An Open-Label Phase II Study of the Safety and Efficacy of Doxorubicin and Cyclophosphamide in Combination With Bortezomib, Lenalidomide, and Dexamethasone for Treatment of Patients With Newly Diagnosed Multiple Myeloma
1. Male or female subjects ≥ 18 years at the time of signing informed consent.
2. Subject is diagnosed with symptomatic multiple myeloma based on the International
Myeloma Working Group Diagnostic Criteria (Kyle 2009):
- Monoclonal plasma cells in the bone marrow ≥ 10% and/or presence of a
- Monoclonal protein present in the serum and/or urine. If no monoclonal protein
is detected (non-secretory disease), then ≥ 30% monoclonal bone marrow plasma
cells and/or a biopsy-proven plasmacytoma is required.
- Myeloma-related organ dysfunction
3. The myeloma disease burden must be measurable with at least one of the following
criteria (Durie et al. 2006):
- Serum M-protein ≥ 10 g/l
- Urine M-protein ≥ 200 mg/24 h
- Involved FLC ≥ 100 mg/l provided serum FLC ratio is abnormal
- Bone marrow plasma cells > 30%
4. Subject has a Karnofsky performance status of ≥ 60.
5. Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.
6. Subject is willing and able to comply with the protocol as judged by the
1. Any prior systemic therapy for multiple myeloma.
2. Other therapies such as biologic therapy and chemotherapy less than 3 months prior to
3. Any prior treatment with doxorubicin or other anthracycline.
4. Concurrent or recent (less than 2 weeks prior to Screening) radiotherapy or surgery.
5. Prior glucocorticoid treatment of multiple myeloma exceeding dexamethasone 20mg/day
for a maximum of 7 days. Topical glucocorticosteroid therapy to treat non-malignant
comorbid disorders is permitted.
6. More than or equal to grade 2 peripheral neuropathy according to the NCI-CTC criteria
on clinical examination within 14 days before enrolment (Day 1 of Cycle 1).
7. Evidence of mucosal or internal bleeding and/or platelet counts < 50 x 10^9/l.
Platelet transfusions may not be used to meet PLT eligibility criteria.
8. Absolute neutrophil count (ANC) < 1 x 10^9/l. Growth factors may not be used to meet
ANC eligibility criteria.
9. Hemoglobin < 5.0 mmol/l. The subject may be included after correction of the
hemoglobin level by transfusion or treatment with erythropoietin.
10. Alanine aminotransferase (ALAT) > 2 x ULN.
11. Myocardial infarction within 6 months prior to enrolment or New York Heart
Association (NYHA) Class IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities. Prior to study entry, any ECG abnormality at
screening has to be documented by the investigator as not medically relevant.
12. Clinically relevant active infection or serious co-morbid medical conditions, such as
chronic obstructive or chronic restrictive pulmonary disease, and cirrhosis.
13. Any condition, including laboratory abnormalities, that in the opinion of the
Investigator places the subject at unacceptable risk if he/she were to participate in
14. Prior malignancy except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, in situ breast cancer, or in situ prostate cancer
for which the subject has been disease-free for at least 3 years.
15. Female subject is pregnant or breast-feeding. The first serum pregnancy test to be
done within 10-14 days prior to the study treatment start and repeated serum
pregnancy test to be done within 24 hours prior to the start of study treatment.
16. Female subjects who are of childbearing potential (biologically capable of becoming
pregnant) or men with partners of childbearing potential, who are unwilling or unable
to use effective means of contraception. The means of contraception must be TWO
acceptable methods of birth control, one highly effective method (hormonal
contraceptives pills, injections or implants, tubal ligation, partner's vasectomy)
and one additional effective method (condom, diaphragm, cervical cap) AT THE SAME
TIME, at least 28 days before she or he starts ACVDL and for at least 28 days after
the last dose of ACVDL.
17. Serious medical or psychiatric illness likely to interfere with participation in this
18. Uncontrolled diabetes mellitus at the discretion of the investigator.
19. Hypersensitivity and/or contraindication to any one of the Investigational Medicinal
Products (IMP), acyclovir or similar anti-viral drug.
20. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes).
21. Known HIV infection.
22. Known active hepatitis B or C viral infection.
23. Known intolerance to steroid therapy.
24. Current or recent (within 30 days prior to Screening) treatment with another
25. Unable to comply with the administration of the study treatment.