Dr. Kenneth Anderson opened the session by thanking Dr. Doug Joshua for stimulating academic excitement surrounding multiple myeloma therapy.
Dr. Paul Richardson made the first presentation at Tuesday’s plenary sessions reviewing preclinical and clinical study trial results of bortezomib (Velcade®), the first drug in the class of proteasome inhibitors. Bortezomib represents an important advance in the treatment of multiple myeloma (MM), increasing chemosensitivity of myeloma cells and decreasing chemoresistance and apopotosis. When used in combination with dexamethasone, bortezomib is able to overcome chemoresistance to other agents, including doxorubicin, melphalan, and dexamethasone. Preclinical trial results showed the success and tolerability of bortezomib therapy. SUMMIT, a Phase 2 study in 202 relapsed, refractory (RR) MM patients who had received prior treatment, evaluated the responses to bortezomib (1.3 mg/m2 IV bolus x 8 cycles) using European Group for Blood and Marrow Transplantation criteria. Overall, 35% of patients achieve a response to bortezomib monotherapy; 24% achieved stable disease, and side effects were reported as manageable. Notably, responses were independent of the number of types of prior treatment regimens with 89% of patients with a complete response (CR) being refractory to prior treatment. The responses achieved with bortezomib were durable, lasting for more than 1 year after the 23 month follow up period. The median overall survival (OS) was 16 months and the median time to progression (TTP) was 7 months. CREST, another Phase 2 study, looked at 2 doses of bortezomib (1.0 or 1.3 mg/m2) using the same treatment pattern and response criteria as SUMMIT. Patients receiving 1.0 mg/m2 bortezomib monotherapy had similar response rate to the SUMMIT trial (33%) while combination therapy (bortezomib + dexamethasone) showed a higher response rate (44%). In comparison, the higher dose of bortezomib (1.3 mg/m2, same dose as SUMMIT trial) showed higher response rates for both monotherapy (50%) and combination therapy (62%). The responses were durable and similar to the SUMMIT trial. In both Phase 2 trials, side effects were tolerable with peripheral neuropathy (PN) being the most clinically-significant side effect and thrombocytopenia being the most common side effect.
Dr. Richardson then discussed the results of APEX, a key international Phase 3 trial in 669 RR MM patients looking at bortezomib using the same treatment pattern and response criteria as SUMMIT for the first 8 cycles. Bortezomib showed a 78% improvement in median TTP. Response rates were significantly higher for bortezomib monotherapy (38%) compared with combination therapy with dexamethasone (18%). Patients receiving bortezomib had a 41% decreased risk of death and a significant improvement in OS. Notably, patients who received bortezomib following first relapse, making bortezomib second line therapy, had a significant TTP benefit, superior response rat, and a survival advantage. Overall, the safety profile was good with expected and manageable toxicities observed for bortezomib and dexamethasone. The exception was an increased occurrence of herpes zoster in patients receiving bortezomib. To address PN, bortezomib dose was reduced to 1mg/m2 or bortezomib therapy was delayed until resolution of PN symptoms. Dr. Richardson noted that 69% of patients had underlying PN at the time they enrolled in the study. Dr. Richardson closed his presentation by providing insights into future therapies: combination therapies of novel agents and developing therapies which have the goal of enhancing effectiveness and minimizing toxicity.
Dr. Donna Weber followed Dr. Richardson on the podium to discuss lenalidomide (CC-5013, RevlimidTM) and other IMIDS. She reviewed the benefits and limitations of thalidomide therapy to establish the rationale for the development of lenalidomide. In a Phase 2 clinical trial comparing 15mg bid and 30 mg qd lenalidomide, 24% of patients in both treatment groups responded; switching to once-daily dosing minimized side effects. In a large international study in RR MM patients who received <3 prior treatments, lenalidomide and dexamethasone were administered for 4 courses of treatment or until progression of disease. The majority of patients in this trial had stage 3 disease and one third had bone marrow involvement. Lenalidomide showed better responses than lenalidomide + dexamethasone or dexamethasone monotherapy. A 5-fold higher response was seen with lenalidomide + dexamethasone. Common toxicities were present throughout the study; thromboembolic events were more frequent in the North American centers than in the European centers. A study investigating the effects of lenalidomide + dexamethasone in patients previously untreated for MM is enrolling patients. Preliminary results are strong, showing a complete response (CR)/partial response (PR) of 85% and expected manageable toxicities. Dr. Weber ended her presentation by identifying future trials planned for lenalidomide therapy.
Dr. Mohamad Hussein presented findings on the use of pegylated doxorubicin in combination with immune modulators in the management of MM. Dr. Hussein shared results from studies using doxil, vincristine, and reduced-schedule decadron (DVd) that showed a significant reduction of angiogenic activity. Response rates in newly-diagnosed patients were 88%, but with a low CR and near CR (NCR) of less than 2%. In relapsing or refractory patients, overall response was 22% and NCR was less than 5%. In combination with immunomodulator, thalidomide, DVd resulted in a high response rate of 46% for newly-diagnosed patients and 47% for relapsing/refractory patients.
Dr. Hussein pointed to the use of prophylactic supportive care in this regimen to manage side effects of neutropenia, infections, and deep vein thrombosis (DVT). Having achieved these results, a new study combining DVd and lenalidomide (Revlimid [R]) was initiated in relapsed/refractory patients. Patients achieved a CR/NCR of 37%, PR of 45%, and 13% of patients had stabilizing disease. At a 1-year median follow up overall survival was 80%. Dr. Hussein concluded that the DVd-R regimen was extremely effective resulting in improved patient outcomes.
Dr. Paul Richardson put forth his second presentation in this session. He described the preliminary results from a Phase 1 study initiated to determine the safety and efficacy of bortezomib in combination with lenalidomide (Revlimid) in patients with relapsed and refractory MM. Because both agents are antiangiogenic and have immunomodulatory effects, the expectation was that the combination would overcome resistance to therapy and enhance overall efficacy. Dr. Richardson shared the impressive response results of the 12 patients accrued to date91% (CR + PR + minor response [MR]), suggesting the feasibility of using novel agents in a heavily pre-treated population. Dr. Richardson indicated that the future trials will include a Phase 2 study in relapsed/refractory patients and a Phase 2 in newly-diagnosed patients.
Dr. Kenneth Anderson closed the plenary session with an overview of new therapies and directions in the treatment of MM. New therapies are now targeting three areas: the MM cell and bone marrow microenvironment, the MM cell, and the bone marrow microenvironment. Agents targeting the MM cell and microenvironment include proteosome inhibitors (such as bortezomib), immunomodulatory drugs, histone deacetlyase inhibitors, and VEGF inhibitors. Drugs targeting the MM cell surface include IGF-1R tyrosine kinase inhibitor and CD40 antibody; heat-shock protein (HSP)-90 is targeting the cell cytoplasm and mitochondria, while telomerase inhibitor is targeting the cell nucleus. Drugs targeting the microenvironment include p38MAP kinase inhibitor and IKK inhibitors. The hope is that combining novel drugs will overcome resistance and reduce side effects. Dr. Anderson positioned MM as a model for new drug development in the evolving paradigm targeting both the tumor cell and bone marrow microenvironment.
Dr. Melissa Alsina opened Plenary Session 6 with a discussion about the influence of the tumor microenvironment on drug response and drug resistance in multiple myeloma. She identified that drug resistance, both de novo and acquired, limits the success of MM therapies. Drug resistance is accommodated by multiple mechanisms, including increases in DNA repair, altered drug targets, decreased drug accumulation, decreased drug uptake, metabolic changes in cells, and increased efflux of drugs from cells. The microenvironment of tumors, including the bone marrow (BM) and cell adhesion molecules (CAM) likely influence drug interactions with cells and confer drug resistance (cell adhesion mediated drug resistance, CAM-DR). Dr. Alsina and associates, as well as other investigators, use in vitro cell models of drug resistance to determine the causes of drug resistance and to develop therapies or strategies to avoid drug resistance. These models demonstrate that the interaction of myeloma cells with BM or certain molecules (fibronectin, FN) leads to resistance to drugs. When cells from MM patients were tested in these models and exposed to melphalan, the cells were protected from the effects of melphalan. Researchers are investigating whether interaction between myeloma cells and FN may alter the expression of genes that may in turn influence cell survival or de novo drug resistance. Another area of research focuses on comparing de novo and acquired drug resistance. Data suggests that de novo and acquired drug resistance operate by different mechanisms and by expression of different genes and that acquired drug resistance is a more complex process. The clinical relevance of these findings is that the microenvironment of the tumor may influence its ability to survive. Inhibiting interactions between the microenvironment and tumor cells may enhance therapeutic effect of drugs. Dr. Alsina closed by suggesting that tumor microenvironment and drug resistance mechanisms should be explored when developing new drugs.
Dr. Vincent Rajkumar provided an overview of recent literature on angiogenesis in myeloma. Angiogenesis is a striking characteristic of MM and is associated with disease progression, poor prognosis, and low survival rates as myeloma cells take over the bone. The abnormal blood vessels resulting from angiogenesis provide blood supply for the MM tumor to grow. Across the range of normal patients, those with MGUS, smoldering MM (SMM), and MM, the density of microvessels in the BM increases and correlates with progression of disease. Potential therapies targeting angiogenesis include antibodies that inhibit angiogenesis and molecules that inhibit specific growth factors. Cells from MGUS patients and myeloma patients express both growth factors and growth factor receptors. These cells respond differently to the growth factors and the growth factors and growth factor receptors do not appear to be the only influence on angiogenesis. Recent data suggest that inhibition, or lack of inhibition, of angiogenesis may be the key difference between MGUS and MM cells. Dr. Rajkumar’s group recently characterized the angiogenic inhibitory activity of MGUS, SMM, and MM cells. The inhibitor activity decreased from 63% for MGUS to 43% for SMM and 4% for MM cells, correlating with the progression of MM. Dr. Rajkumar’s group is continuing to investigate the inhibition of angiogenic activity in the various cell types involved in MM.
Dr. Guido Tricot continued the presentations by reviewing recent studies on new antiangiogenic agents. In a dose escalation trial, one third of patients achieved a partial remission and approximately one third of patients had a 5-year event-free survival (EFS) with few having evidence of disease at more than 6 years. A trial with revlimid in patients, most of who had relapsed after autotransplantation, showed an EFS of 43% and an overall survival of 66%. The most common toxicity observed was thrombocytopenia. Another trial is looking at the combination therapy revlimid, thalidomide (dose escalated), and dexamethasone. In this trial, 60% of patients had greater than a 50% response. No correlation between thalidomide dose and event free survival was seen. Commonly observed toxicities were mainly hematological events. These studies suggest that combination therapy may provide the best response.
Dr. Ivan Van Riet discussed the molecules that could control disease development, specifically discussing VEGF and PDGF signaling by receptor tyrosine kinase inhibitors (RTKI). In a model system, Dr. Van Riet showed the ability of MM cells to stimulate angiogenesis and increase microvessel density (MVD). RTKI impaired myeloma cell-mediated blood vessel formation in an in vitro system. Using an in vivo mouse model, administration of RTIs resulted in a significant reduction in MVD. These data suggest that RTKIs may be able to inhibit microvessel formation.
Dr. Irene Ghobrial closed the session discussing the molecular mechanism involved in homing and migration of plasma cells to the bone marrow. The therapeutic implication is the delay or prevention of disease progression in early MM. By mobilizing MM cells from BM to the peripheral blood (PB), the cells may become a target for chemotherapeutic agents; while the cells are in the BM, they are protected. Dr. Ghobrial proposed a model homing plasma cells into and out of the BM by inducing growth factors to push the myeloma cells into the vascular space and allowing recirculation. In the future, other specific pathways of migration and the molecules that trigger the migration may be targets for drug development.
This focus session presented insights into the biology, oncogenesis, and treatment of Waldenstrom's Macroglobulinemia (WM) with additional discussions on amyloidosis, cryoglobulinemia, POEMS, and gammopathy-associated neuropathy. Dr. Linda Pilarski opened the session with an overview of WM, which accounts for 2% of hematologic malignancies and has a median survival of 5 years. WM is characterized by lymphoplasmacytic lymphoma and IgM monoclonal gammopathy. Malignant WM cells express a B cell marker (CD20), sIgM, and sIgD. As discussed in Plenary Session 6, hyaloronan synthetase 1 (HAS1) synthesizes hyaluronan (HA), an extracellular matrix protein that is involved in cell signaling and in malignant progression. In WM, HAS1 is overexpressed and undergoes aberrant genetic splicing. She and her associates researched the effect of this abnormal splicing and speculate that abnormalities and mutations in HAS1 may play an important role in WM oncogenesis.
Dr. Steven Treon followed with his presentation with an update from the Third International Workshop on WM (Paris, France). Dr. Treon shared the early reports of a strong link to familial WM. In a study of 257 patients, 1 out of 5 patients have a first degree relative with WM or a B-cell disorder. Interestingly, patients with familial link also present symptoms at an earlier age, almost a decade before other patients with WM. Dr. Treon’s studies revealed significant abnormalities in 4 genes that are expressed in WM: BLIMP1, BCL6, PAX5, and XBP1. Additionally, WM patients tend to have excess bone marrow mast cells (BMMC), which express CD40L, a potent ligand that induces B-cell growth. With this information, several studies are in place to target BMMC or block CD40L. Treatment options include the use of monoclonal antibody, rituximab, with chemotherapy, and in combination with novel agents such as thalidomide and CC-5013 (Revlimid). Data from these studies are to be presented at the 2005 American Society of Hematology meeting. Additional studies for the relapsed/refractory patient involve the use of alemtuzumab or bortezomib. An interesting and more recent study is underway investigating the use of sildenafil (Viagra) in patients with WM.
Dr. Meletios Dimopoulous offered an overview of the current and emerging treatment options for WM. Dr. Dimopoulos detailed the clinical considerations for initiating treatment for the patient with WM as Hb ≤10 g/dL; platelet counts <100 x 109 /L, bulky adenopathy, and significant organomegaly. For symptomatic patients requiring treatment, there are 3 front-line options available: alkylating agents, nucleoside analogues, and monoclonal antibody rituximab. With alkylating agent, chlorambucil, 50% to 70% of patients achieve responses. With nucleoside analogues, fludarabine and cladribine, responses occur in 40% to 80% of previously untreated patients. Fludaribine and cladribine have also shown to be effective as salvage treatment. Limited data are available on high dose therapy (HDT); however, preliminary results show a high response rate even in resistant patients (100% CR). Studies with rituximab show that time to response is slowan average of 4 months. Because rituximab is not myelosuppressive or toxic to stem cells rituximab may be the ideal option for patients who are candidates for stem cell collection, although not a good option for patients requiring rapid disease control. More recently there has been considerable interest in combination therapies with novel agents. With these new options on the horizon, Dr. Dimopoulous encouraged the consideration of patient factors such as age, comorbid conditions, the need for rapid disease control, and candidacy for high-dose therapy to identify the most appropriate treatment for the patient with WM.
Dr. Philip Hawkins' presentation focused on AL amyloidosis, which is a disorder of protein folding. This disease is challenging to diagnose and treat. Diagnosis is made through a biopsy and histological analysis. Underlying monoclonal gammopathies are subtle and some patients present with concurrent MM or other B-cell malignancy. Median survival for untreated patients is less than 2 years. Symptoms of AL amyloidosis include renal dysfunction, neuropathy, and hepatomegaly; cardiac involvement is often missed. There are very few clinical trials on AL amyloidosis; however, various studies suggest that chemotherapy is effective. Treatment options include the use of infusion and stem cell transplant to suppress free light chain (FLC) production. FLC levels correlate with the course and outcome of AL amyloidosis and treatment should be guided based on the measurements of serum FLC. Suppression of FLC by just 50% leads to a better outcome. UK guidelines support the use of VAD as front-line therapy with peripheral blood stem cell transplantation (PBSCT) considered for select eligible patients. Other treatment options include the use of novel agents, which are currently being studied in patients.
Dr. Morie Gertz closed this session with a presentation on monoclonal gammopathies other than MM, MGUS, and AL amyloidosiscryoglobulinemia and POEMS (osteosclerotic myeloma). At the Mayo clinic (Rochester, Minnesota, United States), 139 out of 700 other patients were diagnosed with osteosclerotic myeloma; 227 out of 700 were diagnosed with cryoglobulinemia. The median age of patients with cryoglobulinemia is 58; presenting with symptoms including purpura, renal impairment, edema, peripheral neuropathy, and arthralgia. Underlying disorders include hepatitis C virus (HCV), lymphoplasmacytic disorder (LPD), and autoimmune disease. The most common clinical manifestation with LPD is skin ulceration; whereas neuropathy and Raynaud’s syndrome are the more common autoimmune diseases. Treatment options include plasmapheresis, interferon, immunoglobulin infusion, and recent use of rituximab. Response rates, regardless of type of treatment, are 60% to 70% and the only predictor of survival is age. POEMS is associated with monoclonal protein of the lambda type. The majority of patients present with sclerotic bone lesions and 11% present with Castleman’s disease. The median age of patients is 51 years with the following symptoms: neuropathy, organomegaly, M-protein spike, and thrombocytopenia. This disease is non-fatal and the final outcome is patients becoming wheelchair bound. Treatment options include radiation, melphalan-based chemotherapy, or combination chemotherapy with alkylating agents. More recently, a study using PBSCT was found to be effective in patients who have failed radiotherapy with results of significantly improved neural impairment scores.
For more information regarding these sessions, look for the complete proceedings to be published after the conclusion of this workshop.