14th International Myeloma Workshop (IMW) 2013

The approach to managing relapse in multiple myeloma (MM) has changed dramatically in the last 10-15 years. The choice of therapy has expanded to include novel therapies, but will still depend on the patient group, whether they are healthy elderly, elderly frail or relapsing after a transplant, and whether they are symptomatic or asymptomatic. The present of comorbidities, renal failure and previous experience of toxicities, such as peripheral neuropathy, will also influence treatment choice. In patients who experience long remissions after initial autologous stem cell transplant (ASCT) a second ASCT can be considered. In these patients, where an induction, consolidation and maintenance strategy has been used, the same should be offered again. This decision is based on the outcomes seen in the European trial of bortezomib, thalidomide and dexamethasone versus thalidomide and dexamethasone in relapsed patients, which demonstrated superior outcomes in the bortezomib group. In the elderly, frail or those that do not want to go through aggressive therapy, or those that have comorbidities, renal failure or peripheral neuropathy, treatment will be tailored to the patient's requirements. In the US, a carfilzomib based regimen can be used in a patient with peripheral neuropathy, in which a proteasome inhibitor is warranted. In patients with renal failure, lenalidomide can be used according to current guidelines, or pomalidomide can be considered. In elderly patients who are symptomatic, a treatment regimen should be considered that the patient can tolerate and that will improve outcomes. In asymptomatic patients, observation only may be warranted. In Europe, the approach would be similar, except that carfilzomib and pomalidomide are not yet approved for use. In younger patients, where relapse has occurred within 12 months, treatment can be a particular challenge. A second ASCT has not been found to be effective in this group of patients. These patients are ideal candidates for clinical trials. Allogeneic transplant may be one option. New conditioning regimens for ASCT and innovative post-transplant combinations can also be considered. Cereblon has been shown to predict the response to immunomodulatory drugs. It could become an important predictor of response for MM in the future. Its expression has been shown to correlate to response to lenalidomide and dexamethasone therapy. However, it did not correlate with progression free survival (PFS) or overall survival (OS). However, these initial data need to be confirmed with further studies. A good antibody is needed to detect cereblon expression with immunophenotyping. ELISA could also be used to detect cereblon in serum. In the US lenalidomide maintenance after lenalidomide induction is commonly used. In Europe, lenalidomide maintenance is not approved. It is hoped that more data will be available soon to support the use of lenalidomide as maintenance in Europe, as it has been shown to be particularly beneficial in low risk patients.

ecancertv talks to Eric Low at IMW 2013, Kyoto, Japan, 3-7th April Myeloma UK is a registered charity and is the only organisation in the UK dealing exclusively with myeloma. They are attending IMW 2013, among other major meetings to consolidate current understanding of the pathophysiology, diagnosis and treatment of multiple myeloma (MM) and to enable them to then translate this into clinical relevant information for both patients and clinicians. The understanding of the genetics behind MM could help to stratify patients more appropriately to treatment in the future, and will provide insight in terms of disease progression and prognosis. Although there is significant discussion of the latest imaging techniques, PET/CT and MRI, this are not being used routinely in clinical practice because of cost and access. However, because adoption of new imaging techniques takes so long, there is a need to think about how these would be used in the future for the for the determination of stage of disease, response to therapy and prognosis in clinical practice. The novel agents bortezomib, lenalidomide and thalidomide are all routinely used in clinical practice in the UK, and because MM is a very heterogeneous disease, the drug regimen is chosen to fit individual patient needs. There has been much debate around to positioning of autologous stem cell transplantation (ASCT) in the management of MM; whether it should be used upfront or delayed until further in the disease lifecycle. In the UK, treatment in transplant eligible patients tends to be induction with a novel therapy based regimen, followed by ASCT, consolidation, and in some cases maintenance with thalidomide.

The use of novel agents bortezomib, lenalidomide and thalidomide in Asian patients is discussed. Bortezomib is used as induction therapy and lenalidomide and thalidomide are reserved for relapsed or refractory patients in Japan. Rare reports of complications with these agents have been reported, However these are not believed to be treatment related. The increased incidence of cancer in survivors of the atomic bomb during World War II has been addressed at IMW. Results from the Life Span Study investigating radiation effects on leukaemia, lymphoma and MM incidence in atomic bomb survivors were presented at this year's IMW meeting. This study found that the radiation exposure associated with this may be a possible predisposing factor for MGUS. However, the incidence of multiple myeloma appears to be the same as Western populations. Overall, the incidence of MM appears to be lower in the Asian population, but higher rates have been noted in Vietnamese patients. A number of clinical studies are ongoing covering the use of novel therapies, autologous stem cell transplant and maintenance therapy.

The incidence of MM shows ethnic difference evidenced by US SEER and IARC data. Asians show lower incidence compared to Caucasian. However, there are growing evidences that MM is increasing in Asia. The researchers collected 3,405 patient data from 22 centers of 7countries to build an Asian myeloma data base. Retrospective analyses were carried out to elucidate the presence of clinical and cytogenetic characteristics of MM in Asia. Median age was 62 years, 56% were male, bone lesion, severe anemia, thrombocytopenia, extramedullary plasmacytoma, hypercalcemia, hypoalbuminemia, renal dysfunction, increased LDH was observed in 80/39/8/16/19/52/23/28% respectively. IgG/A/LC was 55/22/17%. ISS was 20/36/44%. Abnormal cytogenetics were observed in 33%, hypodiploid 15%, 13q deletion 12%, FISH analysis shows t (4; 14), t (11; 14), t (14; 16), del 17p, 11/17/4/13% respectively. OS was 47 months. Age, Hemoglobin, platelet, plasmacytoma, BMPC, calcium, albumin, creatinine, beta-2 MG, LDH, ISS, abnormal cytogenetics, 13q- by conventional cytogenetics, t(4;14) by FISH, ASCT, response to treatment, achievement of VGPR were prognostic variables for OS. Among them, azotemia, ISS, heavy chain, plasmacytoma, abnormal cytogenetics, ASCT, response to treatment remain as prognostic variables by multivariate analysis. There were no unique clinical or cytogenetic characteristics identifies in Asian population. However, Dr Lee states that some unique findings, such as high incidence of del 17p in China, need to be explored in future study.

Dr Hiroshi Kosugi, Director of the Department of Haematology at Ogaki Municipal Hospital, and Vice President of the IMW 2013 Kyoto meeting talks to ecancertv about the Japan Myeloma Network, clincial trials in Japan, and problems facing myeloma treatment in Japan.

Consolidation therapy is short term and intended to further enhance the frequency and quality of response obtained with the previous treatment phases. In the era of novel agents, consolidation therapy is needed to increase the rate of complete response (CR), even in the transplant setting. Maintenance therapy is a developing concept and is one that is considered to be important in the management of minimal residual disease. A recent meta-analysis of data from the MRC Myeloma IX Study has shown that there was an improvement in progression free survival (PFS) with thalidomide maintenance. The downside to thalidomide therapy was the impaired quality of life associated with this treatment, which resulted in discontinuation at around 7 months in most patients. Lenalidomide is a viable alternative option for maintenance due to the fact that it is an oral drug and is well tolerated. Current dosage regimens in clinical trials in Italy are 3 weeks on and 1 week off, rather than continuous therapy long term. It is well tolerated in the elderly population. It has also been investigated in younger patients following high dose treatment. In these patients it has been associated with benefits in PFS across many patient subgroups. It has also been associated with overall survival (OS). Bortezomib maintenance following autologous stem cell transplant (ASCT) has also been investigated. However, this data was limited in terms of establishing its place as a maintenance option. It has been shown to be beneficial in high risk patients, but more data is needed. In the future it is likely that consolidation and maintenance are likely to be complimentary therapy protocols in the management of multiple myeloma.

This expert panel discussion filmed at the 14th International Myeloma Workshop, 3-7th April, looks at understanding of new data in the diagnosis and prognosis of multiple myeloma. Pomalidomide and carfilzomib have recently been approved in the US for treatment of multiple myeloma (MM). Pomalidomide was approved on the basis of two Phase II trials. A robust response of approximately 30% was seen in both studies in double refractory patients, with durability of response and impressive progression free survival (PFS) and overall survival (OS). In both trials, a predictable and manageable toxicity profile was observed. This drug represents a significant advance in the treatment of MM. Combination studies (with bortezomib and carfilzomib) and subgroup studies are underway. Carfilzomib received accelerated approval last year with low dose dexamethasone as a premedication and now in combination. It has shown clear activity in the context of double refractory relapse disease. Carfilzomib is associated with relatively low rates of neurotoxicity. There are other toxicities, although these are believed to be generally manageable. The oral proteasome inhibitor, MLN9708, has shown favourable tolerability. Its activity in combination also appears to be encouraging. However, it does not seem to be as potent as IV or SC bortezomib. Treatment of high risk smouldering myeloma is a key topic at this year's IMW. Smouldering myeloma is a very heterogeneous group of patients, as it also includes MGUS patients who have a very low rate of progression to MM. At the other end of the spectrum are the high risk patients for progression, sometime referred to as 'early myeloma', most of whom will progress to full-blown MM in 2-3 years. Recent Spanish data has shown that thalidomide and dexamethasone in combination can delay the progression to MM, and improve the OS in this group of patients. Myeloma is not only a heterogeneous disease between individual patients, but also within an individual patient. There is more than one subtype of malignant cell, which has important implications for treatment. At any one time during the disease, a single subtype of clone can be dominant. This has been termed the 'clonal tide' in MM. Because of the changing face of MM over the course of the disease, it is thought that a patient showing initial resistance to a therapy who then relapses can subsequently show sensitivity to this treatment again, as the clonal pattern of their disease changes. It is now possible to track the presence of clones over time and it may be possible to develop a myeloma tool based on next generation sequencing to use in biopsies to monitor the clonal content and intervene early before the clone has become too complex. Several monoclonal antibodies have been investigated in MM in combination with lenalidomide and dexamethasone. Further studies are underway. The assessment of minimal residual disease (MRD) should be assessed both inside the bone marrow and outside the bone marrow. Outside the bone marrow, imaging techniques such as PET scan should become the gold standard. In the bone marrow, there are two imaging techniques available. The first of these is molecular imaging and the second is multiparameter flow cytometry (MFC). The latter is more applicable for use in routine laboratories. A combination of both extramedullary and intramedullary assessments would provide the best tool to help decide on therapy in the future. Currently, studies have shown that a positive MRD can help guide consolidation and maintenance therapy. Bisphosphonates are used routinely in MM patients. A recent study on zoledronic acid has shown that the use of zoledronic acid not only reduced bone disease but improved survival in the patients treated. This is the first time a survival advantage has been seen with supportive care. As a result, guidelines now recom

Dr Kalff and colleagues carried out an extended analysis of the ALLG MM6 trial. Their aims were to determine whether the significant PFS and OS advantages seen for thalidomide consolidation post ASCT at 3 yrs post randomization in the ALLG MM6 trial were durable at longer follow-up. This included comparing the overall response rate (ORR) to salvage therapy and secondary primary malignancy (SPM) incidence. They looked at 243 newly diagnosed MM patients post single MEL200ASCT; randomly assigned to receive indefinite prednisolone (pred) maintenance (50mg alternate days) alone (CA n=125) or in combination with 12 months of thalidomide consolidation(100mg/d increased to 200mg after 2/52) (TA n=111). PFS and OS were measured from date of randomization. After a median follow-up of 5.4 yrs, the post randomization estimated 5 yr PFS rates were 27% and 15% (P=0.005; hazard ratio [HR], 0.16; 95% CI 0.044 to 0.582) and OS rates were 66% and 47% (P=0.007; HR 0.12; 95% CI 0.028 to 0.558) in TA and CA respectively. TA remained beneficial irrespective of pre-ASCT B2M level

Treating special population in multiple myeloma (MM) is a significant problem. This group increasing includes the elderly as the population ages. It is therefore important to understand how best to tailor treatment for these patients. Professor Palumbo has been involved in a number of key studies in elderly patients with MM. High risk patients are currently managed in the same way as standard risk patients, with a view to providing the best chance of progression free survival and overall survival in this patient population. In newly diagnosed elderly patients the benefits of carfilzomib have been investigated. In addition, lenalidomide has been tested in these patients. Relapsed or refractory patients can be a particular challenge in the clinical setting. Pomalidomide is a new therapy that is currently been investigated in this difficult to treat population.

Dr Ely talks to ecancertv at the 14th International Myleoma Workshop, Kyoto, Japan, 3-7th April 2013. There are now several treatment options for myeloma but little data to help decide which drugs to use. A proliferation assay devised in the 1980s showed proof of principle, that assessment of proliferation is an accurate predictor of clinical behavior. Since then, for technical reasons, clinical implementation of a proliferation assay has not been successful. The researchers invented an immunohistochemical platform (U.S. patents applied) to assess myeloma proliferation. Unlike prior methods, it is performed at the single-cell level, on routinely-preserved marrow, using standard laboratory equipment. The test can be read manually or via image analysis, using the software (U.S. copyright applied) which runs on any PC or Mac. The prospective analysis of patients followed 14 years after an IRB-approved BMT trial showed an inverse correlation between survival and myeloma cell proliferation (P = 0.006). Also, the retrospective cohort study showed that each 1% increase in proliferation was associated with a 3% increase in risk of progression (P = 0.02). PFS was 232 weeks vs. 110 weeks for 10%, respectively (P = 0.03). The new assay provides reliable prognostic information that can be used to approach care on a patient-specific basis. Because the assay can be performed currently in any diagnostic laboratory, the researchers believe patients would benefit from its standard use in clinical trials. It would improve upon current practice by providing biologic tumthe behavior data. Such data might predict well, which drugs would work best in an individual patient.

Dr Keats talks to ecancertv at the 14th International Multiple Myeloma Conference in Kyoto, Japan, 4th April 2013. Dr Keats and his team have been looking at the genomes of around 260 multiple myeloma patients from different studies to pull out key mutations and potential targets for new therapies. In an ideal near future each multiple myeloma patient would have their whole genome sequence analysed so that targeted therapy can be administered.

Dr Essex talks to ecancetv at the 14th International Myleoma Workshop, Kyoto, Japan, 3-7th April 2013. Multiple myeloma (MM) plasma cells co-cultured with stroma taken from MM bone marrow demonstrates that it is the stroma, rather than the plasma cell, that acts as a major determinant of disease progression in MM. The role of bone marrow mesenchymal stem cells (BMMSC) in the progression of MM and monoclonal gammopathy of undetermined significance (MGUS) was investigated. BMMSC were isolated from control, MGUS and MM bone marrow. The full genetic profile of these cells was examined using microarrays, with detailed pathway analysis to determine the genes involved in disease progression. 30 patients BMMSC were analysed using U133 plus 2.0 GeneChip microarrays; this highlighted 187 genes that had over a 1.5 fold difference in expression between control and disease BMMSC. Pathway analysis of these genes generated several differentially expressed pathways, with Wnt signalling being the most evident. Two Wnt pathway genes whose expression is significantly decreased in disease BMMSC are secreted frizzled-related proteins (sFRPs) 2 and 4. This decrease in expression was confirmed by RT-PCR, with a concurrent increase in methylation status suggesting these genes have become epigenetically silenced. Splice variant analysis of these particular genes showed a differential expression of exons, which may be functionally significant for Wnt signalling. For the first time Dr Essex's team showed profound silencing of negative regulators of Wnt signalling within MM and MGUS BMMSC, which may help to design early interventions aimed at patients in the premalignant state.