IMW 2017

Dr Garderet speaks with ecancer at the 16th International Myeloma Workshop about the outcome of third salvage autologous stem cell transplantation in multiple myeloma. Autologous stem cell transplantation remains a standard treatment for younger patients with multiple myeloma. With the aid of new drugs, the patients live longer and third salvage ASCT is an increasingly used option. However, the outcome of third salvage autologous stem cell transplantation has not yet been analysed.

Dr Lentzsch speaks with ecancer at the 16th International Myeloma Workshop about genomics and disease monitoring and debating wether precision medicine is more hype than reality.

Monica Morris speaks with ecancer at the 16th International Myeloma Workshop about guidelines for screening and management of late and long-term consequences of myeloma and its treatment.

Dr Garderet speaks with ecancer at the 16th International Myeloma Workshop about the highlights of IMW 2017, particularly antibodies and immunotherapy.

Monica Morris speaks with ecancer at the 16th International Myeloma Workshop about findings from a study into the experience of caring for myeloma patients.

Dr Lentzsch speaks with ecancer at the 16th International Myeloma Workshop about the CASTOR trial. The CASTOR trial is a phase III randomised controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma.

Prof Chng speaks with ecancer at the 16th International Myeloma Workshop about the landscape of current international trials in multiple myeloma, focusing on Asia-Pacific countries. He highlights the issues in variation of clinical practice and drug accessibility in the region, and why a clinical trial network has been set up.

Dr Lesokhin speaks with ecancer at the 16th International Myeloma Workshop about the biology behind immunotherapy in MM and its implications for the future.

Dr Majumder speaks with ecancer at the 16th International Myeloma Workshop about increased mutational burden and alterations to DNA damage repair genes are associated with poor prognosis and sensitivity to PI3K-mTOR inhibitors in multiple myeloma.

Dr Raje speaks with ecancer at the 16th International Myeloma Workshop about an international, randomised, double blind trial comparing denosumab with zoledronic acid for the treatment of bone disease in patients with newly diagnosed multiple myeloma.

Dr Boccia speaks with ecancer at the 16th International Myeloma Workshop about the CHAMPION-2 study. The study evaluated different dose levels of carfilzomib in combination with fixed-dose cyclophosphamide and dexamethasone for the treatment of newly diagnosed multiple myeloma (MM). Carfilzomib is a selective and irreversible second-generation proteasome inhibitor. Carfilzomib (56 mg/m2) twice weekly combined with cyclophosphamide and dexamethasone had manageable toxicity and was effective for treating patients with newly diagnosed MM.

Dr Salomon Manier speaks with ecancer at the 16th International Myeloma Workshop about cell-free DNA (cfDNA) and circulating tumour cells (CTCs) sequencing that enable serial temporal sampling. The team looked at whole-exome sequencing (WES) and ultra low pass-whole genome sequencing (ULP-WGS) of cfDNA and CTCs in multiple myeloma. The study demonstrated that WES and ULP-WGS of cfDNA and CTCs are consistently representative of tumour DNA alterations in terms of CNAs and SNVs. This approach could therefore be used to longitudinally follow clonal evolution and minimal residual disease in MM, personalising and improving treatment. It also reduces the need for bone marrow biopsy, greatly improving the patient experience.

Prof Mateos speaks with ecancer at the 16th International Myeloma Workshop about an overview of sessions at IMW 2017, first discussing the rationale and mechanism of action for monoclonal antibodies (mAbs) in the treatment of myeloma. She then focuses on the clinical impact of some mAbs, including elotuzumab, daratumumab, isatuximab and checkpoint inhibitors. An overview of some of the key results for these treatments are discussed, highlighting the benefits that mAbs can provide to multiple myeloma patients. Summarising the future role of mAbs, it is suggested that results coming from daratumumab show that it should be a backbone to which the backbone regimes should be added.

Dr Niesvizky speaks with ecancer at the 16th International Myeloma Workshop about promising agents in phase II trials for the management of myeloma. He discusses the difficulty of integrating new agents into new molecules, and the challenge that patients face when trying to select effective drugs for their treatment.

Dr Zonder talks to ecancer at the 16th International Myeloma Workshop about emerging strategies tailoring immunotherapy to individual patients with multiple myeloma.

Dr Siegel speaks with ecancer at the 16th International Myeloma Workshop about an updated analysis of efficacy and safety of pomalidomide and low-dose dexamethasone following second-line lenalidomide -based treatment in patients with relapsed or refractory multiple myeloma.

Prof Terpos speaks with ecancer at the 16th International Myeloma Workshop about the bone related complications seen with myeloma patients (MM) and how these are managed. Approximately 80% of MM patients present with detectable lesions of osteolytic bone disease, meaning it is a critical consideration to the overall treatment and management of patients with multiple myeloma. The current management of MM bone disease is based on the use of bisphosphonates and mainly Zoledronic Acid due to favourable study results. In some patients with side effects such as renal impairments it is recommended to stop bisphosphonates, however new studies involving Denosumab suggest that a solution may be on its way.

Dr Siegel talks to ecancer at the 16th International Myeloma Workshop about the ASPIRE trial, looking at carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. He also discusses the ENDEAVOUR trial looking at carfilzomib in combination with low-dose dexamethasone (Kd), versus bortezomib with low-dose dexamethasone (Vd) in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. Since presentation at ASH 2015 the data from both trials has matured. Consistent with the primary analyses, the results show that incorporation of carfilzomib into treatment regimens in patients with relapsed or refractory multiple myeloma results in clinically meaningful improvements in progression free survival and a favourable benefit–risk profile.

Prof Terpos speaks with ecancer at the 16th International Myeloma Workshop about late breaking data from IMW 2017, assessing the efficacy and safety of denosumab compared with zoledronic Acid in newly diagnosed symptomatic myeloma patients. Targeting RANKL, this Phase III study with denosumab met its primary endpoint of non-inferiority to zoledronic Acid in delaying time to first on-study skeletal related events in patients with newly diagnosed myeloma. Denosumab also showed comparable overall survival and for the first time superior PFS compared with zoledronic Acid. Renal adverse events were also greatly reduced with denosumab. These results and the fact that denosumab can be administered subcutaneously, lead to the suggestion that it will become a new standard of care for the management of bone disease in multiple myeloma.

Dr Krishnan speaks with ecancer at the 16th International Myeloma Workshop about the StaMINA trial, which looked at autologous haematopoietic cell transplant (autoHCT) followed by lenalidomide maintenance vs auto HCT and lenalidomide and bortezomib and dexamethasone consolidation lenalidomide maintenance vs tandem autoHCT lenalidomide maintenance The primary results of the largest randomised US transplant trial in multiple myeloma demonstrated comparable progression free survival (PFS) and overall survival (OS). The addition of dexamethasone consolidation or a second auto HCT was not superior to a single auto HCT followed by lenalidomide maintenance in the upfront treatment of multiple myeloma. Tandem autoHCT did not improve PFS or OS compared to single Auto HCT. Consolidation therapy with revlimid-velcade-dexamethasone had a trend towards improved PFS at 38 months but did not achieve statistical significance. However, the high 38 month survival in all arms is encouraging and is in keeping with the high PFS of the lenalidomide maintenance arms in the Myeloma XI trial (median PFS 60 months) and CALGB100104 (median PFS 53 months). Alternate strategies such as combinations with monoclonal antibodies pre and post transplant may lead to further improvements in PFS and OS in high risk patients. A long term follow-up trial to track outcomes in these patients is ongoing.

Following on from their discussion around the treatment of smoldering multiple myeloma patients, Professor Maria-Victoria Mateos (University Hospital of Salamanca, Salamanca, Spain) and Professor Paul Richardson (Dana-Farber Cancer Institute, Boston, USA) focus on advances in the treatment of relapsed/refractory multiple myeloma (RRMM) at IMW 2017 in Delhi. First discussed was the update to the POLLUX trial presented at IMW. After median 17.3 months of follow-up, the addition of daratumumab to lenalidomide and dexamethasone (DRd) demonstrated significantly prolonged PFS compared to lenalidomide and dexamethasone (Rd). As well as showing “the best PFS in a Phase III RR trial”, the DRd combination also resulted in positive overall and complete response rates. With the updates of the trial focusing on depth of response and the role of MRD, MRD negativity was observed in over three times as many patients receiving DRd verses Rd, with no MRD-negative, high-risk patients progressing during the study. Prof Richardson and Prof Mateos then focused discussion on the use of mAbs combined with Pomalidomide and Dexamethasone (POM-D) as a backbone in the treatment of RRMM. A multi-arm, phase 1b study presented at IMW 2017 evaluated daratumumab with POM-D in patients with two or more prior lines of therapy. Deep, durable responses were observed across all subgroups and the results showed a safety profile consistent with individual therapies, with the exception of a higher incidence of neutropenia. Another mAb evaluated in combination with POM-D is Isatuximab, with preliminary data presented at IMW suggesting that the combination is well tolerated and clinically active in patients with heavily treated RRMM. With a number of novel agents and combinations producing promising results in RRMM, the options for patients are set to expand.

Professor Sagar Lonial (Emory University School of Medicine, Atlanta, USA) discusses key advances from IMW 2017, such as the emerging role of new immunotherapies where standard cytotoxic therapies have not been successful. Looking at genetics and genomics, Prof Lonial notes how precision medicine has been very successful in solid tumours but has not previously shown a similar impact for the haem malignancies. He suggests that if we are to cure myeloma it won’t come through one approach but will instead be by utilising all three of immunotherapy, precision medicines and “biology-based” approaches. Touching on MRD, Prof Lonial notes how there is controversy around whether to use flow or next-generation sequencing to measure MRD, suggesting that the latter will be the modality of the future. Whilst MRD is useful as an investigational tool, Prof Lonial suggests that it is not ready for “prime time”. Finally, Prof Lonial discusses the three new treatment guidelines coming from the chairs of IMW 2017. This includes definitions of smoldering myeloma and risk stratification, guidelines for how clinicians could assess risk and suggested treatment approaches, and a consensus statement around vaccination and infection prophylaxis in patients with myeloma. Summarising the recent advances and what this means for patients, Prof Lonial said the overriding message is one of hope for the treatment of myeloma, as well as strong global alignment in the myeloma community due to meetings such as IMW.

Professor Jesus San Miguel (University Hospital of Salamanca, Salamanca, Spain) outlines how the role of minimal residual disease (MRD) negativity has evolved to become part of the central narrative of how multiple myeloma is treated. In the 1980s a cure in multiple myeloma was considered unattainable due to the small proportion of patients achieving a complete response. However, with the introduction of new agents the landscape has changed. This movement led to the International Myeloma Working Group recently publishing a consensus criteria for response and minimal residual disease assessment in multiple myeloma. In this review several aspects of disease response assessment are clarified, as well as endpoints for clinical trials and future directions. Professor San Miguel adds that while the concept of MRD is usually associated with depth of treatment response in multiple myeloma, there could be growing utility around measuring treatment efficacy with long term follow up, as seen in other diseases. The impact that MRD negativity has on patients is then discussed, with clear associations between patients being MRD negative and a positive response. Whilst questions remain, the potential of MRD negativity being a surrogate marker for cure in multiple myeloma is a distinct possibility.

Discussing the latest advances in multiple myeloma from IMW2017, Prof Philippe Moreau (University Hospital of Nantes, Nantes, France) chairs a roundtable discussion with Prof Phillip McCarthy (Roswell Park Cancer Institute, New York, USA), Prof Meletios Dimopoulos (University of Athens, Athens, Greece) and Dr Jens Hillengass (University of Heidelberg, Heidelberg, Germany). The discussion is introduced by looking at SCT-ineligible newly diagnosed multiple myeloma (NDMM) patients and the FIRST trial. Recently updated analyses show that an OS benefit was maintained with continuous lenalidomide plus low-dose dexamethasone (Rd) and was better tolerated compared to melphalan, prednisone, and thalidomide (MPT). Conversation then moved on to the SWOG S0777 study, recently published in The Lancet which looked at how Rd combined with bortezomib resulted in significantly improved progression-free and overall survival, leading many to suggest that this frontline triplet regimen could become a new standard of care in certain NDMM patients. One of the LBA’s at IMW was the CLARION study, which assessed carfilzomib, melphalan and prednisone (KMP) v bortezomib, melphalan and Prednisone (VMP) in NDMM. The panel suggested that it was “surprising” that KMP did not improve PFS compared to VMP in transplant-ineligible NDMM patients, adding that questions remain following the results. Although these results provide great promise at first-line, as patients are going to progress it was asked to the panel how they would treat at first relapse. General consensus was that it depends on the individual patient, however a backbone of Rd plus a novel agent is where the evidence is pointing. Specific mention was made to the addition of daratumumab, with the POLLUX trial suggesting this is the “most effective combination”, with patients reaching MRD negativity “for the first time” in the relapsed setting. Comparing two different proteasome inhibitors for the first time and as one of the LBAs at IMW, the ENDEAVOR trial showed that treatment with carfilzomib and dexamethasone significantly prolonged OS compared to RRMM patients receiving bortezomib and dexamethasone. With the role of MRD becoming more apparent, imaging remains a critical component in the management of multiple myeloma. The panel provide their thoughts on the most effective current imaging methods, as well as looking to the future of imaging techniques.

Prof Maria-Victoria Mateos (University Hospital of Salamanca, Salamanca, Spain) talks to Prof Paul Richardson (Dana-Farber Cancer Institute, Boston, USA) discuss key advances in the treatment of smoldering multiple myeloma for ecancer at the 16th International Myeloma Workshop in New Delhi, India. With the standard of care for smoldering multiple myeloma (SMM) being observation, a number of trials have assessed the early treatment of selected SMM patients to identify whether alternative treatment options should be explored. Prof Mateos first discusses the QuiRedex trial that selected patients at high risk for progression. In these patients, early treatment with lenalidomide plus dexamethasone compared to observation provided a significant benefit both in terms of time to progression to active disease and overall survival. Further studies are discussed that if positive would support the use of early treatment for patients with high-risk SMM. Summarising the discussion, it was suggested that based on current evidence ultra-high risk SMM patients should be treated and “strive for cure”. With the potential for novel biological and genomic markers to more accurately predict the risk of progression, it is clear the therapeutic landscape for both high risk and ultra-high risk SMM patients is set to evolve.

​Prof Pieter Sonneveld (University Hospital Rotterdam, Netherlands) chairs a roundtable discussion for ecancer at the 16th International Myeloma Workshop in Delhi, India. Focusing on newly diagnosed multiple myeloma (NDMM) and the management of bone disease, he is joined by Prof Michele Cavo (Seràgnoli Institute of Hematology, Bologna, Italy), Dr Peter Voorhees (Levine Cancer Institute, North Carolina, USA) and Professor Evangelos Terpos (University of Athens, Greece). First discussed was the treatment of symptomatic transplant-eligible multiple myeloma patients, with Prof Cavo suggesting that although trials continue to explore old and new agents, high dose melphalan supported by ASCT should remain the standard of care for the treatment of fit NDMM patients. Trials assessing these agents were discussed, such as the StaMINA trial presented at ASH 2016, which showed that the addition of bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation or a second Autologous Hematopoietic Cell Transplant (autoCHT) was not superior to a single autoHCT followed by Len maintenance in the upfront treatment of MM. Moving on to asymptomatic patients, Dr Voorhees provided an overview of the treatment of smoldering myeloma (SM). Discussion focused on the evolving therapeutic landscape in SM, with agents such as elotuzumab and checkpoint inhibitors pembrolizumab and nivolumab showing promise. Proteasome inhibition was also discussed, looking at the CESAR and ASCENT trials, with Dr Voorhees commenting that with the latter it will be “interesting to see if this leads to cure”. The panel then focussed on the management of bone disease – the most common complication of multiple myeloma with 80% of patients presenting with detectable lesions. Bisphosphonates such as zoledronic acid are the current mainstay for the treatment of myeloma bone disease, with several novel agents, including denosumab, showing positive results. These advances show that for NDMM patients the future is promising for both first-line treatment options and the management of common complications.

Dr Krishnan speaks with ecancer at the 16th International Myeloma Workshop about phase III trials in myeloma looking at optimal post transplant approaches to improve response. Autologous stem cell transplantation has been shown to improve progression free survival compared to standard dose chemotherapy for multiple myeloma in several phase III trials. However, despite major improvements in response to treatment, relapse remains the major cause of mortality. We now have sufficient evidence to justify the upfront use of autologous stem cell transplantation for suitable patients with myeloma. The use of maintenance therapy post transplant also can be justified on the basis of several randomised trials. Consolidation therapy remains a matter of controversy which may become clearer as the data from two large trials one in the US and one in Europe matures. The most definitive thing to note is that in all these trials overall survival is encouraging and suggests that we continue to advance in our therapy of multiple myeloma.