Disease and outcome disparities in multiple myeloma: exploring the role of race/ethnicity in the Cooperative Group clinical trials.

Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities. Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal. We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM. Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002-2011). African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase. Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents. While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival. While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials. Improved minority accrual in therapeutic clinical trials needs to be a priority.

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10-5 to 10-6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980-93. ©2017 AACR.

Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997.

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL (#) . With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n = 109) and FC (n = 118), respectively (p < 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p = 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p = 0.002, p < 0.001), Rai stage (p = 0.006, p = 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p < 0.0001, p = 0.005, respectively), trisomy 12 with mutated Notch1 (p = 0.003, p = 0.03, respectively) and unmutated IGHV (p = 0.009, p = 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.

A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434.

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein. Patients had to have adequate renal, hepatic, hematologic, and cardiac function with a Zubrod performance status of 0-2. Patients were given 400 mg sorafenib by mouth twice daily for 28-day treatment cycles. These patients were followed up for a maximum of 3 years to assess responses and adverse events. Twenty-three patients were enrolled. Of these, five were found to be ineligible for the following reasons: four had insufficient documentation of the baseline disease and one patient did not have measurable disease. All eighteen eligible patients were evaluable for toxicities. Three patients experienced grade 4 toxicities: one with thrombocytopenia, one with anemia, and one with renal failure. Four of the eighteen eligible patients were not assessable for response due to removal from protocol treatment prior to adequate disease assessment. Specifically, three were removed for either grade 4 toxicity or progression of disease and one was removed per patient choice (due to reasons unrelated to treatment). Of the 18 patients who were assessed for toxicities, 5 (27.8%) received at least one fully dosed cycle, 2 (11.1%) of whom had all cycles fully dosed. No responses were observed on this study of the 14 patients who were assessable for response. All patients have discontinued protocol treatment as of August 2008. Overall survival at 12 months was 50% (95% CI 27-73%) and median progression-free survival was 1.2 months (95% CI 1.0-5.4). The trial did not exhibit activity by the International Uniform Response Criteria for MM. Further research should focus on combination therapy of sorafenib with standard treatments in selected patients with RR MM.

Mature results of MM-011: a phase I/II trial of liposomal doxorubicin, vincristine, dexamethasone, and lenalidomide combination therapy followed by lenalidomide maintenance for relapsed/refractory multiple myeloma.

A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥ 5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 1), dexamethasone (40 mg on days 1-4), and intravenous vincristine (2 mg on day 1). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624).

Phase II study of pegylated liposomal doxorubicin, low-dose dexamethasone, and lenalidomide in patients with newly diagnosed multiple myeloma.

Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥ VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m(2) intravenously, day 1; dexamethasone 40 mg orally, days 1-4; lenalidomide 25 mg orally, days 1-21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability (ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high-dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent-to-treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression-free survival was 28 months (95% CI 18.1-34.8), with 1- and 2-year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide-based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated.

Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997.

Chemotherapy-related myeloid neoplasia (t-MN) is a significant late toxicity concern after cancer therapy. In the randomized intergroup phase 3 E2997 trial, initial therapy of chronic lymphocytic leukemia with fludarabine plus cyclophosphamide (FC) compared with fludarabine alone yielded higher complete and overall response rates and longer progression-free, but not overall, survival. Here, we report t-MN incidence in 278 patients enrolled in E2997 with a median 6.4-year follow-up. Thirteen cases (4.7%) of t-MN occurred at a median of 5 years from initial therapy for chronic lymphocytic leukemia, 9 after FC and 4 after fludarabine alone. By cumulative incidence methodology, rates of t-MN at 7 years were 8.2% after FC and 4.6% after fludarabine alone (P = .09). Seven of the 9 cases of t-MN after FC occurred without additional therapy. Abnormalities involving chromosomes 5 or 7 were found in 10 cases, which suggests alkylator involvement. These data suggest that FC may induce more t-MN than fludarabine alone.

Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232).

The Southwest Oncology Group conducted a randomized trial comparing lenalidomide (LEN) plus dexamethasone (DEX; n = 97) to placebo (PLC) plus DEX (n = 95) in newly diagnosed myeloma. Three 35-day induction cycles applied DEX 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 together with LEN 25 mg/day for 28 days or PLC. Monthly maintenance used DEX 40 mg/day on days 1 to 4 and 15 to 18 along with LEN 25 mg/day for 21 days or PLC. Crossover from PLC-DEX to LEN-DEX was encouraged on progression. One-year progression-free survival, overall response rate, and very good partial response rate were superior with LEN-DEX (78% vs 52%, P = .002; 78% vs 48%, P < .001; 63% vs 16%, P < .001), whereas 1-year overall survival was similar (94% vs 88%; P = .25). Toxicities were more pronounced with LEN-DEX (neutropenia grade 3 or 4: 21% vs 5%, P < .001; thromboembolic events despite aspirin prophylaxis: 23.5% [initial LEN-DEX or crossover] vs 5%; P < .001). This trial was registered at www.clinicaltrials.gov as #NCT00064038.

Single agent lenalidomide in newly diagnosed multiple myeloma: a retrospective analysis.

Recently, lenalidomide and low dose dexamethasone were found to result in superior overall survival compared to lenalidomide and high dose dexamethasone. The immune suppressive effects of dexamethasone can antagonize lenalidomide immunomodulatory activity and may explain this observation. We conducted a retrospective analysis to evaluate the single agent activity of lenalidomide in newly diagnosed myeloma. Records of patients with newly diagnosed symptomatic multiple myeloma treated with single agent lenalidomide at H. Lee Moffitt Cancer Center and Roswell Park Cancer Institute were reviewed. Data were collected on disease characteristics, demographics, and treatment outcomes. Responses were assessed as per the International Myeloma Working Group criteria. From March 2007 to July 2009, 17 patients with newly diagnosed multiple myeloma were treated with single agent lenalidomide at both institutions. The median age was 70 years (range 46-84 years). Lenalidomide was generally well tolerated and no grade 4 hematologic toxicities were noted. The overall response rate (> or =partial remission) to lenalidomide alone was 47% at a median follow-up of 7 months (range 1-26). This experience suggests that lenalidomide alone can induce an anti-myeloma effect in previously untreated patients who are considered poor candidates for concurrent dexamethasone.

Prediction of response and progression in multiple myeloma with serum free light chains assay: corroboration of the serum free light chain response definitions.

BACKGROUND: The International Myeloma Working Group (IMWG) proposed response and progression criteria using serum free light chain (sFLC) testing for patients with nonsecretory multiple myeloma (MM). We attempt to validate these criteria by comparing paraprotein responses with sFLC responses in patients with secretory myeloma. PATIENTS AND METHODS: Prospectively entered data for 89 patients with MM enrolled on various clinical trials at the Cleveland Clinic between April 2004 and December 2006 were reviewed. RESULTS: By standard paraprotein criteria, 4 patients had complete remission (CR), 22 had partial remission (PR), 34 had stable disease (SD), 26 had progressive disease (PD), and 3 were inevaluable. Only 43 patients (48%) had an involved sFLC > or = 10 mg/dL (which is considered evaluable by the IMWG), of which 14 had PR, 8 had SD, 18 had PD, and 3 were inevaluable. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for sFLC in predicting response were 81%, 83%, 64%, and 92% respectively. The sensitivity, specificity, PPV, and NPV for sFLC in predicting progression were 93%, 80%, 72%, and 95% respectively. CONCLUSION: sFLC reliably predicts response and progression in MM. However, half of the patients had inevaluable disease by sFLC, thus limiting the utility of sFLC testing in patients with nonmeasurable disease by electrophoretic methods.

Phase II study of thalidomide plus dexamethasone induction followed by tandem melphalan-based autotransplantation and thalidomide-plus-prednisone maintenance for untreated multiple myeloma: a southwest oncology group trial (S0204).

PURPOSE Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. PATIENTS AND METHODS Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. CONCLUSION Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.

An association between renal cell carcinoma and multiple myeloma: a case series and clinical implications.

OBJECTIVE: To describe an association between renal cell carcinoma (RCC) and multiple myeloma (MM) in patients with both disorders, and suggest possible explanations for the association. PATIENTS AND METHODS: We retrospectively reviewed the records of patients with MM and RCC at the Cleveland Clinic between 1990 and 2005, and identified 1100 with MM, 2704 with RCC and eight with concomitant MM and RCC. The medical records of these eight patients were reviewed. RESULTS: In four of the eight patients, RCC was diagnosed after the MM at 3, 8, 23 and 46 months, respectively; in the remaining four, the RCC was diagnosed before MM by 108, 35, 13 and 1 months, respectively. The number of cases of RCC expected in the present 1100 patients with MM over 15 years was lower than the four recorded (P < 0.001, Fisher's exact test). Similarly, the number of cases of MM expected in the 2704 patients with RCC was also lower than the four recorded (P < 0.001, Fisher's exact test). CONCLUSIONS: RCC and MM can occur in the same patient at an incidence higher than the expected rate. Possible explanations include genetic abnormalities, environmental exposures or immune-related mechanisms predisposing to the second malignancy. These findings are particularly relevant in the management of patients with known RCC and lytic bone lesions, or those with known MM and subsequent or concomitant renal masses, especially those involving the right kidney.

G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells.

The effectiveness of IFN-alpha2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-alpha2b apoptosis in myeloma. In this study we assessed the effects of IFN-alpha2b signaling on the apoptotic activity of TRAIL and human myeloma cell survival. While TRAIL was one of the most potently induced proapoptotic genes in myeloma cells following IFN-alpha2b treatment, less than 20% of myeloma cells underwent apoptosis. Thus, we hypothesized that an IFN-stimulated gene (ISG) with prosurvival activity might suppress TRAIL-mediated apoptosis. Consistent with this, IFN-alpha2b stabilized mitochondria and inhibited caspase-3 activation, which antagonized TRAIL-mediated apoptosis and cytotoxicity after 24 hours of cotreatment in cell lines and in fresh myeloma cells, an effect not evident after 72 hours. Induced expression of G1P3, an ISG with largely unknown function, was correlated with the antiapoptotic activity of IFN-alpha2b. Ectopically expressed G1P3 localized to mitochondria and antagonized TRAIL-mediated mitochondrial potential loss, cytochrome c release, and apoptosis, suggesting specificity of G1P3 for the intrinsic apoptosis pathway. Furthermore, RNAi-mediated downregulation of G1P3 restored IFN-alpha2b-induced apoptosis. Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies.

Preclinical rationale, mechanisms of action, and clinical activity of anthracyclines in myeloma.

Multiple myeloma is an incurable disease for which there are 2 clinical research strategies. One strategy is to focus on managing the disease as a chronic process aiming to minimize the negative impact on survival with minimal or no compromise of the quality of life. The other strategy is to pursue total eradication of the malignant clone, thus achieving cure for the disease. Over the past decade, the myeloma communities have seen several new agents approved for the therapy of multiple myeloma. Although these agents do not result in cure, they target the disease microenvironment, allowing for a better overall response rate and improved quality of response. The latter appears to be influencing the disease outcome in improved progression-free survival, translating into a longer overall survival. Despite the advances in the discovery of immune modulator compounds, chemotherapy continues to be an important part of the myeloma therapeutic armamentarium. Recently, several investigators have explored combining traditional chemotherapeutic agents with proteasome inhibitors and immune modulators.

Multiple myeloma: most common end-organ damage and management.

End-organ damage is the factor that differentiates plasma cell dyscrasia requiring therapy (active multiple myeloma [MM]) from disease that does not require therapy (monoclonal gammopathy of undetermined significance and smoldering [asymptomatic] MM). Progressive skeletal destruction is the hallmark of MM and responsible for principle morbidity in the disease. The spine is the most afflicted skeletal organ, and vertebral fractures have significantly contributed to its poor prognosis. Early mortality in MM is usually attributed to the combined effects of active disease and comorbid factors. Infection and renal failure are the main direct causes of early mortality. Using bisphosphonates to manage skeletal events mainly by preventing or slowing the destructive process has become an important adjunctive treatment in MM. Advances in minimally invasive surgical techniques, such as percutaneous vertebroplasty and kyphoplasty, offer these patients less-invasive options for treating vertebral collapse and restoring function. The aggressive management of other complications of the disease through more effective and less toxic therapy that targets the primary disease, in addition to supportive care, is resulting in patients experiencing less morbidity and probably lower mortality. This article reviews recent advances in the understanding of bone disease in MM, the role of bisphosphonates in preventing skeletal events, and available data on percutaneous vertebroplasty and kyphoplasty, and discusses the management of infection and renal failure, which seem to be responsible for high initial mortality and thereby compromise the current advances in therapy.

CD28-mediated regulation of multiple myeloma cell proliferation and survival.

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFkappaB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.

Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997.

PURPOSE: The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL. PATIENTS AND METHODS: Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m2 intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m2 IV day 1 and fludarabine 20 mg/m2 IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles. RESULTS: A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812). CONCLUSION: Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.

Proteasome inhibitors in the clinical setting: benefits and strategies to overcome multiple myeloma resistance to proteasome inhibitors.

The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341), a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and other malignancies.

The emerging role of arsenic trioxide as an immunomodulatory agent in the management of multiple myeloma.

Multiple myeloma is a clonal disorder of plasma cells which is considered incurable with currently available therapies. Substantial advances have been achieved in the past decade with the identification of cellular mechanisms that confer drug resistance. This has resulted in newer agents such as arsenic trioxide (Trisenoxt), lenalidomide (Revlimid) and bortezomib (Velcade) with promising activity in this disease. In this review article we will outline the history, mechanisms of action, pharmacology, and clinical trials of arsenic trioxide in multiple myeloma.