Annemiek Broijl

Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System

Patients with multiple myeloma have variable survival and require reliable prognostic and predictive scoring systems. Currently, clinical and biological risk markers are used independently. Here, International Staging System (ISS), fluorescence in situ hybridization (FISH) markers, and gene expression (GEP) classifiers were combined to identify novel risk classifications in a discovery/validation setting. We used the datasets of the Dutch-Belgium Hemato-Oncology Group and German-speaking Myeloma Multicenter Group (HO65/GMMG-HD4), University of Arkansas for Medical Sciences-TT2 (UAMS-TT2), UAMS-TT3, Medical Research Council-IX, Assessment of Proteasome Inhibition for Extending Remissions, and Intergroupe Francophone du Myelome (IFM-G) (total number of patients: 4750). Twenty risk markers were evaluated, including t(4;14) and deletion of 17p (FISH), EMC92, and UAMS70 (GEP classifiers), and ISS. The novel risk classifications demonstrated that ISS is a valuable partner to GEP classifiers and FISH. Ranking all novel and existing risk classifications showed that the EMC92-ISS combination is the strongest predictor for overall survival, resulting in a 4-group risk classification. The median survival was 24 months for the highest risk group, 47 and 61 months for the intermediate risk groups, and the median was not reached after 96 months for the lowest risk group. The EMC92-ISS classification is a novel prognostic tool, based on biological and clinical parameters, which is superior to current markers and offers a robust, clinically relevant 4-group model.

Treatment of relapsed and refractory multiple myeloma.

The approach to the patient with relapsed or relapsed/refractory multiple myeloma (RRMM) requires a careful evaluation of the results of previous treatments, the toxicities associated with them and an assessment of prognostic factors. Since the majority of patients will have received prior therapy with drug combinations including a proteasome inhibitor and/or an immunomodulatory drug (IMiD), it is the physician’s task to choose the right moment for the start of therapy and define with the patient which goals need to be achieved. The choice of regimen is usually based on prior responsiveness, drugs already received, prior adverse effects, the condition of the patient and expected effectiveness and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs like pomalidomide, carfilzomib and monoclonal antibodies are, or will be, available shortly, while other options can be tried in clinical studies. Finally, supportive care and palliative options need to be considered in some patients. It is becoming increasingly more important to consider the therapeutic options for the whole duration of the disease rather than take a step by step approach, and to develop a systematic approach for each individual patient.

Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18–65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65–0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74–1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl−1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

Chemotherapy-induced peripheral neuropathies in hematological malignancies

Recent developments in the treatment of hematological malignancies, especially with the advent of proteasome inhibitors and immunomodulatory drugs in plasma cell dyscrasias, call for an increased collaboration between hematologists and neurologists. This collaboration involves differentiating chemotherapy-induced peripheral neuropathies (CiPN) from disease-related neurologic complications, early recognition of CiPN and treatment of neuropathic pain. Multiple myeloma, Waldenstrom’s macroglobulinemia and light-chain amyloidosis frequently present with peripheral neuropathy. In addition, multiple myeloma, non-Hodgkin lymphomas and leukemia’s may mimic peripheral neuropathy by compression or invasion of the extra/intradural space. Platinum compounds, vinca alkaloids, proteasome inhibitors and immunomodulatory drugs may all cause CiPN, each with different and often specific clinical characteristics. Early recognition, by identifying the distinct clinical phenotype of CiPN, is of crucial importance to prevent irreversible neurological damage. No recommendations can be given on the use of neuroprotective strategies because of a lack of convincing clinical evidence. Finally, CiPN caused by vinca-alkaloids, proteasome inhibitors and immunomodulatory drugs is often painful and neurologists are best equipped to treat this kind of painful neuropathy.

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma.

The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease

Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/β-catenin signaling and loss of CYLD sensitizes MM cells to NF-κB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFκB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF-κB and Wnt/β-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity.

Phase I/II trial of weekly bortezomib with lenalidomide and dexamethasone in first relapse or primary refractory myeloma

The use of the proteasome inhibitor bortezomib and immunomodulatory drugs such as thalidomide and lenalidomide have markedly improved outcome in patients with multiple myeloma (MM).[1][1] However, the majority of patients will eventually relapse, necessitating salvage therapy. HOVON 86 is a dose

An update in treatment options for multiple myeloma in nontransplant eligible patients.

Introduction: Despite the fact that multiple myeloma (MM) is still an incurable disease, the outcome of patients who are eligible and ineligible for high-dose therapy has dramatically improved with the introduction of novel agents, that is proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). However, this improvement is often not seen in elderly patients (above 75 years). Areas covered: This review will focus on the impact of known prognostic factors in elderly MM patients, and risk factors to identify frail elderly patients. Furthermore, data on known and novel PIs and IMiDs, as well as data on other promising novel treatment strategies, chosen based on current practice and anticipated timely approval, will be discussed. Novel treatment strategies include the use of monoclonal antibodies, such as elotuzumab, daratumumab, SAR650984 and more targeted therapies, such as histone deacetylase inhibitors, kinesin spindle protein inhibitors, and selective inhibitors of nuclear export. Expert opinion: Besides efficacy of treatment, toxicity and quality of life play an important role in treatment choice. Treatment and treatment dosing for the frail elderly as well as risk factors to identify the frail elderly require further consideration, as these patients frequently do not benefit from these novel agents due to early discontinuation of treatment due to toxicity.

Predicting treatment benefit in multiple myeloma through simulation of alternative treatment effects

Many cancer treatments are associated with serious side effects, while they often only benefit a subset of the patients. Therefore, there is an urgent clinical need for tools that can aid in selecting the right treatment at diagnosis. Here we introduce simulated treatment learning (STL), which enables prediction of a patient’s treatment benefit. STL uses the idea that patients who received different treatments, but have similar genetic tumor profiles, can be used to model their response to the alternative treatment. We apply STL to two multiple myeloma gene expression datasets, containing different treatments (bortezomib and lenalidomide). We find that STL can predict treatment benefit for both; a twofold progression free survival (PFS) benefit is observed for bortezomib for 19.8% and a threefold PFS benefit for lenalidomide for 31.1% of the patients. This demonstrates that STL can derive clinically actionable gene expression signatures that enable a more personalized approach to treatment.Selection of the right cancer treatment is still a challenge. Here, the authors introduce a framework to analyze treatment benefits, using the idea that patients with similar genetic tumor profiles receiving different treatments can be used to model their responses to the alternative treatment.

Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients

Multiple myeloma (MM) patients who become refractory to anti-MM drugs have a very poor prognosis. Therefore, it is important to gain insight into the mechanisms of resistance to these drugs. Immunomodulatory drugs (IMiDs) have immune-stimulatory and anti-angiogenic properties as well as direct anti-