A Study Evaluating Venetoclax (ABT-199) in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy
Condition: Relapsed/Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Venetoclax; Bortezomib; Dexamethasone; Placebo for venetoclax
Intervention description: Participants self-administered venetoclax tablets by mouth QD in combination with bortezomib. Venetoclax was to be given before other agents administered on the same day, if applicable. Each venetoclax dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling.; Bortezomib (subcutaneous injection [preferred] or IV) was given following administration of venetoclax or placebo in Cycles 1 -8 on Days 1, 4, 8 and 11, and for Cycles 9 and beyond, on Days 1, 8, 15 and 22 and was to be administered per the prescribing information. The route of administration was to stay the same during the study.; Dexamethasone was to be given orally, administered per the prescribing information, the day of bortezomib dosing and the following day, given the protocol-defined dosing window (bortezomib dosing window is ± 1 day) is maintained. If bortezomib was interrupted or a dose is skipped, dexamethasone was to be administered as scheduled per protocol (unless dexamethasone was interrupted due to toxicity).; Participants self-administered placebo tablets by mouth QD in combination with bortezomib. Placebo was to be given before other agents administered on the same day, if applicable. Each placebo dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling.
Intervention MeSH terms: Dexamethasone; Bortezomib; Venetoclax
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 291.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Relapsed/refractory multiple myeloma; Relapsed multiple myeloma; Refractory multiple myeloma; Multiple myeloma

Summary:

      This was a Phase 3, multicenter, randomized, double blind, placebo-controlled study
      evaluating the efficacy and safety of venetoclax plus bortezomib and dexamethasone in
      participants with relapsed or refractory multiple myeloma who are considered sensitive or
      naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple
      myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2

          -  Participant has documented relapsed or progressive multiple myeloma on or after any
             regimen or who are refractory to the most recent line of therapy. Relapsed myeloma is
             defined as previously treated myeloma that progresses and requires initiation of
             salvage therapy, but does not meet the criteria for refractory myeloma. Refractory
             myeloma is defined as disease that is nonresponsive (failure to achieve minimal
             response or development of progressive disease [PD]) while on primary or salvage
             therapy, or progresses within 60 days of last therapy.

          -  Participant must have received prior treatment with at least one, but no more than
             three, prior lines of therapy for multiple myeloma. A line of therapy consists of ≥ 1
             complete cycle of a single agent, a regimen consisting of combination of several
             drugs, or a planned sequential therapy of various regimens.

          -  Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided ALL
             of the following criteria are met: Disease is NOT refractory to any proteasome
             inhibitor, defined as no disease progression (i.e., PD, per International Myeloma
             Working Group [IMWG] or European Society for Blood and Marrow Transplantation [EBMT]
             criteria) while receiving proteasome inhibitor therapy or within 60 days after the
             last dose, AND best response achieved with any proteasome inhibitor therapy (alone or
             in combination) was at least a Partial Response (PR), AND participant did not
             discontinue any proteasome inhibitor due to intolerance or ≥ Grade 3 related toxicity.

          -  Participant has measurable disease at Screening, defined as at least one of the
             following: Serum M-protein ≥ 0.5 g/dL, OR Urine M-protein ≥ 200 mg in 24-hours, OR
             serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is
             abnormal.

        Exclusion Criteria:

          -  Participant is refractory to any proteasome inhibitor, defined as progression on or
             within 60 days of the last dose of a proteasome inhibitor-containing regimen.

          -  Participant has had prior treatment with proteasome inhibitor within 60 days prior to
             first dose of study drug.

          -  Participant has any of the following conditions:

        Non-secretory multiple myeloma, active plasma cell leukemia i.e., either 20% of peripheral
        white blood cells or greater than 2.0 X 10^9/liter (L) circulating plasma cells by standard
        differential, Waldenstrom's macroglobulinemia, amyloidosis, POEMS syndrome (polyneuropathy,
        organomegaly, endocrinopathy, monoclonal protein, and skin changes), known Human
        Immunodeficiency Viral (HIV) infection, active hepatitis B or C infection based on blood
        screen tests, significant cardiovascular disease, including uncontrolled angina, severe or
        uncontrolled arrhythmia, recent myocardial infarction within 6 months of randomization, or
        congestive heart failure New York Heart Association (NYHA) Class ≥ 3, major surgery within
        4 weeks prior to randomization, acute infections requiring parenteral therapy (antibiotic,
        antifungal, or antiviral) within 14 days prior to randomization, peripheral neuropathy ≥
        Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to randomization, uncontrolled diabetes
        or uncontrolled hypertension within 14 days prior to randomization, any other medical
        condition that, in the opinion of the Investigator, would adversely affect the
        participant's participation in the study

          -  Participant has a history of other active malignancies, including myelodysplastic
             syndrome (MDS), within the past 3 years prior to study entry, with the following
             exceptions: Adequately treated in situ carcinoma of the cervix uteri or the breast,
             basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin,
             prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen
             (PSA) levels off treatment, previous malignancy with no evidence of disease confined
             and surgically resected (or treated with other modalities) with curative intent and
             unlikely to impact survival during the duration of the study

          -  If participant had prior allogeneic stem cell transplant (SCT), participant has
             evidence of ongoing graft-versus-host disease (GvHD)