (IV) infusion (into the vein) as per the following schedule: once a week during treatment cycles 1 and 2; every 2 weeks during treatment cycles 3 to 6; and every 4 weeks for cycles 7 and onwards. Following amendment 8, participants receiving daratumumab IV have the option to switch to daratumumab subcutaneous (SC) 1800 mg/dose until documented progression, unacceptable toxicity, or the end of study on Day 1 of any cycle, at the discretion of the investigator. Drug: Lenalidomide Drug: Dexamethasone
Lenalidomide + dexamethasone During each 28-day treatment cycle, participants will receive lenalidomide and dexamethasone.	Drug: Lenalidomide Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [From randomization to either disease progression or death whichever occurs first (up to 21 months)]
   PFS: duration from date of randomization to either progressive disease (PD)/death, whichever occurred first. PD: defined as meeting any 1 of following criteria: Increase of greater than equal to (>=)25 percent(%) in level of serum M-protein from lowest response value and absolute increase must be >=0.5 gram per deciliter (g/dL); Increase of >=25% in 24-hours(h) urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24h; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 mg/dL; Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) attributed solely to plasma cell (PC) proliferative disorder.

Secondary Outcome Measures

1. Time to Disease Progression (TTP) [From randomization to disease progression (up to 21 months)]
   TTP was defined as time from date of randomization to date of first documented evidence of progressive disease (PD). PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5 g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 milligram per deciliter (mg/dL); Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to plasma cell (PC) proliferative disorder.
2. Percentage of Participants Who Achieved Very Good Partial Response (VGPR) or Better [From randomization to disease progression (up to 21 months)]
   VGPR or better is defined as the percentage of participants who achieved VGPR, complete response (CR) and stringent complete response (sCR) according to the International Myeloma Working Group criteria (IMWG). IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >90% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry.
3. Percentage of Participants With Negative Minimal Residual Disease (MRD) [From randomization to the date of first documented evidence of PD (up to 87.5 months)]
   Minimal residual disease was assessed for all participants who achieved a complete response (CR) or stringent complete response (sCR). CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry. The MRD negativity rate was defined as the percentage of participants who had negative MRD assessment at any time point after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood at 10^ minus (-) 4, 10^-5, 10^-6 threshold.
4. Overall Response Rate [From randomization to disease progression (up to 21 months)]
   Overall response rate was defined as the percentage of participants who achieved a partial response (PR) or better according to the International Myeloma Working Group (IMWG) criteria, during or after study treatment. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.
5. Overall Survival (OS) [From randomization to date of death due to any cause (up to 87.5 months)]
   Overall survival was measured from the date of randomization to the date of the participant's death.
6. Time to Response [From randomization up to first documented CR or PR (up to 21 months)]
   Time to response was defined as the time between the date of randomization and the first efficacy evaluation that the participant met all criteria for partial response (PR) or better.
7. Duration of Response (DOR) [From randomization to the date of first documented evidence of PD (up to 21 months)]
   DOR was defined for participants with confirmed response (PR or better) as time between first documentation of response and disease progression/death due to PD, whichever occurs first. PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be >10mg/dL; Definite increase in size of existing bone lesions/soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5mg/dL) that can be attributed solely to PC proliferative disorder.
8. Time to Subsequent Anticancer Treatment [From randomization to date of start of subsequent anticancer treatment or death due to PD, whichever occured first (up to 87.5 months)]
   Time to subsequent anticancer treatment was defined as the time from randomization to the start of subsequent anticancer treatment or death due to progressive disease (PD), whichever occurs first.

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
Inclusion Criteria	Must have documented multiple myeloma and measurable disease Must have received at least 1 prior line of therapy for multiple myeloma and achieved a response (partial response or better) to at least one prior regimen Must have documented evidence of progressive disease as defined by the International Myeloma Working Group criteria on or after their last regimen Must have an Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2 If a participant has received subsequent anticancer therapy (salvage therapy), the participant must have a "wash-out period" defined as 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the planned start date of daratumumab monotherapy. The only exception is the emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 milligram per day for a maximum of 4 days) before Daratumumab monotherapy
Exclusion Criteria	Has received any of the following therapies: daratumumab or other anti-CD38 therapies Has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment Disease shows evidence of refractoriness or intolerance to lenalidomide or if previously treated with a lenalidomide-containing regimen the participant is excluded if he or she discontinued due to any adverse event related to prior lenalidomide treatment Has received autologous stem cell transplantation within 12 weeks before the date of randomization, or previously received an allogenic stem cell transplant (regardless of timing), or planning to undergo a stem cell transplant prior to progression of disease History of malignancy (other than multiple myeloma) within 5 years before the first dose of daratumumab monotherapy (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years)

Contacts and Locations

Sponsors and Collaborators	Janssen Research & Development, LLC
Locations	| Little Rock, Arkansas, United States, | Gainesville, Florida, United States, | West Palm Beach, Florida, United States, | Atlanta, Georgia, United States, | Chicago, Illinois, United States, | Iowa City, Iowa, United States, | Louisville, Kentucky, United States, | Baton Rouge, Louisiana, United States, | New Orleans, Louisiana, United States, | Bethesda, Maryland, United States, | Columbia, Maryland, United States, | Boston, Massachusetts, United States, | Rochester, Minnesota, United States, | Omaha, Nebraska, United States, | New Brunswick, New Jersey, United States, | New York, New York, United States, | Charlotte, North Carolina, United States, | Eugene, Oregon, United States, | Spartanburg, South Carolina, United States, | Austin, Texas, United States, | Dallas, Texas, United States, | Houston, Texas, United States, | Fairfax, Virginia, United States, | Camperdown, Australia, | Geelong, Australia, | Heidelberg, Australia, | Malvern, Australia, | South Brisbane, Australia, | Southport, Australia, | Anderlecht, Belgium, | Antwerpen, Belgium, | Edegem, Belgium, | Gent, Belgium, | Kortrijk, Belgium, | Leuven, Belgium, | Liege, Belgium, | Calgary, Alberta, Canada, | Edmonton, Alberta, Canada, | Surrey, British Columbia, Canada, | Vancouver, British Columbia, Canada, | Halifax, Nova Scotia, Canada, | Hamilton, Ontario, Canada, | London, Ontario, Canada, | Toronto, Ontario, Canada, | Montreal, Quebec, Canada, | Quebec City, Quebec, Canada, | Copenhagen, Denmark, | Odense, Denmark, | Vejle, Denmark, | Argenteuil, France, | Caen, France, | Lille, France, | Limoges, France, | Nantes Cedex 1, France, | Paris, France, | Pessac, France, | Pierre Benite, France, | Rennes, France, | Toulouse Cedex 9, France, | Tours Cedex 9, France, | Vandoeuvre les Nancy, France, | Berlin, Germany, | Bonn, Germany, | Hamburg, Germany, | Hamm, Germany, | Heidelberg, Germany, | Jena, Germany, | Karlsruhe, Germany, | Koblenz, Germany, | Köln, Germany, | Saarbrücken, Germany, | Villingen-Schwenningen, Germany, | Athens Attica, Greece, | Haifa, Israel, | Jerusalem, Israel, | Nahariya, Israel, | Netanya, Israel, | Petah Tikva, Israel, | Ramat Gan, Israel, | Tel Aviv, Israel, | Hitachi, Japan, | Kanazawa, Japan, | Kobe, Japan, | Kurume, Japan, | Matsuyama, Japan, | Nagoya, Japan, | Narita, Japan, | Ohgaki, Japan, | Okayama, Japan, | Osaka, Japan, | Sendai-City, Japan, | Shibukawa, Japan, | Shibuya, Japan, | Tachikawa, Japan, | Tokyo, Japan, | Gyeonggi-do, Korea, Republic of, | Incheon, Korea, Republic of, | Seoul, Korea, Republic of, | Amsterdam, Netherlands, | Rotterdam, Netherlands, | Utrecht, Netherlands, | Zwolle, Netherlands, | Brzozow, Poland, | Chorzów, Poland, | Gdansk, Poland, | Legnica, Poland, | Lublin, Poland, | Poznan, Poland, | Slupsk, Poland, | Wroclawa, Poland, | Dzerzhinsk, Russian Federation, | Ekaterinburg, Russian Federation, | Moscow, Russian Federation, | Nizhny Novgorod, Russian Federation, | Petrozavodsk, Russian Federation, | Ryazan, Russian Federation, | Samara, Russian Federation, | St-Petersburg, Russian Federation, | St. Petersburg, Russian Federation, | Syktyvkar, Russian Federation, | Badalona, Spain, | Barcelona, Spain, | La Laguna (Santa Cruz De Tenerife), Spain, | Madrid, Spain, | Pamplona, Spain, | Salamanca, Spain, | Sevilla, Spain, | Falun, Sweden, | Göteborg, Sweden, | Helsingborg, Sweden, | Huddinge, Sweden, | Lund, Sweden, | Stockholm, Sweden, | Uppsala, Sweden, | Changhua, Taiwan, | Taichung City, Taiwan, | Tainan, Taiwan, | Taipei, Taiwan, | Taoyuan, Taiwan, | Birmingham, United Kingdom, | Leeds, United Kingdom, | London, United Kingdom, | Oxford, United Kingdom, | Southampton, United Kingdom, | Surrey, United Kingdom, | Wolverhampton, United Kingdom,
Investigators

More Information

Publications

• Cavo M, San-Miguel J, Usmani SZ, Weisel K, Dimopoulos MA, Avet-Loiseau H, Paiva B, Bahlis NJ, Plesner T, Hungria V, Moreau P, Mateos MV, Perrot A, Iida S, Facon T, Kumar S, van de Donk NWCJ, Sonneveld P, Spencer A, Krevvata M, Heuck C, Wang J, Ukropec J, Kobos R, Sun S, Qi M, Munshi N. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022 Feb 10;139(6):835-844. doi: 10.1182/blood.2021011101.

• Plesner T, Dimopoulos MA, Oriol A, San-Miguel J, Bahlis NJ, Rabin N, Suzuki K, Yoon SS, Ben-Yehuda D, Cook G, Goldschmidt H, Grosicki S, Qin X, Fastenau J, Garvin W, Carson R, Renaud T, Gries KS. Health-related quality of life in patients with relapsed or refractory multiple myeloma: treatment with daratumumab, lenalidomide, and dexamethasone in the phase 3 POLLUX trial. Br J Haematol. 2021 Jul;194(1):132-139. doi: 10.1111/bjh.17435. Epub 2021 Apr 6.

• Avet-Loiseau H, San-Miguel J, Casneuf T, Iida S, Lonial S, Usmani SZ, Spencer A, Moreau P, Plesner T, Weisel K, Ukropec J, Chiu C, Trivedi S, Amin H, Krevvata M, Ramaswami P, Qin X, Qi M, Sun S, Qi M, Kobos R, Bahlis NJ. Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR. J Clin Oncol. 2021 Apr 1;39(10):1139-1149. doi: 10.1200/JCO.20.01814. Epub 2021 Jan 29.

• Mateos MV, Spencer A, Nooka AK, Pour L, Weisel K, Cavo M, Laubach JP, Cook G, Iida S, Benboubker L, Usmani SZ, Yoon SS, Bahlis NJ, Chiu C, Ukropec J, Schecter JM, Qin X, O'Rourke L, Dimopoulos MA. Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies. Haematologica. 2020 Jan 31;105(2):468-477. doi: 10.3324/haematol.2019.217448. Print 2020.

• Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.

Additional Relevant MeSH Terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Neoplasms by Histologic Type
• Neoplasms
• Hemostatic Disorders
• Vascular Diseases
• Cardiovascular Diseases
• Paraproteinemias
• Blood Protein Disorders
• Hematologic Diseases
• Hemorrhagic Disorders
• Lymphoproliferative Disorders
• Immunoproliferative Disorders
• Immune System Diseases