Treatment Of Refractory Multiple Myeloma Research Articles

A case report of venous thrombosis in a leprosy patient treated with corticosteroid and thalidomide

Thalidomide is the drug of choice in the treatment of severe erythema nodosum leprosum (ENL) in men. It has recently been associated with deep venous thrombosis (DVT) when used in treatment of refractory multiple myeloma along with combination chemotherapy. We report a case of DVT in a patient treated for ENL with corticosteroids and thalidomide, and suggest a possible mechanism for the association.

Oral Melphalan, Dexamethasone, and Thalidomide for the Treatment of Refractory Multiple Myeloma

We present a patient with refractory multiple myeloma who showed a good response to a combination therapy with oral melphalan, dexamethasone, and thalidomide (MDT). A 48-year-old woman with myeloma refractory to thalidomide, dexamethasone, and clarithromycin received 6 mg melphalan for 4 days every 6 weeks in combination with thalidomide (100 mg daily) and dexamethasone (5 mg daily for 2 days every week). Four months after the initiation of MDT therapy, a 78% reduction of monoclonal protein was achieved. Although the efficacy of oral MDT combination therapy in elderly patients with newly diagnosed myeloma has been reported, the present data demonstrate the effectiveness of MDT therapy for refractory myeloma and warrant further exploration with this MDT regimen to treat myeloma.

Extensive Immunoglobulin Production Sensitizes Myeloma Cells for Proteasome Inhibition

Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine muH-chain-transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications.

Efectividad de la talidomida y la dexametasona en el tratamiento del mieloma múltiple resistente al tratamiento: estudio retrospectivo de 36 casos consecutivos

Multiple myeloma (MM) is a plasm-cell neoplasm characterized by a monoclonal protein in the serum or urine. Thalidomide is effective as second line treatment. We performed a retrospective study of 36 consecutive patients with refractory MM treated with thalidomide and dexamethasone as second line therapy, with the objective of analyzing the rate of response (primary end point), progression-free survival (PFS) and toxicity profiles (second end points). In our study the overall response rate was 55.6%, with a median of PFS of 12.6 months (95% confidence interval: 4-21 months). PFS at 6, 12 and 18 months was 61.11%, 50% and 22.22% respectively. 30.6% of the patients had neuropathy, 11.11% had rash and 5.55% had deep vein thrombosis. The combination of thalidomide and dexamethasone is an effective and safe second line treatment for refractory MM, with a manageable toxicity.

A Phase II Study of Single Agent Bortezomib in Patients with Metastatic Breast Cancer: A Single Institution Experience

PS-341, now known as bortezomib (Velcade[Millenium Pharmaceuticals, Inc., Cambridge, MA; and Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring house, PA]), is a proteasome inhibitor approved for the treatment of refractory multiple myeloma. Preclinical and early clinical studies showed PS-341 to be effective in solid tumors, one of which was breast cancer. We conducted a single institution, phase II study using PS-341 in the treatment of patients with metastatic breast cancer. The primary objective of this study was to determine the objective tumor response in patients with metastatic breast cancer (MBC) receiving PS-341. The secondary objectives were to estimate progression-free survival of patients receiving single-agent PS-341 and to evaluate toxicity related to PS-341. In all 12 patients who met criteria for enrollment, there were no observed objective responses. Further, all 12 patients progressed while receiving therapy with PS-341. This study was terminated after the first stage due to the lack of any objective response.

BSc2118, a Novel Proteasome Inhibitor, Shows Anti-Tumor Activity in Multiple Myeloma and Mantle Cell Lymphoma.

The ubiquitin-proteasome pathway was recently identified as a promising new therapeutic target in cancer treatment. An increased proteasome activity was described in certain cancer types, especially in multiple myeloma (MM) and also in mantle cell lymphoma (MCL). The proteasome inhibitor bortezomib has been approved for the treatment of refractory MM and has also shown reproducible activity in MCL. Recently we described a novel tripeptide compound, BSc2118, with inhibitory activity against all three proteolytic activities (post-glutamyl peptide hydrolase-like, trypsin-like and chymotrypsin-like activities) of the 20S proteasome (Cancer Res 2006; 66:7598–605). We investigated the in vitro effects of BSc2118 in MM and MCL cell lines by MTT cell viability and AnnexinV apoptosis-assays. Furthermore, the intracellular chymotrypsin-like proteasome activity and NF-κB activity were detected in MM and MCL cells by detection of proteasome-degraded peptides or NF-κB p65 subunit. In MM cell lines OPM-2 and U266 we could show a significant time and dose-dependent reduction of cell viability by BSc2118 with an IC50 at 48hrs of 52nM and 65nM, respectively, whereas the MM cell line RPMI-S was less sensitive with an IC50 of 287nM. Using AnnexinV assay, a dose-dependent induction of apoptosis by BSc2118 was shown after 48hrs incubation. Comparably, in MCL we also found a time and dose-dependent reduction of cell viability in the cell lines HBL-2, JeKo-1 and Granta-519 with an IC50 of 82nM, 130nM and 262nM, respectively. Furthermore, BSc2118 induced apoptosis in all three MCL cell lines. Additionally, we detected a significant dose-dependent inhibition of intracellular chymotrypsin-like proteasome activity in MM and MCL cells, and a dose-dependent inhibition of TNFα-induced NF-κB activation in the MM cell lines OPM-2 and RPMI-S. This is the first report of anti-tumor effects of the novel proteasome inhibitor BSc2118 in MM and MCL cells. The compound effectively reduces the cell survival and shows a high pro-apoptotic activity in the MM cell lines OPM-2 and U266 and a significant activity in MCL cell lines HBL-2 and JeKo-1. Mechanisms of action are the inhibition of proteasome and NF-κB activity. Since previous clinical trials have shown an activity of the proteasome inhibitor bortezomib in MM and MCL, and adverse effects of other proteasome inhibitors may differ, our preclinical data support the idea to consider BSc2118 as a promising new agent in anti-tumor drug development.

Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.

Combined administration of darbepoetin and zoledronic acid in the treatment of refractory multiple myeloma (MM)

Combined administration of darbepoetin and zoledronic acid in the treatment of refractory multiple myeloma (MM)

The Pharmacokinetics of Low-Dose Thalidomide in Japanese Patients with Refractory Multiple Myeloma

Thalidomide has been used for the treatment of refractory multiple myeloma, the dosage in Japan is lower than in other countries; however, there is little information on the pharmacokinetics and their relationship with the drug response. The aim of this study was to characterize the pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma, and to examine the relationship between pharmacokinetics and adverse events. On the first and second days, a 100 mg capsule was administered to 8 Japanese patients after breakfast and blood samples were obtained. The plasma concentrations were measured using HPLC and analyzed based on a one-compartment model. If intolerable adverse events were not observed for 14 d, the dose was increased to 200 mg. The average apparent volume of distribution (Vd/F), apparent total clearance (CL/F) and area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity), which were 45.3 l, 5.5 l/h and 21.7 microg.h/ml, respectively, with smaller Vd/F and CL/F and larger AUC0-infinity than in Caucasian populations. This pharmacokinetic difference may explain the dose difference between Japan and other countries. Adverse events were associated with AUC0-infinity, which was best correlated with plasma concentration at 12 h after administration. The 12-h time point was suggested to be a capable indicator for "safety-oriented" therapeutic drug monitoring of thalidomide.

Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature

An association between chronic hepatitis C virus (HCV) infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma (NHL) has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C (CHC) who has been followed up since 1998 due to a high viral load, genotype 1b and moderately elevated liver function tests (LFTs). Laboratory data and liver biopsy revealed moderate activity (grade: 5/18, stage: 1/6). In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. A CT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed (IgG-kappa, bone ma-rrow biopsy: 50% plasma cell infiltration). MRI revealed a compression fracture of the 5th lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone (VAD) was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line treatment of refractory multiple myeloma (MM) was initiated, and followed by peginterferon-alpha2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients.

Synergistic Activity of the Proteasome Inhibitor PS-341 with Non-Myeloablative 153-Sm-EDTMP in a Syngeneic, Orthotopic Model of Multiple Myeloma.

Multiple myeloma is a highly radiosensitive malignancy but, at the present time, radionuclide-based interventions have no proven place in disease management. Bone-seeking radionuclides such as 153-Sm-EDTMP and 166-Ho-DOTMP are promising agents for systemic delivery of ionizing radiation to sites of myeloma disease activity, but they are associated with significant myelosuppression at therapeutically effective doses and have therefore been used only in the context of myeloma stem cell transplantation protocols. We previously reported that the proteasome inhibitor PS-341 potently and selectively sensitizes myeloma cell lines and primary myeloma cells to the lethal effects of ionizing X-irradiation (Goel et al, Exp Hematol . 33, 784, 2005). To determine whether PS-341 is equally effective in sensitizing myeloma cells to ionizing beta-radiation and to extend our initial observations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP. In vitro clonogenic assays were performed using a panel of myeloma cell lines and demonstrated synergistic killing following co-treatment with PS-341 and 153-Sm-EDTMP. Using the orthotopic, syngeneic 5TGM1 myeloma model, the median survivals of mice treated with saline, two doses of PS-341 (0.5 mg/kg), or a single non-myeloablative dose of 153-Sm-EDTMP (22.5 MBq) were 21, 22 and 28 days, respectively. In contrast, mice treated with combination therapy comprising two doses of PS-341 (0.5 mg/kg), one day prior to and one day following 153-Sm-EDTMP (22.5 MBq) showed a greatly prolonged median survival of 49 days. Correlative studies indicated that, compared to single-agent therapy, combination treatment with PS-341 and 153-Sm-EDTMP rapidly reduced the clonogenicity of bone-marrow resident 5TGM1 cells, slowed the elevation of serum myeloma-associated paraprotein levels, and was associated with longer term preservation of bone mineral density. The myelotoxicity of single agent and combination therapies was evaluated by comparing peripheral blood cell counts in each of the treatment groups, and by clonogenicity assays of hematopoietic progenitors isolated form normal mice receiving identical treatment regimens. Treatment with 153-Sm-EDTMP led to significant, but transient, myelosuppression which did not differ between animals treated with 153-Sm-EDTMP alone versus those treated with the combination of PS-341 plus 153-Sm-EDTMP. In summary, PS-341 is a potent in vivo radiosensitizer that greatly enhances the therapeutic potency, without increasing myelotoxicity, of skeletal targeted radiotherapy in the syngeneic, orthotopic 5TGM1 myeloma model. Based on these findings, we propose to conduct a phase I clinical trial at Mayo Clinic to evaluate the combination of PS-341 plus non-myeloablative skeletal targeted radiotherapy (using 153-Sm-EDTMP) in patients with advanced or treatment-refractory multiple myeloma.

Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib

Proteasome inhibitors, such as the dipeptide boronic acid bortezomib, are emerging as important tools in the treatment of the fatal hematologic malignancy multiple myeloma. Despite the recent US Food and Drug Administration approval of bortezomib (PS341, Velcade) for the treatment of refractory multiple myeloma, many of the basic pharmacologic parameters of bortezomib and its mode of action on myeloma cells remain to be determined. We describe the synthesis and use of a cell-permeant active site-directed probe, which allows profiling of proteasomal activities in living cells. When we compared proteasome activity patterns in cultured cells and crude cell extracts with this probe, we observed substantial differences, stressing the importance for bioassays compatible with live cells to ensure accuracy of such measurements. Using this probe, we investigated the in vivo subunit specificities of bortezomib and another inhibitor, MG132.

Proteasome Inhibiters Up-Regulate TRAIL/Apo2L and Its Receptors Significantly Contributing to Proteasome Inhibitor-Induced Apoptosis in Primary Chronic Lymphocytic Leukemia (CLL) Cells.

The proteasome inhibitor, bortezomib has recently emerged as a new therapeutic treatment for refractory multiple myeloma and is presently being evaluated for other hematological malignancies either alone or in combination with other antitumor agents. Proteasome inhibitors cause the accumulation of many proteins but the precise mechanism responsible for their antitumor effect is unclear. In the present study, we have determined that cytotoxic effect the proteasome inhibitor MG-132 in primary chronic lymphocytic leukemia (CLL) cells is through the activation of the TRAIL (tumor necrosis factor-related apoptosis inducing ligand) apoptotic pathway. MG-132 induced apoptosis in approximately 70% of primary CLL cells as measured by annexin V staining. Addition of DR4:Fc that prevents TRAIL ligation with its receptors decreased the amount of MG-132 induced apoptosis by approximately 40% suggesting MG-132 caused activation of the TRAIL apoptotic pathway. MG-132 also up-regulated both the mRNA and protein levels of TRAIL and protein levels of TRAIL receptors DR4 and DR5. This upregulation correlated with activation of caspase 8 and cleavage of pro-apoptotic Bcl-2 family member Bid. Moreover, MG-132 treatment also induced a substantial reduction in the FLICE-like inhibitory protein (c-FLIP) protein levels. In contrast to CLL cells, proteasome inhibitors failed to activate the TRAIL apoptotic pathway in normal B-cells. This indicates that proteasome inhibitors are inducing apoptosis in primary CLL cells through activation of the TRAIL apoptotic signaling pathway through up-regulation of TRAIL and its cognate receptors and reduced FLIP expression. Thus, proteasome inhibitors may have a therapeutic role in CLL, either when used alone or in combination with TRAIL or antibodies against DR4/DR5.

Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis

New options are needed for the treatment of B-cell chronic lymphocytic leukemia (CLL). Proteasome inhibitors represent a potential therapeutic strategy. One such agent, bortezomib, was recently approved for the treatment of refractory multiple myeloma. In this study, lymphocytes were isolated from the blood of CLL patients, treated in vitro with bortezomib, and evaluated for apoptosis by flow cytometry. Bortezomib promoted apoptosis in CLL cells in a dose- and time-dependent manner. At 18 h incubation time, 10 nM bortezomib induced an average 4.27 fold (+/−2.57) increase in the percentage of apoptotic cells versus untreated controls. These data indicate that bortezomib has in vitro activity in CLL and support further investigations of this promising new drug.

Discordant Response or Progression in Patients with Myeloma Treated with Thalidomide-based Regimens

Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution. Patients and methods: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein. Results: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients. Conclusion: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.

Low Dose Thalidomide in Patients with Relapsed or Refractory Multiple Myeloma

Remarkable results of the treatment of refractory multiple myeloma with thalidomide have been reported. In most preceding studies, the given thalidomide dose was escalated to a maximum tolerated dose of up to 800 mg/d. The frequency of adverse effects correlates with dose intensity. Since a significant gain of therapeutic effects could not be observed as thalidomide dosage was escalated, the optimal dose of thalidomide remains to be determined. We report the results of a study with low dose thalidomide (median administered dose 100 mg/d, range 50-400 mg/d). Twenty-four relapsed <formula>(<italic>n</italic>=19)</formula> or resistant <formula>(<italic>n</italic>=5)</formula> multiple myeloma patients were included in the study. Twelve patients (50%) received thalidomide as monotherapy, 8 patients (33%) received a combination of thalidomide and dexamethasone (every 4 weeks 40 mg/day for 4 days) and 4 patients (17%) who were resistant to vincristine, doxorubicin, dexamethasone (VAD) received VAD combined with thalidomide. Overall, a response was observed in 12 patients (50%). Of the 12 patients treated with low dose thalidomide alone 5 (42%) responded, of the 8 patients who received a combination of thalidomide and dexamethasone 5 (63%) responded and of the 4 patients who had thalidomide in addition to VAD 2 patients (50%) responded. In 3 patients, thalidomide treatment had to be discontinued because of side effects and 1 patient died before response could be assessed. We conclude that low dose thalidomide is an effective and safe rescue therapy in relapsing or refractory multiple myeloma. Response to thalidomide might be dependent on prognostic parameters and tumor burden. To answer these questions larger prospective studies are necessary.

Thalidomide for the treatment of refractory multiple myeloma: association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome.

Recent reports showed that thalidomide has anti‐angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty‐four evaluable patients (42%) showed more than 25% reduction of M‐protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2–4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (≥2.0 μg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near‐normal ranges in responders but were still high in most non‐responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P=0.025), but not in non‐responders (P=0.37). Reduction of plasma VEGF level might be an important indicator for anti‐myeloma effect of thalidomide.

Ascorbic Acid Augments Arsenic-Mediated Cell Death in Multiple Myeloma (MM) Cells.

INTRODUCTION. Greater than 90% of MM patients progress to a chemoresistant state (1). New therapies are clearly needed for the treatment of refractory MM that overcome or bypass the adaptive cellular changes associated with refractory disease: P-glycoprotein expression, increased Bcl-xL expression, elevated glutathione (GSH). Arsenic cytotoxicity is independent of Bcl-xL expression (2), making it a promising anti-neoplastic agent for MM. Ascorbic acid (AA) has recently been shown to deplete GSH via autooxidation and subsequent reduction reactions (3). Therefore, we hypothesized that the combination of arsenic and AA is likely to induce apoptosis in refractory MM cells.

Treatment of refractory multiple myeloma with the vincristine-adriamycin-dexamethasone (VAD) regimen

Seventeen patients with advanced refractory multiple myeloma were treated with a 4-day continuous infusion of vincristine and adriamycin in combination with 4-day intermittent high-dose dexamethasone (VAD). Ten patients entered a partial remission (59%). Complete remission was not achieved in any patients. The median response duration was 11 months and the median survival of the responding patients was 18 months versus 5 months for non-responders. Major complications during VAD treatment were infections probably due to a combination of myelosuppression and intensive corticosteroid therapy. The VAD regimen offers a useful chemotherapy that produces an overall high response rate even in intensively pretreated patients resistant to first line therapy. The treatment results in a clear tendency to longer survival in responding patients.

Phase II Trial of Methylglyoxal-Bis (guanylhydrazone) (MGBG) in Patients with Refractory Multiple Myeloma: An Eastern Cooperative Oncology Group (ECOG) Study

Twenty patients with refractory multiple myeloma were treated with methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis. MGBG 500 mg/m2 was administered on days 1 and 8, and then every 14 days. The dose was escalated to 600 mg/m2 on day 22, as tolerated. Of 14 evaluable patients, none met ECOG criteria for an objective response. The major toxicity was hematologic and related infections. MGBG demonstrated insufficient activity in the treatment of refractory multiple myeloma to warrant further study.