A Randomized, Open-label Phase 3 Study of Carfilzomib, Melphalan, and Prednisone versus Bortezomib, Melphalan, and Prednisone in Transplant ineligible Patients with Newly Diagnosed Multiple Myeloma

Please refer to the study protocol section 1.6 "Study rationale"

Primary Objective:
To compare the progression-free survival (PFS) of transplant-ineligible
subjects with newly diagnosed multiple myeloma who are treated with
carfilzomib, melphalan, and prednisone (CMP) versus those treated with
bortezomib (Velcade), melphalan, and prednisone (VMP).
Secondary Objectives:
To compare the following between the treatment groups:
1. Overall survival (OS)
2. Overall response rate (ORR; defined as the proportion of best overall
response of stringent complete response [sCR], complete response [CR],
very good partial response [VGPR], and partial response [PR])
3. Complete response rate (CRR; defined as the proportion of best overall
response of stringent complete response [sCR] or complete
Response [CR])
4. Neuropathy events (defined as the incidence of grade 2 or higher peripheral
neuropathy [PN] events)
5. European Organization for Research and Treatment of Cancer [EORTC] Quality
of Life Questionnaire (QLQ) C30 Global Health Status/QoL scale
6. Safety and tolerability

This is a Phase 3 multicenter, open-label, randomized study in
transplant-ineligible subjects with newly diagnosed multiple myeloma.
Subjects will be randomized to receive 1 of 2 treatment regimens, CMP or VMP,
as outlined in the Study Treatment section.
The randomization will be stratified on the basis of the following criteria:
International Staging System (ISS) stage: Stage 1 versus Stages 2 or 3
Choice of route of bortezomib administration (if the subject were to receive
bortezomib): intravenous (IV) versus subcutaneous (SC)
Region: (1) North America, (2) Europe, (3) Asia Pacific, or (4) other
Age: < 75 years versus >= 75 years
A permuted-block randomization will be used to randomize subjects within each
stratum. The estimated sample size is 882 subjects.
Subjects will receive the treatment determined by randomization until confirmed
disease progression, unacceptable toxicity, withdrawal of consent, death, or
completion of nine 6-week treatment cycles (whichever occurs first). No
crossover between the 2 treatment arms will be allowed. Subjects in both
treatment arms will be assessed for multiple myeloma disease response according
to the International Myeloma Working Group (IMWG)-Uniform Response Criteria
(URC) using central laboratory test results every 3 weeks, irrespective of
treatment delays or the timing of treatment cycles, during the first 54 weeks
of the study. Afterwards, disease response assessments will be extended to
every 6 weeks until confirmed progressive disease (PD).
For subjects who discontinue treatment before PD occurs (such as for an AE,
noncompliance), disease response assessments using central laboratory results
will be performed every 3 weeks during the first 54 weeks of the study and
every 6 weeks thereafter, until confirmed PD.
Long-term follow up (LTFU) for survival and PFS2 will continue approximately
every 12 weeks (± 1 week) for each subject after their disease progresses,
until the subject has withdrawn consent for further participation, is lost to
follow-up, has died, a total of 400 deaths have occurred, or the study is
closed, whichever is earliest. For any subject who is lost to follow-up, the
study site will attempt to ascertain survival information via public database
search.
This study is designed to detect a 35% improvement in PFS (hazard ratio [HR] =
0.74) for CMP over VMP with 85% power and a 1-sided significance level of
0.025. It is assumed that the PFS for the control arm (VMP regimen) is 21
months. One interim analysis will be performed when 75% (302) of the total 403
PFS events have occurred.

Study Treatment Regimens
CMP Regimen: 9 cycli of 42 days

Cyclus/cycli Days Study Treatment
1 1, 2 Carfilzomib 20 mg/m2
1 8, 9, 22, 23, 29, 30 Carfilzomib 36 mg/m2
2-9 1, 2, 8, 9, 22, 23, 29, 30 Carfilzomib 36 mg/m2
1-9 1-4 Melfalan 9 mg/m2
1-9 1-4 Prednison 60 mg/m2
1 8, 9, 22, 23, 29, 30 Dexamethason 4 mg

VMP Regimen: 9 cycli of 42 days
Cyclus/cycli Days Study Treatment
1-4 1, 4, 8, 11, 22, 25, 29, 32 Bortezomib 1,3 mg/m2
5-9 1, 8, 22, 29 Bortezomib 1,3 mg/m2
1-9 1-4 Melfalan 9 mg/m2
1-9 1-4 Prednison 60 mg/m2

Patients may experience drug-related side effect. For full list of side effects
please refer to Appendix III of the main patient information sheet and infomed
consent from.
In addition to side effects patients may experience discomforts and risks
associated with the study procedures such as blood drawing, bone marrow
sampling, ECHO, X-rays exposure.
Carfilzomib has an adequate safety profile without apparent long-term toxicity,
including in patients with renal impairment, and those on dialysis. The
benefit/risk ratio of carfilzomib appears favorable and may be preferable to
some available agents, allowing for improved therapy for patients with multiple
myeloma and possibly other neoplastic conditions.
The results of preclinical and clinical studies to date suggest that a clinical
study of efficacy and safety of carfilzomib in patients with multiple myeloma
is advisable and justifiable with regard to the risk/benefit ratio.