Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

Patient-Reported Outcomes among Multiple Myeloma Patients Treated with Standard of Care Idecabtagene Vicleucel.

Idecabtagene vicleucel (ide-cel) was the first FDA-approved chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma (RRMM) patients. This was the first study to evaluate patient-reported outcomes (PROs) among RRMM patients receiving ide-cel in standard of care (SOC). We prospectively assessed health-related quality of life (HRQOL) and symptoms from pre-infusion (baseline) through day (D)90 post-infusion. Baseline PRO associations with patient characteristics, mean PRO changes, and time to stable change were evaluated with t-tests, linear mixed-effects models, and Kaplan-Meier analyses, respectively. Within-person change scores and minimally important difference thresholds determined clinical and meaningful significance. Participants (n = 42) were a median of 66 years old (range: 43-81). At baseline, extramedullary disease was associated with worse physical well-being (p = 0.008), global pain (p < 0.001), performance status (p = 0.002), and overall symptom burden (p < 0.001). Fatigue (p < 0.001) and functional well-being (p = 0.003) worsened by D7 before returning to baseline levels. Overall HRQOL (p = 0.008) and physical well-being (p < 0.001) improved by D60. Most participants reported PRO improvement (10-57%) or maintenance (23-69%) by D90. The median time it took to stabile deterioration in functional well-being was 14 days. The median time it took to stabile improvement in physical and emotional well-being was 60 days. Overall, RRMM patients reported improvements or maintenance of HRQOL and symptom burden after SOC ide-cel.

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma.

Background: Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis. Methods: Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis. Results: The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9-22.3, p = 5.42*10-7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10-6). Conclusions: We identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.

Cardiac events after standard of care idecabtagene vicleucel for relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis.

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

Multiple myeloma presenting as an intramedullary spinal cord tumor: a case report and review of the literature.

BACKGROUND: Extramedullary disease in multiple myeloma often portends a worse diagnosis. In approximately 1% of cases, multiple myeloma may metastasize to the central nervous system as either leptomeningeal involvement or an intracranial, intraparenchymal lesion. Spinal cord metastases, however, are exceedingly rare. We present a case of spinal cord multiple myeloma as well as a literature review of reported cases. CASE PRESENTATION: A 66-year-old African American man with multiple myeloma presented with acute midthoracic pain and lower extremity paresis and paresthesia. Magnetic resonance imaging of the spine revealed two contrast-enhancing intramedullary enhancing lesions in the T1-T2 and T6-T7 cord. Resection with biopsy yielded a diagnosis of metastatic multiple myeloma. CONCLUSION: To date, only six cases of extramedullary disease to the spinal cord in patients with multiple myeloma have been reported, including our patient's case. In all cases, neurologic deficit was observed at presentation, and magnetic resonance imaging of the spine revealed an intramedullary, homogeneously enhancing lesion. Current evidence suggests worse prognosis in patients with extramedullary disease to the central nervous system, and treatment paradigms remain debatable.

Waldenström Macroglobulinemia: Review of Pathogenesis and Management.

Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M. Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve, given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.

Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6-80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials.gov as #NCT01432600.

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

INTRODUCTION: BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. METHODS: Patients (n = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. RESULTS: The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population (n = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. CONCLUSION: BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. FUNDING: This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. TRIAL REGISTERED: ClinicalTrials.gov identifier, NCT00775502.

A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma.

BACKGROUND: Despite the impact of proteasome inhibitors and immunomodulatory agents, infusional chemotherapy regimens continue to be used for patients with multiple myeloma. To the authors' knowledge, contemporary data regarding salvage chemotherapy regimens are sparse, with no direct comparisons. METHODS: The authors performed a single-institution study comparing 3 salvage chemotherapy regimens in 107 patients with recurrent/refractory multiple myeloma: dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in 52 patients; bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) in 22 patients; and cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) in 33 patients. RESULTS: Differences between treatment groups existed, including higher baseline creatinine for patients treated with CVAD (P<.001) and greater prior use of infusional chemotherapy for those receiving VTD-PACE (P<.001). There was no significant difference in response noted among the 3 regimens: 55% overall (P = .18). For the intent-to-transplant population, a similar percentage were successfully bridged to transplant without further therapy (62%; P = .9). There was no difference in survival observed across the 3 regimens, with an overall median progression-free survival of 4.5 months (95% confidence interval, 3.6-5.5 months [P = .8]) and a median overall survival of 8.5 months (95% confidence interval, 6.1-11 months [P = .8]). Furthermore, there was no statistically significant difference noted among clinically relevant adverse events, although there was a suggestion of fewer adverse events with DCEP. Patients treated with the intent to transplant had superior outcomes for response (odds ratio, 3.40; P = .01), progression-free survival (hazard ratio, 0.28; P<.001), and overall survival (hazard ratio, 0.19; P<.001). CONCLUSIONS: The 3 salvage regimens demonstrated similar responses, survival, and adverse events. Given the short response durations observed in the recurrent/refractory disease setting, infusional chemotherapy is best suited for cytoreduction before more definitive therapy is administered.

Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms.

PURPOSE: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. RESULTS: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. CONCLUSIONS: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.

Quantification of peptides from immunoglobulin constant and variable regions by LC-MRM MS for assessment of multiple myeloma patients.

PURPOSE: Quantitative MS assays for Igs are compared with existing clinical methods in samples from patients with plasma cell dyscrasias, for example, multiple myeloma (MM). EXPERIMENTAL DESIGN: Using LC-MS/MS data, Ig constant region peptides, and transitions were selected for LC-MRM MS. Quantitative assays were used to assess Igs in serum from 83 patients. RNA sequencing and peptide-based LC-MRM are used to define peptides for quantification of the disease-specific Ig. RESULTS: LC-MRM assays quantify serum levels of Igs and their isoforms (IgG1-4, IgA1-2, IgM, IgD, and IgE, as well as kappa (κ) and lambda (λ) light chains). LC-MRM quantification has been applied to single samples from a patient cohort and a longitudinal study of an IgE patient undergoing treatment, to enable comparison with existing clinical methods. Proof-of-concept data for defining and monitoring variable region peptides are provided using the H929 MM cell line and two MM patients. CONCLUSIONS AND CLINICAL RELEVANCE: LC-MRM assays targeting constant region peptides determine the type and isoform of the involved Ig and quantify its expression; the LC-MRM approach has improved sensitivity compared with the current clinical method, but slightly higher inter-assay variability. Detection of variable region peptides is a promising way to improve Ig quantification, which could produce a dramatic increase in sensitivity over existing methods, and could further complement current clinical techniques.

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.

Effects of a brief multimedia psychoeducational intervention on the attitudes and interest of patients with cancer regarding clinical trial participation: a multicenter randomized controlled trial.

PURPOSE: The negative attitudes of patients with cancer regarding clinical trials are an important contributor to low participation rates. This study evaluated whether a brief psychoeducational intervention was effective in improving patients' attitudes as well as their knowledge, self-efficacy for decision making, receptivity to receiving more information, and general willingness to participate in clinical trials. PATIENTS AND METHODS: A total of 472 adults with cancer who had not been asked previously to participate in a clinical trial were randomly assigned to receive printed educational information about clinical trials or a psychoeducational intervention that provided similar information and also addressed misperceptions and concerns about clinical trials. The primary (attitudes) and secondary outcomes (knowledge, self-efficacy, receptivity, and willingness) were assessed via patient self-report before random assignment and 7 to 28 days later. RESULTS: Patients who received the psychoeducational intervention showed more positive attitudes toward clinical trials (P = .016) and greater willingness to participate (P = .011) at follow-up than patients who received printed educational information. Evidence of an indirect effect of intervention assignment on willingness to participate (estimated at 0.168; 95% CI, 0.088 to 0.248) suggested that the benefits of psychoeducation on willingness to participate were explained by the positive impact of psychoeducation on attitudes toward clinical trials. CONCLUSION: A brief psychoeducational intervention can improve the attitudes of patients with cancer toward clinical trials and thereby increase their willingness to participate in clinical trials. Findings support conducting additional research to evaluate effects of this intervention on quality of decision making and rates of participation among patients asked to enroll onto therapeutic clinical trials.

Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review.

Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.

Leptomeningeal myeloma as the sole manifestation of relapse: an unusual presentation.

We report a case of a 57-year-old African American male patient with standard risk (IIIA) IgA kappa multiple myeloma. This patient presented with neurologic complaints (manifesting as generalized muscle weakness and swallowing dysfunction associated with a poor cough reflex) 10 months after achieving a very good partial remission and without evidence of systemic progression. Examination of the cerebrospinal fluid revealed leptomeningeal involvement. Very little is known about the mechanisms of myelomatous spread to the leptomeninges, a very rare event, and the presentation of this case could raise awareness of this rare complication in those involved in caring for patients with multiple myeloma.

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.

Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy.

BACKGROUND: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted. METHODS: In total, 120 patients with metastatic clear-cell RCC received bevacizumab, sorafenib, sunitinib, or axitinib on 1 of 9 prospective clinical trials at the Cleveland Clinic. Clinical features associated with outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and to form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. RESULTS: The overall median PFS was 13.8 months, and the objective response according to the Response Criteria in Solid Tumors was 34%. Multivariate analysis identified time from diagnosis to current treatment <2 years; baseline platelet and neutrophil counts >300 K/microL and >4.5 K/microL, respectively; baseline corrected serum calcium <8.5 mg/dL or >10 mg/dL; and initial Eastern Cooperative Oncology Group performance status >0 as independent, adverse prognostic factors (PF) for PFS. Three prognostic subgroups were formed based on the number of adverse prognostic factors present. The median PFS in patients with 0 or 1 adverse prognostic factor was 20.1 months compared with 13 months in patients with 2 adverse prognostic factors and 3.9 months in patients with >2 adverse prognostic factors. CONCLUSIONS: Five independent prognostic factors for predicting PFS were identified and were used to categorize patients with metastatic RCC who received VEGF-targeted therapies into 3 risk groups. These prognostic factors can be incorporated into patient care and clinical trials that use such novel, VEGF-targeted agents.

Phase II study of lenalidomide in patients with metastatic renal cell carcinoma.

BACKGROUND: Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open-label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS: Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS: In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression-free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow-up for those 11 patients was 13.5 months (range, 8.3-17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS: LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC.