A Study of Subcutaneous Versus (vs.) Intravenous Administration of Daratumumab in Participants With Relapsed or Refractory Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT03277105
• Recruitment Status: Completed
• First Posted: September 8, 2017
• Results First Posted: July 27, 2020
• Last Update Posted: March 13, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: September 7, 2017
• First Posted Date: September 8, 2017
• Results First Submitted Date: June 19, 2020
• Results First Posted Date: July 27, 2020
• Last Update Posted Date: March 13, 2024
• Actual Study Start Date: October 27, 2017
• Actual Primary Completion Date: June 27, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 5, 2024)

• Overall Response Rate (ORR) [ Time Frame: Up to 1 year 8 months ]
  ORR was defined as the percentage of participants who achieved partial response (PR) or better according to International Myeloma Working Group (IMWG) criteria, during or after study treatment. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 200 milligrams (mg)/24 hours, If the serum and urine M-proteins are not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels were required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, >=50% reduction in bone marrow plasma cells (PCs) was required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas was also required.
• Maximum Trough Concentration (Ctrough) of Daratumumab [ Time Frame: Predose on Cycle 3 Day 1 (each cycle of 28 days) ]
  Maximum Ctrough was defined as the serum predose concentration of daratumumab on Cycle 3 Day 1.

Original Primary Outcome Measures (submitted: September 7, 2017)

• Overall Response Rate (ORR) [ Time Frame: At 6 months after last participant randomized (approximately 2 years) ]
  The ORR is defined as the proportion of participants who achieve partial response (PR) or better according to international myeloma working group (IMWG) criteria, during or after study treatment. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to lesss than (<) 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 free light chain (FLC) levels is required in place of the Mprotein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.
• Maximum Trough Concentration (Ctrough) of Daratumumab [ Time Frame: Cycle 3 (each cycle 28 days) Day 1 ]
  Maximum Ctrough is defined as the serum predose concentration of daratumumab on Cycle 3 Day 1.

Current Secondary Outcome Measures (submitted: January 5, 2024)

• Percentage of Participants With Treatment-emergent Infusion-related Reactions (IRR) [ Time Frame: Up to 3 years ]
  Percentage of participants with treatment-emergent infusion-related reactions were reported.
• Progression Free Survival (PFS) [ Time Frame: Up to 3 years ]
  PFS was defined as time from date of randomization to either progression of disease (PD), death due to any cause, whichever occurs first. IMWG criteria for PD: Increase of 25% from lowest response value in any one of the following: Serum M component (absolute increase must be >=0.5 gram per deciliter (g/dL), Urine M-component (absolute increase must be >=200 mg/24 hours), Participants without measurable serum and urine Mprotein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be >10 milligrams per deciliter (mg/dL), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
• Percentage of Participants With Very Good Partial Response (VGPR) or Better [ Time Frame: Up to 3 years ]
  VGPR or better was defined as the percentage of participants who achieved VGPR or better (VGPR, complete response (CR) or stringent complete response [sCR]), based on computerized algorithm as per IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >=90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligrams (mg)/24 hours, CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PCs) in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescencea or 2- to 4 color flow cytometry.
• Percentage of Participants With Complete Response (Including sCR) or Better [ Time Frame: Up to 3 years ]
  CR or better was defined as percentage of participants with a CR or better (CR or stringent complete response [sCR]) based on computerized algorithm as per IMWG criteria. IMWG criteria for CR- negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by IHC, immunofluorescencea or 2- to 4 color flow cytometry.
• Time to Next Therapy [ Time Frame: Up to 3 years ]
  Time to next therapy was defined as the time from randomization to the start of the first subsequent anti-cancer therapy.
• Overall Survival (OS) [ Time Frame: Up to 3 years ]
  OS was defined as the time from the date of randomization to the date of the participant's death due to any cause.
• Patient-Reported Satisfaction With Therapy as Assessed With Cancer Therapy Satisfaction Questionnaire (CTSQ) [ Time Frame: Cycle 1 (Days 8,15 and 22), Cycle 2 (Days 1,8,15 and 22), Cycle 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 (Day 1) ]
  Modified-CTSQ contain 9 items (2 items for Thoughts about Cancer Therapy and 7 items in a defined domain of Satisfaction with Therapy) specific to satisfaction with therapy and for comparison of SC and IV administration. Satisfaction with therapy was calculated based on 7-items using 5-point verbal rating scale, where 1= never and 5= always. Scores were averaged and transformed to a 0-100 scale; higher scores represent better health. At least 5 of the 7 items within the Satisfaction with Therapy domain had to be completed to calculate a domain score. No domain score was calculated for Thoughts about Cancer Therapy.
• Duration of Response [ Time Frame: Up to 3 years ]
  Duration of response was defined as the duration from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG criteria. PD was defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
• Time to Partial Response (PR) or Better [ Time Frame: Up to 3 years ]
  Time to PR or better was defined as the time from randomization until onset of first response of PR or better.
• Time to Very Good Partial Response (VGPR) or Better [ Time Frame: Up to 3 years ]
  Time to VGPR or better was defined as the time from randomization until onset of first VGPR or better.
• Time to Complete Response (CR) or Better [ Time Frame: Up to 3 years ]
  Time to CR or better was defined as the time from randomization until onset of first CR or better.

Original Secondary Outcome Measures (submitted: September 7, 2017)

• Percentage of participants With Infusion-Related Reactions (IRR) [ Time Frame: At 6 months after last participant randomized (approximately 2 years) ]
  The Percentage of Participants with infusion reactions will be reported.
• Progression-Free Survival (PFS) [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  PFS is defined as time from date of randomization to either progression of disease (PD), death due to any cause, whichever occurs first. According to IMWG criteria: Increase of 25% from lowest response value in any one of the following: Serum M component (absolute increase must be >=0.5 gram per deciliter (g/dL), Urine M-component (absolute increase must be >=200 mg/24 hours), Participants without measurable serum and urine Mprotein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be >10 milligrams per deciliter (mg/dL), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
• Very Good Partial Response (VGPR) or Better Rate [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  The VGPR or better rate, defined as the proportion of participants achieving VGPR and complete response (CR) (including stringent complete response [sCR]) according IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligram (mg)/24 hours, CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cellS (PCs) in bone marrow. sCR: CR plus normal free light chain (FLC) ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescencea or 2- to 4 color flow cytometry.
• Complete Response (Including sCR) or Better Rate [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  Complete response is based on serum M-Protein assessments. IMWG criteria for CR: Negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by IHC, immunofluorescencea or 2- to 4 color flow cytometry.
• Time to Next Treatment [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  Time to next therapy is defined as the time from randomization to the start of the first subsequent anti-cancer therapy.
• Overall Survival (OS) [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  OS is defined as the time from the date of randomization to the date of the participant's death.
• Patient-Reported Satisfaction With Therapy [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  Patient-reported satisfaction with therapy is defined as the mean of responses to 7 of 9 questions in the modified cancer therapy satisfaction questionnaire (modified-CTSQ). Modified-CTSQ contain 9 items specific to satisfaction with therapy and for comparison of IV with SC administration. Satisfaction with therapy is calculated based on 7-items using 5-point verbal rating scale, 1, never; 5, always. Scores will be averaged and transformed to a 0-100 scale; higher scores represent better health.
• Duration of Response [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  Duration of response is defined as date of onset of first response until date of disease progression or death.
• Time to response [ Time Frame: At 6 months after last participant randomized (approximately 2 years) and 18 months after the last participant randomized (approximately 3 years) ]
  Time to response is defined as the time from randomization until onset of first response.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Subcutaneous Versus (vs.) Intravenous Administration of Daratumumab in Participants With Relapsed or Refractory Multiple Myeloma
• Official Title: A Phase 3 Randomized, Multicenter Study of Subcutaneous vs. Intravenous Administration of Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma
• Brief Summary: The purpose of this study is to show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant human hyaluronidase PH20 (Dara SC) is non-inferior to intravenous (IV) administration of daratumumab (Dara IV) in terms of the overall response rate (ORR) and maximum trough concentration (Ctrough).
• Detailed Description: The study population will consist of adults diagnosed with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD. The study consists of 3 phases: a screening phase (up to 28 days), a treatment phase, and a follow-up phase. Efficacy, pharmacokinetics, immunogenicity, biomarkers and safety will be assessed at scheduled time. Follow-up will continue until the end of the data collection period, approximately 24 months after the last participant was randomized or when the median overall survival for both arms has been reached, whichever occurs first. The primary hypotheses is that the ORR and maximum Ctrough for Dara SC 1800 milligram (mg) are not inferior to the ORR and maximum Ctrough, respectively, for Dara IV 16 mg per kilogram (mg/kg) in participants with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Dara SC
  Participants will receive a fixed dose of Dara SC as 1800 mg daratumumab with rHuPH20 2000 U/mL, once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.
• Drug: Dara IV
  Participants will receive Dara IV 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.
  Other Name: JNJ-54767414

Study Arms

• Experimental: Dara SC
  Participants will receive a fixed dose of daratumumab as 1800 milligram (mg) subcutaneously (Dara SC) co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Unit per milliliter (U/mL), once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks.
  Intervention: Drug: Dara SC
• Active Comparator: Dara IV
  Participants will receive daratumumab for intravenous infusion (Dara IV) 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks on Day 1 in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks. For Participants still receiving treatment with Dara-IV at the time of Protocol Amendment 4 the duration of infusion may be shortened to a 90-minute infusion or participants will have the option to switch to Dara 1800 mg subcutaneous (SC) on Day 1 of any cycle, at the discretion of the investigator.
  Interventions:

  • Drug: Dara SC
  • Drug: Dara IV

Publications *

• Usmani SZ, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis NJ, Flogegard M, Blade J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Lantz K, O'Rourke L, Heuck C, Delioukina M, Qin X, Nnane I, Qi M, Mateos MV. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022 Oct 1;107(10):2408-2417. doi: 10.3324/haematol.2021.279459.
• Iida S, Ishikawa T, Min CK, Kim K, Yeh SP, Usmani SZ, Mateos MV, Nahi H, Heuck C, Qin X, Parasrampuria DA, Gries KS, Qi M, Bahlis N, Ito S. Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study. Ann Hematol. 2021 Apr;100(4):1065-1077. doi: 10.1007/s00277-021-04405-2. Epub 2021 Feb 18.
• Usmani SZ, Mateos MV, Hungria V, Iida S, Bahlis NJ, Nahi H, Magen H, Cavo M, Hulin C, White D, De Stefano V, Fastenau J, Slavcev M, Heuck C, Qin X, Pei H, Masterson T, Lantz K, Gries KS. Greater treatment satisfaction in patients receiving daratumumab subcutaneous vs. intravenous for relapsed or refractory multiple myeloma: COLUMBA clinical trial results. J Cancer Res Clin Oncol. 2021 Feb;147(2):619-631. doi: 10.1007/s00432-020-03365-w. Epub 2020 Aug 27.
• Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, Blade J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Clemens PL, Masterson T, Lantz K, O'Rourke L, Heuck C, Qin X, Parasrampuria DA, Yuan Z, Xu S, Qi M, Usmani SZ. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020 May;7(5):e370-e380. doi: 10.1016/S2352-3026(20)30070-3. Epub 2020 Mar 23. Erratum In: Lancet Haematol. 2020 Oct;7(10):e710.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 28, 2019): 522
• Original Estimated Enrollment (submitted: September 7, 2017): 480
• Actual Study Completion Date: January 12, 2024
• Actual Primary Completion Date: June 27, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Evidence of a response (Partial response [PR] or better based on investigator's determination of response by international myeloma working group [IMWG] criteria) to at least 1 prior treatment regimen
• Received at least 3 prior lines of therapy including a proteasome inhibitor (PI) (greater than or equal to [>=] 2 cycles or 2 months of treatment) and an immunomodulatory drug (IMiD) (>=2 cycles or 2 months of treatment) in any order during the course of treatment (except for participants who discontinued either of these treatments due to a severe allergic reaction within the first 2 cycles/months). A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 milligram/day [mg/day] for 4 days) would not be considered prior lines of therapy

• Documented multiple myeloma as defined by the criteria below:

  1. Multiple myeloma diagnosis according to the IMWG diagnostic criteria

  2. Measurable disease at Screening as defined by any of the following:

     1. Serum M-protein level >=1.0 gram per deciliter (g/dL) or urine M-protein level >=200 mg/24 hours; or
     2. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) >=10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• Meet the clinical laboratory criteria as specified in the protocol
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization

Exclusion Criteria:

• Received daratumumab or other anti-CD38 therapies previously
• Received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) before treatment
• Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing)
• Plans to undergo a stem cell transplant prior to progression of disease on this study (these participants should not be enrolled to reduce disease burden prior to transplant)
• History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further 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 3 years

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, Czechia, France, Greece, Israel, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03277105
• Other Study ID Numbers: CR108342; 2017-000206-38 ( EudraCT Number ); 54767414MMY3012 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: March 2024