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Phase II Study of Combination Bortezomib, Dexamethasone, and Rituximab in Previously Untreated Patients With Waldenstrom's Macroglobulinemia: A Multicenter Trial of the European Myeloma Network

Phase 2
18 Years
Open (Enrolling)
Waldenstrom's Macroglobulinemia

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Trial Information

Phase II Study of Combination Bortezomib, Dexamethasone, and Rituximab in Previously Untreated Patients With Waldenstrom's Macroglobulinemia: A Multicenter Trial of the European Myeloma Network

Waldenstrom's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder
characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with
demonstration of an IgM monoclonal gammopathy. This condition is considered to correspond to
the lymphoplasmacytoid lymphoma as defined by the REAL2 and WHO classification systems. WM
is a rare disease, with an incidence that is less frequent than multiple myeloma, and
accounts for approximately 2% of all hematologic malignancies. The age-adjusted incidence
rate is 3.4 per million among males and 1.7 per million among females in the US, with a
geometrical increase with age. Despite continuing advances in the therapy of WM, the disease
remains incurable with a median survival of 5 to 8 years from the time of diagnosis thereby
necessitating the development and evaluation of novel therapeutics. Overall response rates
(ORR) of 30-70% with complete response (CR) rates of up to 10% have been reported with the
use of alkylator agents (e.g. chlorambucil), nucleoside analogues (cladribine or
fludarabine), and the monoclonal antibody rituximab these therapeutic agents in the upfront
therapy of WM with median durations of response averaging 2-3 years. Higher response rates
including CR rates of up to 20% have been reported in studies combining nucleoside analogues
with rituximab, and/or alkylator agents. Importantly, individual patients including the
presence of cytopenias, need for more rapid disease control, age, and in particular
candidacy for autologous transplant therapy should be taken into account in making the
choice of first line therapy. For patients who are candidates for autologous transplant
therapy, and in whom such therapy is seriously considered, exposure to alkylator or
nucleoside analogue therapy should be limited. Monoclonal antibodies have been successfully
used to treat patients with Waldenstrom's macroglobulinemia (WM). Most of these efforts to
date have focused on the use of rituximab, a chimeric IgG1 monoclonal antibody which targets
CD20, an antigen which is widely expressed in WM. Several studies employing standard dose
rituximab therapy have demonstrated major response (>50% reduction in serum IgM) rates of
30%, and durations of response of about 8 months13-17. More recently, the use of extended
schedule rituximab has been evaluated. Time to response after rituximab is slow and exceeds
3 months on the average. In many patients a transient increase of serum IgM may occur
immediately following initiation of rituximab. Such an increase does not herald treatment
failure and most patients will return to their baseline serum IgM by 12 weeks. However,
patients with baseline serum IgM levels of >50g/L may be particularly at risk for a
hyperviscosity-related event. Bortezomib is a small molecule proteasome inhibitor developed
by Millennium Pharmaceuticals, Inc., (MPI) as a novel agent to treat human malignancies.
Bortezomib is currently approved by the US FDA and by the European EMEA for the treatment of
multiple myeloma. By inhibiting a single molecular target, the proteasome, bortezomib
affects multiple signaling pathways. The anti-neoplastic effect of bortezomib likely
involves several distinct mechanisms, including inhibition of cell growth and survival
pathways, induction of apoptosis, and inhibition of expression of genes that control
cellular adhesion, migration and angiogenesis. Thus, the mechanisms by which bortezomib
elicits its anti-tumor activity may vary among tumor types, and the extent to which each
affected pathway is critical to the inhibition of tumor growth could also differ. The
mechanism of anti-tumor activity in NHL is not known; however, bortezomib inhibits the
growth of various human lymphoma cell lines, as well as the survival primary WM cells.
Bortezomib has been administered to patients with WM in the context of prospective studies.
Chen et al administered bortezomib to 16 patients with either untreated or pretreated WM who
had received ≤3 prior regimens. Six of 13 evaluable patients (46%) achieved a partial
response. Dimopoulos et al administered bortezomib to 10 patients with relapsed or
refractory WM. Six of these patients achieved a partial response which occurred at a median
of 1 month. The median time to progression in the responding patients is expected to exceed
11months. The more common toxicities were mild or moderate thrombocytopenia, fever and
fatigue; peripheral neuropathy occurred in 3 patients. The WM Clinical Trials Group (WMCTG)
conducted a Phase II Study (DFCI Protocol 03-248) of single-agent bortezomib in 27 patients
with relapsed or refractory WM. In an interim analysis, the safety and efficacy results for
15 patients who completed at least 2 cycles of therapy were reported.37 Eight and 7 of these
patients had relapsed and refractory disease, respectively. With a median of 3 completed
cycles (range 2-8), 12 of 15 (80%) patients have demonstrated a response with 5 partial
responses (>50% decrease in serum IgM) and 7 minor responses (>25% decrease in serum IgM)
observed. Three other patients remain with stable disease. Therapy was generally well
tolerated with greater than grade II adverse events as follows: neuropathy (n=3; 20%);
neutropenia (n=3; 20%); thrombocytopenia (n=1; 7%); and rash (n=1; 7%). Adverse events were
generally reversible and returned to baseline after holding or dose modifying the study

Bortezomib (velcade) in combination with Rituximab have been shown to act synergistically in
in vitro and in vivo models. Bortezomib plus Rituximab in combination have been used in a
phase 2 clinical study for previously treated patients with indolent non-Hodgkin's lymphoma.
Patients received either Bortezomib 1,3mg/m2 on d1,4,8,11 q21 days (Group A), or Bortezomib
1,6mg/m2 weekly on d1,8,15,22 q35 days (Group B). Rituximab 375mg/m2 was administered weekly
for 4 weeks in all patients. Response rated were similar in groups A and B, but patients in
Group B (weekly bortezomib at increased dose) experienced less toxicity. Furthermore,
glucocorticoids acte synergistically with Rituximab in inducing apoptosis against various
malignant NHL B cell lines. A single dose of dexamethasone administered immediately before
rituximab was adequate for this synergistic effect. Furthermore, we have tested this
sequence in vivo in the context of a prospective trial of dexamethasone, rituximab and
cyclophosphamide for previously untreated patients with WM. This combination induced
responses in 74% of patients. Based on the above we investigate a combination of bortezomib,
dexamethasone and rituximab (BDR) as primary treatment for patients with WM. The following
points are of importance:

A) Only patients who have an indication for treatment will be included and will exclude
asymptomatic patients. This is one of few multicenter trials designed specifically for WM
patients who have a predefined indication for treatment.

B) By avoiding any stem cell toxic agent, we believe that we will be able to collect
adequate number of blood stem cells from our patients≤70 years of age. These stem cells
could be used to support high dose therapy at the time of relapse after BDR.

C) Our previous experience with single agent bortezomib indicates a median time to response
of one month. Thus, by starting treatment with bortezomib alone, we believe that we will
abrogate the "IgM flare" phenomenon that occurs in almost 50% of patients receiving
single-agent rituximab.

D) We will limit the use of dexamethasone to one dose (40mg) just before the administration
of rituximab based on in vitro data. In contrast to multiple myeloma, there is no evidence
that dexamethasone is essential for the treatment of WM. Furthermore repetitive
administration of dexamethasone may be associated with increased risk for opportunistic

E) We plan to administer no more than 5 cycles of bortezomib in order to avoid the increased
incidence of neuropathy which usually occurs with more exposure to bortezomib. Subsequently
the patients will be followed with no treatment until there is evidence of progressive

Inclusion Criteria:

- Clinicopathological diagnosis of Waldenstrom's macroglobulinemia as defined by
consensus panel one of the Second International Workshop on Waldenstrom's
macroglobulinemia.1 All patients with the diagnosis of WM will be evaluable for
response according to the response criteria (section 8.1)

- No prior systemic treatment for WM. Prior plasmapheresis to control hyperviscosity,
is allowed. In that case baseline monoclonal protein levels for assessment of
response will be the levels prior to plasmapheresis, if this is the higher value
prior to treatment initiation

- Patients must have at least one of the following indications to initiate treatment as
defined by "Consensus Panel Two" recommendations from the Second International
Workshop on Waldenstrom's Macroglobulinemia41.

1. Recurrent fever, night sweats, weight loss, fatigue

2. Hyperviscosity

3. Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter)

4. Symptomatic hepatomegaly and/or splenomegaly

5. Symptomatic organomegaly and/or organ or tissue infiltration

6. Peripheral neuropathy due to WM

7. Symptomatic cryoglobulinemia

8. Cold agglutinin anemia

9. Immune hemolytic anemia and/or thrombocytopenia

10. Nephropathy related to WM

11. Amyloidosis related to WM

12. Hemoglobin ≤10g/dL

13. Platelet count <100x109/L

14. Serum monoclonal protein >5g/dL even with no symptoms

- CD20 positive disease based on any previous bone marrow immunohistochemistry or flow
cytometric analysis performed up to 3 months prior to enrollment.

- Karnofsky performance status >=60.

- Life-expectancy >3 months.

- Baseline platelet count >=50 10^9/L, and absolute neutrophil count >= 0.75 10^9/L.

- Meet the following pretreatment laboratory criteria at the Screening visit conducted
within 28 days of study enrollment:

- AST (SGOT): >3 times the upper limit of institutional laboratory normal.

- ALT (SGPT): >3 times the upper limit of institutional laboratory normal.

- Total Bilirubin: >2 times the upper limit of institutional laboratory normal, unless
clearly related to the disease.

- Calculated or measured creatinine clearance: >=30 mL/minute.

- Serum sodium >130 mmol/L.

- 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.

Exclusion Criteria:

- Prior systemic treatment with WM (plasmapheresis is allowed)

- Myocardial infarction within 6 months prior to enrollment or has New York Hospital
Association (NYHA) Class III or 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

- Patient has hypersensitivity to dexamethasone, bortezomib, boron or mannitol.

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

- Cardiac amyloidosis

- Peripheral neuropathy or neuropathic pain grade 2 or higher as defined by NCI CTCAE
version 3

- Women who are pregnant. Women who are breast-feeding and do not consent to
discontinue breast-feeding. Women of childbearing age who are not willing to use
effective anti-conceptive methods for the duration of the study and 6 months
thereafter. Men who do not consent not to father a child during the treatment period
and six months thereafter.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the response rate [the combined complete response (CR) + partial response (PR) + minimal response (MR)] following treatment with BDR in patients with previously untreated WM.

Outcome Time Frame:

Every cycle while on active therapy and thereafter every 3 to 4 months for up to 2 years, or until progression of disease is documented.

Safety Issue:


Principal Investigator

Meletios A Dimopoulos, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Athens, School of Medicine


Greece: National Organization of Medicines

Study ID:




Start Date:

March 2007

Completion Date:

Related Keywords:

  • Waldenstrom's Macroglobulinemia
  • lymphoma
  • Bortezomib
  • Rituximab
  • Waldenstrom Macroglobulinemia