Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Risk factors for the development of orthostatic hypotension during autologous stem cell transplant in patients with multiple myeloma.

Orthostatic hypotension (OH) is a well-recognized phenomenon occurring in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), and is associated with significant morbidity and mortality. A retrospective analysis of patients admitted for first ASCT between June 2012 and April 2014 found that 161/222 (73%) patients were diagnosed with OH during the course of ASCT, including 51 patients who were found to have OH on the day of first orthostatic vitals check. Excluding these 51 patients, 110/171 (64%) patients developed OH during the peri-transplant period, at a median of 7 days post ASCT (95% CI: 6.5-8.5). OH did not significantly impact length of hospitalization, progression free and overall survival. Multivariable analysis revealed four risk factors (i.e. ≥0.5% weight loss/day, white race, gabapentin, antihypertensives) and two protective factors (i.e. antihistamine, proton pump inhibitor) associated with the development of peri-transplant OH.

Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.

Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.

Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling.

Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacologic inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quantitative and qualitative changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as molecular mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clinical development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment.

Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma.

We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m2 . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov, NCT00903968.

A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.

PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.

A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma.

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant-ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population and was administered over a 35-day cycle. Lenalidomide 15 mg was given orally on days 1-21; bortezomib 1·3 mg/m2 weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS) and overall survival (OS). Fifty-three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9-not reached) and median OS was not reached at a median follow-up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well-tolerated and highly effective regimen, with robust PFS and OS, in the transplant-ineligible MM population.

Patient-reported outcomes of multiple myeloma patients treated with panobinostat after ≥2 lines of therapy based on the international phase 3, randomized, double-blind, placebo-controlled PANORAMA-1 trial.

The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ-Myeloma module (EORTC QLQ-MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients' QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed.

Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma: a review of options for and against.

INTRODUCTION: Lenalidomide has multifaceted antimyeloma properties, including direct tumoricidal and immunomodulatory effects. Several randomized controlled trials have demonstrated improved patient outcomes with lenalidomide maintenance after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM). Currently, single-agent lenalidomide is the only approved post-ASCT maintenance therapy in the United States and European Union for patients with NDMM. Areas covered: This review article summarizes the efficacy and safety data of lenalidomide maintenance, as monotherapy and in combination with other agents, following ASCT in patients with NDMM. In addition, emerging therapies with newer agents in this setting are discussed. Expert opinion: Following ASCT, maintenance therapy with lenalidomide until progressive disease is an effective and well-tolerated regimen and represents the standard of care for patients with NDMM. Studies evaluating maintenance with lenalidomide in combination with next-generation proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors may further improve patient outcomes.

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial.

BACKGROUND: In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. METHODS: Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated ß2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. FINDINGS: Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. INTERPRETATION: Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. FUNDING: The National Cancer Institute.

Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial.

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. FINDINGS: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50). INTERPRETATION: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this. FUNDING: Novartis Pharmaceuticals.

Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment.

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308.

Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations.

Proteasome inhibitors (PI) and immunomodulatory agents (IMIDs) have improved the overall survival (OS) of patients with multiple myeloma (MM), but concerns have been raised about increased incidence of extramedullary disease (EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6·1 years; range 0·1-10·2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34·2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0·9 years (range 0·1-4·8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups (P > 0·2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD.

Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation.

Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation.

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.

BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals.

Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy.

BACKGROUND: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. METHODS: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. RESULTS: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. CONCLUSION: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs.