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Bone Effect of Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma

Phase 2
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

Bone Effect of Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma

Multiple myeloma (MM) accounts for approximately 1% of all malignancies and 10% of
hematological tumors, representing the second most frequently occurring hematological
malignancy in the United States. At any one time, 50,000 people suffer from MM, and
approximately 15,000 are diagnosed each year. The median age is approximately 65 years,
although occasionally MM occurs in the second decade of life. Myeloma is a disease of
neoplastic plasma cells that synthesize abnormal amounts of immunoglobulin or immunoglobulin
fragments. Myeloma is the only hematological malignancy associated with bone disease.
Myeloma is a B-cell neoplasia characterized by clonal expansion of plasma cells in the bone
marrow. It is the most malignant stage of plasma cell dyscrasias, which also include the
precursor stages of MGUS and indolent or smoldering myeloma. Myeloma is frequently
associated with lytic bone disease that is responsible for the most debilitating
manifestations of the disease, including bone pain and fractures.

Bone disease in myeloma results from the activation of osteoclast and suppression of
osteoblast activity in the myelomatous bone marrow. Change in bone turnover rates, expressed
as increased osteoblastic and osteoclastic activity, precede the progression pf MGUS or
smoldering myeloma to overt myeloma by as long as three years.

Treatment with bisphosphonates reduces bone resorption and also to some degree, bone
formation, and over the long-term moderately increases bone density. Other approved
antiresorptive therapies have been shown to reduce the risk of fracture in osteoporotic
women, but none have been shown to restore normal bone mass or strength. As a result,
treatments that directly stimulate bone formation may overcome these limitations, increase
bone mass, and improve the quality of life of myeloma patients. Bone disease is responsible
for the most severe complications associated with multiple myeloma. As treatment and
survival of myeloma patients improve, new therapies to improve complications are important
and vitally needed VELCADE™ (bortezomib) for Injection is a small molecule proteasome
inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to
treat human malignancies. VELCADE is currently approved by the United States Food and Drug
Administration (US FDA) and it is registered in Europe for the treatment of multiple myeloma
patients who have received at least one prior therapy.

The clinical response to bortezomib observed in a 63-year-old woman with multiple myeloma
and the parallel increase in alkaline phosphatase (ALP) has led us and other groups to
evaluate the correlation between bone anabolism and myeloma response to bortezomib. After
similar elevations were noted in patients responding to bortezomib, thalidomide,
dexamethasone combination, ALP levels were analysed in two large bortezomib trials (Roodman,
2008). Giuliani and coworkers (2007) found that bortezomib significantly increased the
activity of the critical osteoblast transcription factor, RUNX2, in human osteoblast
precursors and stimulated bone nodule formation in vitro. Importantly, they found a
significant increase in the number of osteoblasts per mm2 of bone tissue and the number of
RUNX2 positive osteoblastic cells in marrow biopsies from myeloma patients that responded to
bortezomib. Again, the effect on osteoblasts was only seen in patients whose myeloma
responded to bortezomib, making it difficult to distinguish if the increase in osteoblast
activity was due to the anti-myeloma effects of bortezomib or direct effects on osteoblasts
or both. Terpos and colleagues (2006) have reported that bortezomib also decreased DKK1 and
RANKL concentrations and normalized bone remodeling indices in the serum of patients with
relapsed myeloma. However, the majority of patients that showed an increase in bone
formation markers also showed an antitumor response to bortezomib, making it unclear if the
stimulatory effects on bone formation were secondary to the effects of bortezomib on myeloma
or due to direct effects on osteoblast differentiation After similar elevations were noted
in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels
were analysed in two large bortezomib trials.

We first completed a retrospective analysis of large Phase 3 trials comparing ALP levels in
responders (≥PR) vs nonresponders (≤PR) patients.

Data obtained from the APEX Crest and Summit protocols, have shown that a total of 85
myeloma patients were treated with bortezomib at the dose of 0.7 mg/m2 for different reasons
with significant antimyeloma efficacy for multiple cycles. This dose (0.7 mg/m2) will be
used in this trial to test if the antimyeloma activity of bortezomib is still associated to
bone anabolic effect. Data for the APEX, summit, and CREST trials is on file at Millennium

Given that this study is a continuation of a previous protocol (UARK 2004-22) when at the
dose of 1.3 and 1.0 mg/m2 an antimyeloma effect and associated bone formation were observed.
This trial will test the effect of 0.7 mg/m2 (which has been shown to be effective on
antimyeloma treatment) on bone formation to determine the minimal dose associated to bone

Inclusion Criteria:

1. History of histologically documented MM with relapsed or progressive disease after at
least one line of prior therapy.

2. Patient has measurable disease in which to capture response, defined as one or more
of the following:

1. Serum M-protein level > 1.0 gm/dl (10.0 g/L) measured by serum protein
electrophoresis or immunoglobulin electrophoresis; or

2. Urinary M-protein excretion > 200 mg/24 hrs; or

3. Bone marrow plasmacytosis of > 30% by bone marrow aspirate and/or biopsy; or

4. Serum Free Light Chains (By the Freelite test) > 2X ULN, in the absence of renal

5. Radiographic evidence of disease

3. Performance status of < 2 as per ECOG scale, unless PS of 3-4 based solely on bone

4. Patients must have a platelet count > 100,000/L and an ANC of at least 1,000/μl.

5. Patients must have adequate renal function defined as serum creatinine ≤2.5 mg/dL.

6. Patients must have adequate hepatic function defined as serum transaminases and
direct bilirubin < 3 x the upper limit of normal.

7. Male or female adults of at least 18 years of age.

8. 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.

9. Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

10. Growth factors are allowed during the study

11. Male subject agrees to use an acceptable method for contraception for the duration of
the study.

Exclusion Criteria:

1. Platelet count of <100x 10(9)/L within 14 days before enrollment.

2. Absolute neutrophil count (ANC) <1.0 x 10(9)/L

3. Serum creatinine ≥ 2.5 mg/dL within 14 days before enrollment.

4. Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment.

5. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see section 1.4), 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.

6. Patients with a history of treatment for clinically significant ventricular cardiac

7. Patient has hypersensitivity to bortezomib, boron or mannitol.

8. Chemotherapy or radiotherapy received within the previous 4 weeks of study

9. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women.

10. Patient has received other investigational drugs with 14 days before enrollment

11. Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

12. Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

13. POEMS Syndrome

14. Clinically significant hepatic dysfunction as noted by bilirubin or AST > 3 times the
upper normal limit or clinically significant concurrent hepatitis.

15. Uncontrolled, active infection

16. Patients that have taken bisphosphonates within 30 days of screening will not be
eligible for this trial.

17. Must not have received VELCADE 90 days prior to enrolling in this trial.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the effect of Velcade at 0.7 mg/m2 dose on inducing osteoblast activation as measured by ALP and other bone markers in patients with relapsed/refractory myeloma.

Outcome Time Frame:

January 2012

Safety Issue:


Principal Investigator

Maurizio Zangari, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Huntsman Cancer Institute


United States: Institutional Review Board

Study ID:




Start Date:

January 2010

Completion Date:

December 2013

Related Keywords:

  • Multiple Myeloma
  • Cancer
  • Hematologic malignancy
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Huntsman Cancer Institute Salt Lake City, Utah  84112