Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.     

Longer‐term follow‐up and outcome by tumour cell proliferation rate (Ki‐67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL‐001(EMERGE) pivotal trial

Patients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.     

Immune checkpoint blockade immunotherapy to activate anti‐tumour T‐cell immunity

The tumour microenvironment plays a dual role in cancer: it can promote tumour progression by establishing pro‐tumour survival conditions but can also suppress tumour progression by killing cancer cells or inhibiting their outgrowth. These dynamically interconnected processes are under intense investigation to better understand cancer pathophysiology and allow identification of new therapeutic approaches. The ability of cancer cells to evade anti‐tumour T‐cell activity in the microenvironment has recently been accepted as a hallmark of cancer progression. This review will highlight the most promising therapeutic approach aimed at activating anti‐tumour T‐cell immunity in the cancer microenvironment: blocking inhibitory immune regulatory proteins (immune checkpoint ligands and receptors). There is emerging evidence that haematological tumours co‐opt immune checkpoints as a major immune resistance mechanism. Pre‐clinical findings indicate that targeted therapies and blockade of immune checkpoints could be combined to promote therapeutic synergy and long‐term anti‐tumour immunity to improve clinical outcomes for cancer patients.     

High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone

Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs) and its downregulation has been linked to resistance to lenalidomide. Here, we studied CRBN expression by real time polymerase chain reaction in 49 bone marrow samples of newly diagnosed patients with multiple myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was 3·45 in patients who achieved complete response, and 3·75, 2·01, 0·78, and 0·70 in those with very good partial response, partial response, stable disease and progressive disease respectively. CRBN expression levels correlated significantly with response to lenalidomide treatment (r = 0·48; P < 0·001). Among established prognostic parameters, only beta‐2‐microglobulin correlated with cereblon (r = 0·66; P < 0·001). A close association of CRBN with interferon regulatory factor 4 (IRF4) (P < 0·001) and with CTNNB1 (P < 0·001) was found. Overall, a statistically significant association between baseline CRBN expression and response in MM patients treated with lenalidomide is shown. CRBN expression is closely associated with IRF4, which is an important target of IMiD therapy.     

Thalidomide and lenalidomide in multiple myeloma

Multiple myeloma is a treatable but not necessarily a curable plasma-cell cancer. After decades of minimal progress, two new classes of drugs with novel mechanisms of action - immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) - have been introduced for the treatment of this disease. Thalidomide and lenalidomide have shown great activity as single agents and in combination with glucocorticoids for the treatment of chemotherapy-refractory myeloma. Thalidomide - and more recently lenalidomide - in combination with dexamethasone have shown promising results as induction therapy. These drugs can easily be combined with other chemotherapeutic agents to potentiate the anti-myeloma effect. The immunomodulatory function of these drugs can be successfully exploited to control residual disease during remission. Thus, both thalidomide and lenalidomide have ushered in a new era of optimism in the management of this incurable cancer.     

Lenalidomide and thalidomide in the treatment of chronic pain

ABSTRACT

Introduction: Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood.

Areas Covered: A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found.

Expert Opinion: The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.     

How to treat patients with relapsed/refractory multiple myeloma: evidence-based information and opinions

Introduction: Relapsed/refractory multiple myeloma (rrMM) remains a difficult condition to treat despite the availability of new drugs. This review aims to provide evidence to guide physicians in the choice of salvage therapy in certain subgroups of patients.

Areas covered: The review attempts to present evidence-based information and suggest possible approaches based on data on previous therapies, previous remission duration and toxicity of previous treatments, patient's co-morbidities and disease characteristics at relapse. Unfortunately, little evidence is available; there are no large and/or randomized trials, direct comparisons of drugs or combinations for rrMM patients to draw any definite conclusion.

Expert opinion: Almost all the studies presented here suggest that depth of response is a key factor also for patients with rrMM. Identifying the best approach between combinations and sequential therapies remains controversial. Several studies favor the former approach in early relapse as it leads to a higher complete response rate, regardless of previous therapies. However, in both strategies, achieving maximal response should always remain a main goal. Consolidation/maintenance therapy is beneficial both in combination and sequential therapies also in rrMM. Second generation new drugs, such as pomalidomide, carfilzomib, bendamustine and HDAC inhibitors, will probably expand the rescue possibilities also in this setting.