Phase III Study of Lenalidomide and Dexamethasone With or Without Elotuzumab to Treat Relapsed or Refractory Multiple Myeloma

• Lenalidomide (Drug), also known as Revlimid®: Capsules, Oral, 25 mg, once daily, on Days 1-21, Repeat every 28 days until subject meets criteria for discontinuation of study drug
• Dexamethasone (Drug), also known as Decadron®, Dexamethasone Intensol®, Dexpak®, Taperpak®: Tablets, Oral, 40 mg, weekly, on Days 1, 8, 15, 22, Repeat every 28 days until subject meets criteria for discontinuation of study drug
• Dexamethasone (Oral) (Drug), also known as Decadron®, Dexamethasone Intensol®, Dexpak®, Taperpak®: On weeks without Elotuzumab dosing: Tablets, Oral, 40mg, Repeat every 28 days until subject meets criteria for discontinuation of study drug. On weeks with Elotuzumab dosing: Tablets, Oral, 28 mg, Repeat every 28 days until subject meets criteria for discontinuation of study drug
• Dexamethasone (IV) (Drug), also known as Decadron®, Dexamethasone Intensol®, Dexpak®, Taperpak®: On weeks without Elotuzumab dosing: Not Applicable (N/A) On weeks with Elotuzumab dosing: Solution, Intravenous (IV), 8 mg, weekly, Repeat every 28 days until subject meets criteria for discontinuation of study drug
• Elotuzumab (BMS-901608; HuLuc63) (Biological): Solution, IV, 10 mg/kg, weekly, on Days 1, 8, 15, 22 (cycles 1\&2); Days 1 and 15 (cycles 3 and beyond), Repeat every 28 days until subject meets criteria for discontinuation of study drug

Primary outcomes

• Median Progression Free Survival (PFS) [From randomization up to 326 events (up to approximately 38 months)]: Primary definition of Progression-free survival (PFS) defined as the time from randomization to the date of first documented tumor progression or death due to any cause. Participants were censored at the last adequate assessment prior to the start of any subsequent systemic-therapy or at the last adequate assessment prior to 2 missing assessments (> 10 weeks). Participants who died more than 10 weeks after the randomization date and had no on-treatment assessment were censored at the randomization date. Clinical deterioration was not considered progression. The primary analysis of PFS was based on the primary definition using the Independent Review Committee (IRC) tumor assessment using the European Group for Blood and Bone Marrow Transplant (EBMT) criteria. Tumor assessments were made every 4 weeks (±1 week) relative to the first dose of study medication.
• Objective Response Rate (ORR) [From randomization up to approximately 38 months]: Objective response rate (ORR) defined as the percentage of participants with a best response on-study of partial response (PR) or better (stringent CR \[sCR\], complete response \[CR\], very good partial response \[VGPR\], and partial response \[PR\]) based on the Independent Review Committee (IRC) assessment of best response using the European Group for Blood and Bone Marrow Transplant (EBMT) assessment criteria. Participants were censored at the last adequate assessment prior to the start of any subsequent systemic-therapy or at the last adequate assessment prior to 2 missing assessments (> 10 weeks). Participants who died more than 10 weeks after the randomization date and had no on-treatment assessment were censored at the randomization date. Clinical deterioration was not considered progression. Assessments were made every 4 weeks.

Secondary outcomes

• Median Overall Survival (OS) [Randomization to the date of death from any cause (up to approximately 9 years)]: Overall survival is defined as the time from randomization to the date of death from any cause. If a subject has not died, their survival time will be censored at the date of last contact ("last known alive date"). A subject will be censored at the date of randomization if they were randomized but had no follow-up. (Based on Kaplan Meier estimates)
• Change From Baseline of Mean Score Pain Severity (BPI-SF) [From baseline up to approximately 38 months]: The change from baseline of the mean score of pain severity at the end of treatment using the Brief Pain Inventory-Short Form (BPI-SF). The BPI-SF is a self administered questionnaire developed to assess the severity of pain (the sensory dimension) as well as the degree to which pain interferes with function (the reactive dimension). The BPI-SF uses 0 ("No pain", "No interference") to 10 ("Pain as bad as you can imagine", "Highest imaginable interference") numeric rating scale.
• Change From Baseline of Mean Score Pain Interference (BPI-SF) [From baseline up to approximately 38 months]: The change from baseline of the mean score of pain interference at the end of treatment using the Brief Pain Inventory-Short Form (BPI-SF). The BPI-SF is a self administered questionnaire developed to assess the severity of pain (the sensory dimension) as well as the degree to which pain interferes with function (the reactive dimension). The BPI-SF uses 0 ("No pain", "No interference") to 10 ("Pain as bad as you can imagine", "Highest imaginable interference") numeric rating scale.

Sex: All, ages: 18 Years to any

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

* Documented progression from most recent line of therapy
* 1-3 prior lines of therapy
* Measurable disease
* Life expectancy ≥3 months
* Prior treatment with Lenalidomide permitted if:

  1. Best response achieved was ≥Partial Response (PR)
  2. Patient was not refractory
  3. Patient did not discontinue due to a Grade ≥3 related adverse event
  4. Subject did not receive more than 9 cycles of Lenalidomide and had at least 9 months between the last dose of Lenalidomide and progression

Exclusion Criteria:

* Subjects with non-secretory or oligo-secretory or serum free light-chain only myeloma
* Active plasma cell leukemia
* Known Human immunodeficiency virus (HIV) infection or active hepatitis A, B, or C

Participant flow

Outcome results

• Median Progression Free Survival (PFS) (Primary), Median, Months: Lenalidomide + Dexamethasone + Elotuzumab 19.35 (16.62 to 22.18); Lenalidomide + Dexamethasone 14.85 (12.09 to 17.22) (p 0.0014)
• Median Progression Free Survival (PFS) - Extended Collection (Post hoc), Median, Months: Lenalidomide + Dexamethasone + Elotuzumab 19.42 (16.62 to 22.31); Lenalidomide + Dexamethasone 14.92 (12.25 to 17.31) (p 0.0005)
• Objective Response Rate (ORR) (Primary), Number, Percentage of participants: Lenalidomide + Dexamethasone + Elotuzumab 78.5 (73.6 to 82.9); Lenalidomide + Dexamethasone 65.5 (60.1 to 70.7) (p 0.0002)
• Median Overall Survival (OS) (Secondary), Median, Months: Lenalidomide + Dexamethasone + Elotuzumab 48.30 (40.34 to 51.94); Lenalidomide + Dexamethasone 39.62 (33.25 to 45.27)
• Change From Baseline of Mean Score Pain Severity (BPI-SF) (Secondary), Mean, Score on a scale: Lenalidomide + Dexamethasone + Elotuzumab 0.52 +/- 2.237; Lenalidomide + Dexamethasone -0.04 +/- 2.408
• Change From Baseline of Mean Score Pain Interference (BPI-SF) (Secondary), Mean, Score on a scale: Lenalidomide + Dexamethasone + Elotuzumab 0.95 +/- 2.466; Lenalidomide + Dexamethasone 0.48 +/- 2.868

Adverse events

Time frame: From first dose up to 60 days post last dose of study therapy (Up to approximately 9 years)

Serious adverse events by term

330 more terms not shown.

Other adverse events by term

37 more terms not shown.

116 more sites not listed.

• Results publication: Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018 Oct 15;124(20):4032-4043. doi: 10.1002/cncr.31680. Epub 2018 Sep 11. PMID 30204239
• Results publication: Passey C, Mora J, Dodge R, Gibiansky L, Sheng J, Roy A, Bello A, Gupta M. An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab. AAPS J. 2017 Mar;19(2):557-567. doi: 10.1208/s12248-016-0033-9. Epub 2017 Jan 9. PMID 28070715
• Results publication: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Rollig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. doi: 10.1056/NEJMoa1505654. Epub 2015 Jun 2. PMID 26035255

• Bristol-Myers Squibb, Study director, Bristol-Myers Squibb