Phase 3 Study Comparing Daratumumab, Bortezomib and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Subjects With Relapsed or Refractory Multiple Myeloma

Multiple myeloma is a malignant disorder of the plasma cells characterized by
uncontrolled and progressive proliferation of a plasma cell clone. The
proliferating multiple myeloma cells displace the normal bone marrow leading to
dysfunction in normal hematopoietic tissue and destruction of the normal bone
marrow architecture, which is reflected by clinical findings such as anemia,
paraprotein in serum or urine, and bone resorption seen as diffuse osteoporosis
or lytic lesions shown in radiographs (Kyle 2003).19 Patients with multiple
myeloma produce a monoclonal protein, also called paraprotein (comprising
monoclonal protein [M-protein] and free-light chain), which is an
immunoglobulin (Ig) or a fragment of one that has lost its function (Palumbo
2011, Kyle 2009).27,20 Normal immunoglobulin levels are compromised, leading to
susceptibility to infections. Furthermore, hypercalcemia, renal insufficiency
or failure, and neurological complications are frequently seen (Palumbo
2011).27 Multiple myeloma is recognized as a source of significant morbidity
and mortality. Approximately 50,000 patients per year are diagnosed with
multiple myeloma in the European Union (EU) and United States (US), and 30,000
patients per year die due to multiple myeloma (ACS 2012, Ferlay 2010).1,13
Treatment choices for multiple myeloma vary with the aggressiveness of the
disease and related prognostic factors (Palumbo 2011).27 Newly diagnosed
patients in good physical health with active disease will generally receive
high-dose chemotherapy with autologous stem cell transplantation (ASCT) (Attal
1996, Child 2003).2,6 Eligibility for ASCT is established primarily by age and
comorbidities (Harousseau 2009).14 For patients in whom transplantation is not
an option, treatment traditionally consists of systemic chemotherapy, with
adjunctive use of radiation or surgery in selected cases associated with
extramedullary disease (Palumbo 2009a, Smith 2005, NCCN 2013).28,38 ,23
The therapeutic landscape of multiple myeloma has changed markedly in the past
decade with the introduction of the novel immunomodulatory agents thalidomide
and lenalidomide, as well as the first-in-class proteasome inhibitor (PI),
VELCADE® (bortezomib). New approaches to therapy that incorporate these agents
have produced significantly higher response rates and improved duration of both
progression-free survival (PFS) and overall survival (OS) in the context of
randomized, controlled studies. Collectively, novel therapies for multiple
myeloma have been associated with substantial improvements in patient outcome
(Kumar 2012).21
There is ample evidence to support the efficacy and safety of VELCADE in the
treatment of patients with relapsed or refractory multiple myeloma. VELCADE is
approved by the FDA and European Regulatory Authorities for this indication.
The regulatory approval is based, in part, on data presented in Richardson
2003.34 In this trial, the investigators treated 202 patients with relapsed
myeloma that was refractory to their most recent line of therapy. Patients
received up to 8 cycles of treatment with VELCADE given at a dose of twice
weekly for 2 concurrent weeks, followed by a 1-week rest. Dexamethasone was
added for patients who had an insufficient response to VELCADE alone. Overall,
the response rate was 35% in this heavily pretreated population with a median
overall survival of 16 months. In the APEX trial, patients who had 1 to 3 prior
myeloma therapies were randomized to either VELCADE or high-dose dexamethasone
as a salvage strategy. Patients in the VELCADE cohort had higher response rates
(defined as partial response (PR) or better), (38% vs 18%), longer time to
progression (189 days vs 106 days), and an improved overall survival (OS) (80%
vs 66% at 1 year) than those randomized to high-dose dexamethasone (Richardson
2005).35 Updated data from this trial confirmed the OS benefit at a median
follow-up of 22 months (29.8 months for Vd vs 23.7 months for dexamethasone)
(Richardson 2007).36 Furthermore, overall response was improved after the
longer interval of follow-up (43% of patients responding to treatment with Vd
at a median follow-up of 22 months vs 38% initially reported).
Although significant progress has been made in the management of multiple
myeloma, it remains an incurable malignancy. Relapsed and refractory disease
constitutes a specific unmet medical need. Patients with relapsed and
refractory disease are defined as those who, having achieved minor response or
better, relapse and then progress while on salvage therapy, or experience
progression within 60 days of their last therapy.

Primary Objective
The primary objective is to compare the efficacy of daratumumab when combined
with VELCADE (bortezomib) and dexamethasone (DVd) to that of VELCADE and
dexamethasone (Vd), in terms of progression-free survival (PFS) in subjects
with relapsed or refractory multiple myeloma.
Major Secondary Objectives
The major secondary objectives are as follows:
* To evaluate clinical outcomes including time to disease progression (TTP),
overall response rate (ORR), and overall survival (OS).
* To evaluate the proportion of subjects with a response of very good partial
response (VGPR) or better.
* To evaluate duration of and time to response.
* To assess the safety and tolerability of daratumumab when administered in
combination with Vd.
* To assess Minimal Residual Disease (MRD) in subjects who achieve >=VGPR.
Other secondary objectives are as follows:
* To assess the pharmacokinetics of daratumumab in combination with Vd.
* To assess the immunogenicity of daratumumab.
* To evaluate treatment effects on patient reported outcomes (PROs) including
the EuroQol-5 Dimensions (EQ-5D-5L) and EORTC QLQ-C30.
* To evaluate clinical efficacy of DVd in high risk molecular subgroups
(del17p, t(4;14), t(14;20), UAMS-70).
Exploratory Objectives
The exploratory objective is as follows:
* To explore biomarkers predictive of response to daratumumab and potential
mechanisms of treatment resistance.

This is a multicenter, Phase 3, randomized, open-label, active-controlled study
comparing daratumumab, VELCADE, and dexamethasone (DVd) with VELCADE and
dexamethasone (Vd) in subjects with relapsed or refractory multiple myeloma.
Approximately 480 subjects will be randomized in a 1:1 ratio to receive either
DVd or Vd. Randomization will be stratified by International Staging System
(ISS), number of prior lines (1 vs. 2 or 3 vs. >3), and prior VELCADE (no vs.
yes). Within each stratum, subjects will be randomized using an equal
allocation ratio of 1:1. Subject participation will include a Screening Phase,
a Treatment Phase, and a Follow-up Phase. Subjects will be treated until
disease progression, unacceptable toxicity, or other reasons as listed in
Section 10.2.

Daratumumab Drug: Daratumumab will be administered as an IV infusion at a dose
of 16 mg/kg weekly for the first 3 cycles, on Day 1 of Cycles 4-9, and then
every 4 weeks thereafter.

VELCADE (Bortezomib) Drug: VELCADE will be administered at a dose of 1.3 mg/m2
subcutaneously (SC) on Days 1, 4, 8 and 11 of each 21-day cycle. Eight VELCADE
treatment cycles are to be administered.

Dexamethasone Drug: Dexamethasone will be administered orally at 20 mg on Days
1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 VELCADE treatment

See "Time and events schedule" in the protocol.