Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma
Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma
This study is for patients with newly diagnosed or relapsed multiple myeloma. The main
 purpose of this study is to see how their disease responds to consolidation treatment
 (treatment aimed at further decreasing cancer cells) with a radioactive antibody (protein)
 called iodine I 131 tositumomab (known by the tradename Bexxar®) and also to look at the side
 effects which occur with this type of treatment. The investigators will also be looking at
 how long disease responds to treatment, if it responds at all, and how long patients who have
 had this treatment survive.

 Bexxar is a monoclonal antibody (protein) to which radioactive iodine 131 is attached. The
 monoclonal antibody in Bexxar (tositumomab), targets a protein called CD20 found on the
 surface of a variety of B-cells, including lymphoma cells, and some myeloma cells. The
 antibody is given as an infusion and finds its way to these cells. The radioactive iodine
 attached to the antibody delivers radiation directly to these cells which works to harm or
 kill the cancer cells. Approximately 20-25% of patients with multiple myeloma have this
 protein on the surface of their tumor cells. In addition, this protein was found on the
 surface of myeloma stem cells. While myeloma stem cells represent a minority of all myeloma
 cells (less than 5%), these cells are resistant to chemotherapy and are believed to be
 responsible for a recurrence of the disease after chemotherapy. In this study, Bexxar will be
 used after patients complete a course of chemotherapy and have residual myeloma cells left in
 their body. The Investigators are hoping that the treatment with Bexxar will decrease and
 possibly eliminate residual myeloma cells resistant to chemotherapy.
Multiple myeloma is ranked second in hematological malignancies in the United States (Munshi
 et al., 2001). Because no curable option exists, patients with early stage disease are
 typically observed without treatment until the disease progresses or symptoms appear.

 The majority of patients will respond to initial chemotherapy, however, all treated patients
 repeatedly relapse with shorter remissions following each subsequent course of chemotherapy
 (Rajkumar et al., 2002a). Regimens most commonly used for initial therapy include melphalan
 and prednisone (MP), which induce remission in approximately 50% of patients (Alexanian et
 al., 1969), VAD-vincristine, adriamycin and dexamethasone with response rates in the 50%
 range (Salmon et al., 1994; Barlogie et al., 1984; Alexanian et al., 1986), dexamethasone
 pulses, and more recently introduced combinations of thalidomide with dexamethasone (Rajkumar
 et al., 2002b; Weber et al., 2003). All these regimens have comparable response rates. With
 the exception of the recent report, which showed a superior response rate to the combination
 of thalidomide with dexamethasone versus dexamethasone pulses (Rajkumar et al., 2004),
 multiple other comparative studies did not show superiority of any of these regimens for
 overall survival. Complete responses to any of these regimens are observed infrequently (<
 5%). Patients who complete initial therapy, usually proceed to high dose chemotherapy with
 autologous stem cell transplant support. Alternatively, patients may be placed on maintenance
 regimen or can be observed. Except for one study with alternate day high dose of Prednisone
 (Berenson et al., 2002), no convincing evidence exists that maintenance impacts the natural
 history of the disease (Kyle, 2002; The Myeloma Trialists' Collaborative Group, 2001).

 High dose chemotherapy has been used as consolidation in multiple myeloma by a number of
 investigators (Barlogie et al., 1986; Cunningham et al., 1994; Harousseau et al., 1995). A
 randomized trial conducted by French Myeloma Intergroup (IFM 90) provided evidence that
 treatment with high dose chemotherapy and autologous stem cell transplant (ASCT) after
 initial therapy results in significantly longer event-free survival (median 28 vs. 18 months)
 and overall survival (57 vs. 42 months) if compared to conventional chemotherapy (Attal et
 al., 1996). The benefit of auto transplantation was seen in patients of all ages (Siegel et
 al., 1999). More recently, similar results were reported from a large randomized study in
 Great Britain (Childs et al., 2003). Based on these studies, in patients eligible for
 transplant, consolidation of initial therapy with high dose therapy followed by ASCT is
 considered a standard of care (NCCN Guidelines 2004). However, ASCT is not curative even in
 patients who achieve complete response (CR), which is observed in 20-30% of patients who
 completed ASCT. Contamination of autologous stem cell collection with malignant myeloma cells
 may play some role. In support of this notion, syngeneic bone marrow transplants showed
 better and more durable outcomes than those seen with ASCT (Gahrton et al., 1999). Another
 reason for failure of autologous stem cell transplant is ineffective eradication of myeloma
 clone with high dose chemotherapy. In an effort to provide more effective elimination of
 malignant clones, some investigators developed intensified treatment regimens. Improved
 results have been reported using Total Therapy, which involves a sequence of treatments,
 including tandem ASCT (Barlogie et al., 1999, Barlogie at al., 2004). The notion that
 intensification of therapy improves outcomes has been validated in a recent randomized study,
 which showed that consolidation of initial therapy with tandem autologous stem cell
 transplant was superior than consolidation with single autologous stem cell transplant as
 measured by an improved duration of responses and overall survival (Attal at al, 2003). In
 contrast to ASCT, allogeneic stem cell transplantation can provide stem cell products free of
 malignant cells, as well as the benefit of graft-versus-myeloma effect.

 However, very high 1-year mortality (30-60%) was reported in early allogeneic bone marrow
 transplant studies, with disease free survival in only 15-30% of patients and no superior
 survival if compared to ASCT (Bensinger et al., 1996; Bjorkstrand et al., 1996; Barlogie et
 al., 1995). More recent studies, including allogeneic transplants with nonmyeloablative
 conditioning regimens, provide more encouraging results (Reynolds et al., 2001; Badros et
 al., 2002). Recently, a combined treatment with ASCT followed by a non-myeloablative
 allogeneic stem cell transplant showed very promising outcomes and improved, although still
 significant toxicity, with CR rates in 55-60% range (Kroger et al., 2002; Maloney et al.,
 2003). It is too early to determine whether improved responses using this approach will
 result in an increased survival.

 Emerging data suggest that achieving CR or near CR (nCR) will result in more durable
 remission and longer survival. Recent analysis of long term outcomes of patients treated on
 randomized French study IMG90 clearly indicates that the longest survivors are those patients
 who achieve at least very good partial response or complete response (Harousseau, 2003). At 7
 years, 60% of patients were alive in a group, which achieved CR or near CR. In contrast, in a
 group of patients who achieved > PR but less than CR or near CR only 30% were alive and among
 patients who had less than PR none were alive. Similar results have bee recently reported for
 patients who underwent allogeneic stem cell transplant (Corradini et al., 2003). It is not
 clear whether CR in response to initial therapy and prior to transplant may have similar
 impact on overall outcomes. Regardless of specific transplant approach, survival curves do
 not plateau and all patients are expected to relapse, regardless of method of intensification
 therapy, possibly due to persistence of residual population of chemotherapy-resistant
 clonogenic myeloma cells.

 For patients who have relapsed or are refractory to therapy, there is no agreed upon standard
 treatment (Anderson et al., 2002; Kyle, 2002). Treatment options include salvage
 chemotherapy, autologous stem cell transplant (if not previously done or as a second
 transplant), or allogeneic stem cell transplant, full or low intensity (Kyle, 2002). Salvage
 chemotherapy is most widely used in clinical practice. Among a variety of salvage regimens,
 both monotherapy and combination therapy have been applied. Monotherapy with Dexamethasone or
 other steroids administered as pulse therapy produced responses in the 35-40% range
 (Alexanian et al., 1983; Gertz et al., 1995). Thalidomide used as a single agent showed a 32%
 response rate in this patient population (Singhal et al., 1999). More recently, VELCADE as a
 single agent induced at least minimal responses (i.e. > 25% reduction in monoclonal protein)
 in 35% of patients and at least a stabilization of the disease in 59% of patients with
 relapsed/refractory multiple myeloma using strict SWOG criteria (Richardson et al., 2003).
 Combination therapies historically show higher response rates. VAD has been demonstrated as
 an effective regimen in patients refractory to alkylating agents, with response rates of 60%
 (Lokhorst et al., 1989). A similar regimen called DVd, with Doxil, Vincristine, and
 dexamethasone, showed comparable efficacy and acceptable toxicity (Hussein et al., 2002;
 Rifkin et al., 2004). Newer combinations, including combinations of VELCADE, thalidomide, and
 Revlimid (analog of thalidomide) are promising, and appear to be able to induce higher
 response rates and complete remissions as per unpublished yet reports from different meetings
 (Agarwal et al, 2003; Orlowski et al, 2003, Richardson et al, 2003; Richardson et al., 2004).

 Clonogenic Multiple Myeloma Cells:

 Myeloma is characterized by an accumulation of malignant plasma cells in bone marrow.
 Numerous observations indicated that malignant plasma cells have low proliferative capacity
 and it is believed that the vast majority of the malignant cell population in myeloma is
 represented by terminally differentiated plasma cells, similar to their normal counterparts
 (Barlogie et al., 1989). It is unclear whether these terminally differentiated malignant
 plasma cells are capable of self-renewal. During the past decade, several studies indicated
 that multiple myeloma, similarly to other malignancies, may consist of heterogenous
 population of malignant cells (Bakkus et al., 1994; Billadeau et al., 1996).

 Clonotypic studies identified a population of circulating B-cells in blood samples of
 patients with myeloma (Bergsagel et al., 1995, Chen and Epstein, 1996), sharing the same
 clonotypic CDR3 region as is detected in the bone marrow malignant plasma cells (Pilarski et
 al, 1996, Szczepek et al., 1998). Further studies provided additional insights into the
 evolution of the myeloma clone supporting a notion of heterogeneity of the population of
 clonal cells in myeloma (Taylor et al., 2002). The B-cell component of the myeloma clone
 appeared to be clonogenic in xenografted mice (Pilarski et al., 2000; Reiman et al., 2001).
 Moreover, clonotypic cells with B-cell phenotype express CD19+/CD20+ antigens and may
 represent a reservoir of disease that persists after therapy, including high dose
 chemotherapy (Kiel et al., 1999; Rottenburger et al., 1999; Pilarski et al., 2002).

 The majority of myeloma cells express CD138, a highly specific surface antigen of terminally
 differentiated plasma cells, which is absent on highly proliferative normal plasmablast and
 earlier stages of B-cells (Jego et al., 2001). Based on these observations, it was
 hypothesized that clonogenic myeloma cells should lack CD138 expression. Using CD138+ and
 CD138- subsets of cells isolated from myeloma cell lines and from primary myeloma patient
 samples, Matsui et al. (2004), showed that only a minority of all myeloma cells have CD138-
 phenotype (<5%). However, only CD138- have clonogenic potential, as demonstrated in colony
 formation assays in methylcellulose and after transplantation to NOD/SCID mice. Moreover,
 these cells express B-cell antigens, including CD19 and CD20 and their growth could be
 inhibited by in vitro treatment with rituximab, an antibody directed against CD20 antigen
 (Matsui et al., 2004).

 Rationale for anti-CD20 Therapy in Myeloma:

 Recent observations that clonogenic cells in myeloma express CD20 (Kiel et al, 1999,
 Rottenburger et al, 1999) and that their growth could be inhibited in vitro by rituximab, an
 anti-CD20 antibody (Matsui et al, 2004), provides a rationale for using CD20-directed therapy
 in patients with myeloma. Moreover, CD19+/CD20+ clonotypic cells appear to be more refractory
 than CD19-/CD20- cells to commonly used chemotherapy regimens in myeloma including high dose
 therapy with stem cell transplant (Kiel et al., 1999, Rottenburger et al, 1999). Therefore,
 CD20+ directed treatment of myeloma would complement chemotherapy by targeting chemoresistant
 clonogenic myeloma cells.

 Previous studies showed that therapy with Rituximab, unlabeled anti-CD20 antibody, could be
 active in multiple myeloma (Hussein et al. 1999, Treon et al, 2002).

 In this study, we propose to apply therapy with Bexxar, a radiolabeled anti-CD20 antibody.
 Bexxar Therapeutic Regimen is composed of the murine anti-CD20 monoclonal antibody
 Tositumomab and Iodine I 131 Tositumomab. Iodine I 131 Tositumomab is a radio-iodinated
 derivative of Tositumomab that has been covalently linked to Iodine-131.

 We hypothesized that radiolabeled anti-CD20 antibody will be more efficacious than unlabeled
 antibody (i.e. rituximab) in eradication of highly radiosensitive myeloma cells, similarly to
 what was observed in non-Hodgkin's lymphoma (Horning et al., 2000; Davis et al, 2001 Flinn et
 al, 2001; Witzig et al, 2002). It is presumed, that higher efficacy of radiolabeled anti-CD20
 antibody, if compared to unlabeled antibody, may be due to "crossfire effect" as the
 radiation is delivered not only to target cells but also to neighboring cells, both
 expressing and not-expressing CD20 (Vose et al, 1999). In the proposed design, we will apply
 Bexxar after completion of a course of initial chemotherapy for newly diagnosed patients or a
 course of salvage chemotherapy, provided that patients achieve at least partial response to
 prior therapy (i.e. > 50% reduction of tumor mass) and reach a plateau of their response to
 prior therapy. By using patients in a period of stable disease, we will have a better chance
 to observe the effects of radioimmunotherapy against CD20+ cells, which represent a minority
 of all malignant cells. In addition, we will evaluate the impact of Bexxar therapy on
 clonogenic myeloma cells using clonogenic assays as described in Methods.

 We anticipate that majority of newly diagnosed patients will be eligible and will
 subsequently proceed to autologous stem cell transplant as part of standard therapy of
 myeloma (NCCN Guidelines 2004) if, as hypothesized, bexxar treatment does have the potential
 to eliminate clonogenic myeloma stem cells; stem cells collected post-bexxar treatment should
 be depleted of re-populating myeloma cells. Therefore, this combination of chemotherapy and
 targeted therapy against clonogenic cells may have a potential of eliminating myeloma clones.
 Although stem cell collections and autologous stem cell transplants have been used without
 apparent difficulties in the past in patients treated with anti-CD20 radio-conjugates
 (Ratanatharatorn et al, 2001; Kaminski et al, 2001; Ansell et al, 2002), we plan to collect
 backup stem cells prior to treatment with Bexxar, to allow to proceed with the standard stem
 cell transplant in the unlikely cases of failure of collection of stem cells post-Bexxar.
 Anti-CD20 radioimmunotherapy was previously used in combination with chemotherapy without
 additional toxicity (Emmanoulides et al, 2001; Gregory et al, 2001, Press et al, 2003).

 Radioimmunotherapy of B-Cell Malignancies:

 Radiolabeled monoclonal antibodies are efficacious in treating B-cell malignancies for the
 following reasons: B-lymphocytes, lymphoma, and myeloma cells are inherently sensitive to
 radiotherapy (Parker et al, 1980); the local emission of ionizing radiation by radiolabeled
 antibodies may kill cells with or without the target antigen in close proximity to the bound
 antibody; and penetrating radiation may obviate the problem of limited access in bulky or
 poorly vascularized tumors.

 Early investigations of therapeutic radiolabeled antibodies for B-cell lymphoma were
 performed with iodinated antibodies (Press et al, 1989; Kaminski et al, 1993; Wahl et al,
 1994; Press et al, 1995). Currently, two treatment regimens have been approved for treatment
 of relapsed/refractory and transformed follicular lymphoma. The Bexxar Treatment Regimen
 includes murine anti-CD20 antibody Tositumomab iodinated with Iodine I 131. The Main
 anti-tumor effect comes from high energy beta particles emitted by I 131. In addition, I 131
 is emitting also low energy gamma radiation, allowing for gamma camera measurements and
 calculation of individualized dose of radioactive tracer for a given patient during
 therapeutic phase (see below). In Zevalin, a murine anti-CD20 antibody ibritumomab is
 covalently linked to 90Yttrium (90Y), which is a pure beta emitter. Lack of gamma radiation
 from 90Y does not allow for dosimetric assessments and a fixed dose of Zevalin is used for
 all patients based on their weight. This can possibly result in either under- or overdosing
 of some patients.

 In addition to treatment of follicular lymphoma, ongoing studies explore a possibility of
 treatment with either Bexxar or Zevalin of other B-cell malignancies. In particular,
 anti-CD20 radioimmunotherapy appears very promising as part of treatment of mantle cell
 lymphoma, large cell lymphoma, and Waldenstrom's macroglobulinemia.

 Iodine I 131 Tositumomab

 Background:

 Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen,
 which is found on the surface of normal and malignant B lymphocytes. Tositumomab is produced
 in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy
 chains of 451 amino acids each and two lambda light chains of 220 amino acids each. The
 approximate molecular weight of Tositumomab is 150 kD. In vitro studies have demonstrated
 that upon binding to the CD20 antigen, Tositumomab is capable of inducing apoptosis. In
 addition, Tositumomab induces antibody-dependent cellular cytotoxicity (ADCC) and
 complement-dependent cellular cytotoxicity (CDC). Iodine I 131 Tositumomab is a
 radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131.
 Unbound radio-Iodine and other reactants have been removed by chromatographic purification
 steps. This agent produces its cytotoxic effect through the antitumor effects of ionizing
 radiation, as well as the more direct antitumor effects of the antibody. The goal of
 treatment with Iodine I 131 Tositumomab is selective delivery of radiotherapy to
 radiosensitive malignant cells, thus minimizing toxicity to the normal organs.

 Bexxar Clinical Experience:

 The dosing regimen and maximally tolerated dose of Bexxar were established in a phase I/II
 single-center study conducted at the University of Michigan (Kaminski et al, 2000). The
 RIT-II-001 trial included 47 patients and was designed to validate the dosing methodology
 developed at Michigan (Vose et al, 2000). The RIT-II-002 trial randomized 78 patients to
 receive either the tositumomab and I 131-tositumomab regimen or the unlabeled tositumomab to
 determine the value added of the radionuclide component (Davis et al, 2001). Patients treated
 on the radiolabeled antibody arm showed a higher overall response rate (OR = 55% vs. 19%) and
 complete response rate (CR = 33% vs. 8%). The RIT-II-004 study enrolled 60 patients with
 chemotherapy-refractory disease (no response or response lasting less than 6 months to the
 last chemotherapy received) to assess the efficacy of the Bexxar therapeutic regimen in this
 patient population (Kaminski et al, 2001). The number of patients who achieved longer
 duration of response to Bexxar was about 5 times higher than the number of patients who had a
 longer duration to chemotherapy (p <0.001). In addition, patients treated with Bexxar
 achieved a higher overall response (OR) rate (47% vs. 12%) and complete response (CR) rate
 (20% vs. 2%) than patients treated with chemotherapy. In summary, all 4 initial studies,
 including the Phase I/II trial, showed high response rates and duration of responses in
 patients with relapsed or refractory low grade or follicular lymphoma, including transformed
 follicular lymphoma previously-treated with chemotherapy. Most remarkably, patients who
 achieved complete responses experienced often particularly long duration of responses lasting
 for years. In recognition of remarkable activity, the FDA approved an expanded indication for
 the Bexxar Therapeutic Regimen on January 3, 2005.
Inclusion Criteria:

 -  Age ≥ 18 years

 -  Expected survival ≥ 6 months

 -  Pre-study performance status of 0, 1, or 2 according to the World Health Organization
 (WHO)

 -  Newly diagnosed or relapsed/refractory myeloma with histologic confirmation of
 multiple myeloma by the Department of Pathology at University of Michigan Cancer
 Center (UMCC)

 -  Not more than 3 lines of therapy for myeloma for patients with relapsed disease

 -  Documented Stage II or III multiple myeloma (Durie and Salmon, 1975) prior to
 initiation of first line therapy

 -  At least 4 cycles of first line (for newly diagnosed patients) or salvage (for
 relapsed/refractory patients) prior therapy and in a plateau of at least partial
 response (Blade et al, 1999) for at least 2 determinations 6 weeks apart

 -  At least 21 days from day 1 of the last cycle and fully recovered from all toxicities
 associated with prior surgery, radiation treatments, chemotherapy, or immunotherapy

 -  Measurable M-proteins with greater than 1 g/dl serum monoclonal protein and/or greater
 than 0.5 g/24 hour urine light chain excretion

 -  Acceptable hematologic status within two weeks prior to patient registration,
 including:

 -  Absolute neutrophil count ([segmented neutrophils + bands] x total white blood
 cell [WBC]) ≥ 1,500/mm3;

 -  Platelet counts ≥ 150,000/mm3; these patients will receive total body dose of 75
 cGy of Bexxar; or

 -  Platelet counts from 100,000/mm3 to 149,000/mm3; these patients will receive a 65
 cGy total body dose of Bexxar;

 -  In patients previously treated with ASCT, total body dose will be 55 cGy in
 patients with platelet count > 150,000 and 45 cGy in patients with platelets
 100,000-149,000.

 -  Female patients who are not pregnant or lactating

 -  Men and women of reproductive potential who are following accepted birth control
 methods (as determined by the treating physician)

 -  Patients previously on Phase II drugs if no long-term toxicity is expected, and the
 patient has been off the drug for three or more weeks with no significant post
 treatment toxicities observed

 -  Patients determined to have < 25% bone marrow involvement with myeloma within six
 weeks of registration (based on bilateral core biopsy).

 Exclusion Criteria:

 -  Patients with impaired bone marrow reserve, as indicated by one or more of the
 following:

 -  Platelet count < 100,000 cells/mm3;

 -  Hypocellular bone marrow;

 -  Marked reduction in bone marrow precursors of one or more cell lines
 (granulocytic, megakaryocytic, erythroid);

 -  History of failed stem cell collection;

 -  Myelodysplastic syndrome (MDS) or evidence of other than myeloma clonogenic
 abnormalities;

 -  Prior radioimmunotherapy;

 -  Prior anti-CD20 therapy;

 -  Other than myeloma malignancy, except B-cell non-Hodgkin's lymphoma, basal and
 squamous cell carcinoma of the skin, and cervical and breast cancer in situ,
 unless patient is cancer free for > 3 years;

 -  Central nervous system (CNS) involvement;

 -  Patients with known HIV infection;

 -  Patients with pleural effusion;

 -  Patients with abnormal liver function: total bilirubin > 2.0 mg/dL;

 -  Patients with abnormal renal function: serum creatinine > 2.0 mg/dL;

 -  Patients who have received prior external beam radiation therapy to > 25% of
 active bone marrow (involved field or regional);

 -  Patients who have received G-CSF or GM-CSF therapy within two weeks prior to
 treatment;

 -  Serious nonmalignant disease or infection which, in the opinion of the
 investigator and/or the sponsor, would compromise other protocol objectives;

 -  Major surgery, other than diagnostic surgery, within four weeks;

 -  Presence of anti-murine antibody (HAMA) reactivity. This result must be available
 prior to receiving treatment for those patients with prior exposure to murine
 antibodies or proteins.