Karen Pekle

BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenström's macroglobulinemia.

Multiple myeloma remains incurable. Despite the pursuit of various chemotherapeutic approaches, little improvement in outcome has been made in the last 30 years. Thalidomide, dexamethasone, and clarithromycin are oral, nonmyelosuppressive agents, each with reported single agent activity against myeloma. We evaluated a regimen of clarithromycin (Biaxin), low-dose thalidomide and dexamethasone (BLT-D) in patients with previously untreated or treated multiple myeloma or Waldenströms macroglobulinemia. Patients were initially given clarithromycin 500 mg twice daily, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly until disease progression. Minimum response was defined as >50% reduction in monoclonal immunoglobulin or light chain levels in serum or urine. Response, toxicity, and survival were determined on an evaluable and/or intent-to-treat basis. Of the 50 patients available for analysis, 92% remain alive and 64% remain on treatment with a median and mean duration of treatment of 7 and 8 months, respectively. Overall, 93% of evaluable patients responded to BLT-D, including 13% complete remissions, 40% near complete responses, 13% major responses, and 27% partial responses. Minimal drug resistance was initially encountered. Neurotoxicity, although usually mild to moderate, was the primary reason for treatment discontinuation. Only four patients died, including three sudden deaths in patients with severe cardiopulmonary disease. It appears that BLT-D is a highly effective, nonmyelosuppressive regimen for myeloma. Caution should be exercised when using thalidomide, alone or in combination, in patients with a preexisting tendency to thromboses, severe cardiopulmonary disease, or neurologic dysfunction.

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.

Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.

BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long term lenalidomide therapy in previously untreated patients with multiple myeloma

The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.

Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization

Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. Results: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand–foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. Conclusion: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. Clin Cancer Res; 19(6); 1534–46. ©2013 AACR.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma

Abstract We studied T-BiRD (thalidomide [Thalomid®], clarithromycin [Biaxin®], lenalidomide [Revlimid®] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1–28; lenalidomide 25 mg/day on days 1–21; and thalidomide 100 mg/day (50 mg/day on days 1–7 of cycle 1 only) on days 1–28. Twenty-six patients received a median of 6 cycles (range 0–41). Overall response rate (ORR) was 80% for the group and 100% in 11 patients who underwent autologous stem cell transplantation as part of first-line therapy. The 4-year overall survival rate was 74.9%, and the median progression-free survival was 35.6 months. Eight patients discontinued due to regimen toxicity. Grade 3 non hematologic toxicity affected 12 patients (46.2%). T-BiRD is a highly active regimen with potential toxicity limitations. ClinicalTrials.gov identifier: NCT00538733

Cellular Proliferation by Multiplex Immunohistochemistry Identifies High-Risk Multiple Myeloma in Newly Diagnosed, Treatment-Naive Patients

Micro‐Abstract The plasma cell labeling index (PCLI) prognosticates survival in multiple myeloma (MM) yet is underutilized as a result of its technical difficulty. We retrospectively evaluated multiplex immunohistochemistry (mIHC) in 151 newly diagnosed patients as a clinically feasible alternative to PCLI. The mIHC correlated with PCLI results and was predictive of overall survival for MM. Introduction: Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Patients and Methods: Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell–specific marker, and Ki‐67. Myeloma cells (CD138+) were counted as proliferating if coexpressing Ki‐67. Retrospective analysis was performed on 151 newly diagnosed, treatment‐naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Results: Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high‐risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty‐three (36%) of the 64 patients with low‐risk disease (ISS stage 1, without high‐risk cytogenetics) were uniquely reidentified as high risk by PCPI. Conclusion: PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.

Clonal plasma cells keep strange company

Multiple myeloma and other clonal plasma cell disorders have long been known to give rise to a diverse set of paraneoplastic phenomena. Some of the paraneoplastic effects are linked to cross-reactivity of the secreted monoclonal immunoglobulin, such as disturbances of Factor X or Von Willebrand Factor, leading to bleeding diatheses, or M-protein attachment to myelin sheaths producing peripheral neuropathy.[1–3] Other non-CRAB (hypercalcemia, renal insufficiency, anemia and bone disease) pathology associated with monoclonal plasma cell disorders, such as scleromyxedema, have idiopathic etiology.[4] Still other plasma cell disorders drive paraneoplastic phenomenon through pathologic alteration of cytokine production. The premier example of such is POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal paraprotein and skin changes) whereby the signs and symptoms do not relate to the ongoing proliferation of malignant cells, but rather are cytokine driven by the paraneoplastic elevation of vascular endothelial growth factor and interleukin-6.[5] Multiple myeloma has also been linked to other malignancies, most notably second primary malignancies seen during coadministration of lenalidomide with oral melphalan alkylating chemotherapy or after autologous stem cell transplant.[6] Multiple myeloma also has been associated with concurrent hematologic, solid tumor and skin malignancies, independent of chemotherapy.[7] Neutrophilia and plasma cell disorders are known to be associated, but the pathophysiology is protean. Case reports have described elevated levels of G-CSF (either secreted by the monoclonal plasma cells or surrounding stroma) driving neutrophilia, while others have shown that chronic neutrophilic leukemia and multiple myeloma can co-exist as two separate clonal processes.[8,9] Interestingly, in one case report, treatment of the clonal plasma cell disorder with concurrent therapy against chronic neutrophilic leukemia (CNL) led to therapeutic response; yet, could treatment of either the CNL or the myeloma alone have led to a similar result if the two disease are inter-related?[10] In this issue of Leukemia and Lymphoma, Stevens et al. provide a case series of five patients with simultaneous neutrophilia and plasma cell disorder.[11] In depth molecular and cytokine analyses were performed in these patients, showing that there may be multiple mechanisms at play in the linkage of the two proliferative processes. In two patients, a SETBP1 mutation, which is associated with CNL, was seen thereby suggesting that the CNL and MM were derived from distinct clonal processes.[12] In the SETBP1 wild type patients, it appears that the clonal plasma cells themselves were the culprit in leading to overproduction of cytokines interleukin-6 and G-CSF and thereby driving a reactive neutrophilia, as confirmed by serum ELISA testing. Treatment of the plasma cell disorder led to improvement of the neutrophilia when no SETBP1 mutation was detected. The authors describe the failure of a patient’s neutrophilia to respond to dasatinib, despite a positive ex vivo drug screen on a primary marrow aspirate. This patient, who was negative for mutated SETBP1, had marked improvement of neutrophilia when given myeloma-directed therapy of bortezomib + dexamethasone followed by autologous stem cell transplantation. In those patients harboring mutated SETBP1, hydroxyurea was able to control the neutrophilia for a period of time, but these patients ultimately expired (one as a consequence of infections in the setting of 7 + 3 induction chemotherapy and the other opting for comfort care upon evolution to AML). Interestingly, another patient in the series who was negative for SETB1 mutation also had predicted sensitivity to dasatinib on ex vivo drug screen. This patient, in contrast to the other SETBP1 negative patient, responded well to dasatinib monotherapy not only clearing the neutrophilia, but also reducing the bone