General MM,   Patients non-eligible for transplant,  Patients eligible for transplant,   & 2 more

COMy 2018 | An Overview

The 4th World Congress on Controversies in Multiple Myeloma (COMy) took place in Paris from 3–5 May 2018 at the Tour de Eiffel Novotel. The congress boasted record attendance of 500 delegates from 30 different countries, along with some of the biggest names in multiple myeloma (MM).

The COMy meeting was originally established in 2014 with the objective ‘to bring to the forefront the latest and most controversial data and information in the field of MM, providing a unique opportunity for world-class leaders in the field to debate vital and contentious issues’. In recent years, the focus of the congress has evolved to include an emphasis on patient-centered care. Therefore, the latest meeting began with a dedicated session for patient advocacy groups to discuss access to new drugs in the European market. This session was well attended, and patient perspectives remained a theme throughout the meeting. The MM Hub will be providing in-depth coverage of many of the individual sessions, but this article aims to provide an overview of the major themes and topics discussed.

Thursday 3 May
Session 1: Advances in disease biology

The first session began with a talk by Herve Avet-Loiseau, who provided an update on cytogenetics and genomics and in particular new definitions of high-risk patients, as well as prognostic implications of mutations in MM. Professor Avet-Loiseau explained, “In the future, we need to revisit our definition of high-risk, as not all t(4;14) patients should be considered high-risk”. Paola Neri talked about the rationale for immunotherapy in MM, describing components of the bone marrow niche and immune dysregulation, and outlined the theoretical basis for the various strategies currently in use. Nikhil Munshi discussed the concept of clonality in MM, describing the inherent clonal heterogeneity and complex mutational landscape, focusing on evolutionary progression from smoldering MM to MM, and therapeutic targeting. Finally, Mark Raab spoke about drug combinations and the role of signaling.

Session 2: Organ damage and practical considerations

Evangelos Terpos introduced the second session and spoke about managing bone disease in MM and the pros and cons of the various therapeutic options currently available. Jean-Paul Fermand then explained how monoclonal gammopathy of undetermined significance (MGUS) can often be clinically significant, leading to renal and skin manifestations requiring clinical intervention. Heinz Ludwig then spoke about the importance of supportive care, in particular in terms of managing infections, vaccination regimens, and other side-effects of ongoing medication. Finally, Richard Baz concluded this session with a talk about health-related quality of life (HRQL) considerations in MM, and in particular how further HQRL studies are required that build on current measurements taking into account ‘real world’ data outside of clinical trials.

Session 3: Special lectures

The day concluded with two special lectures, the first of which was presented by Joan Bladé who spoke about the latest advances in AL amyloidosis, a secondary complication of MM, explaining how it occurs and how it can be diagnosed, as well as clinical presentation and treatment options. Steven Treon then presented a talk about Waldenström macroglobulinemia, describing the molecular basis for the disease and current treatment regimens.

Friday 4 May
Session 4: Treatment guidelines for young patients

Michele Cavo was the first speaker of the day with a talk about the optimal induction regimen, explaining how induction therapy is now part of a new treatment paradigm in order to maximize depth of response after autologous stem cell transplant (ASCT) and explaining that, “the future of frontline regimens is likely to be driven by minimal residual disease (MRD) or cytogenetics”. Pieter Sonneveld then spoke about the role of consolidation in transplant-eligible MM patients and the role that double ASCT might also play, providing fuel for discussion by highlighting the many questions about consolidation that remain unanswered. Sonja Zweegman provided an analysis of options for post-transplant maintenance therapy, focussing on bortezomib maintenance as an alternative to lenalidomide in cases where patients have renal impairment and or presence of del(17p).

Session 5: Modern tools for disease evaluation

Session 5 began with an overview by Joan Bladé on the topic of criteria for disease assessment, comparing the various endpoints used in clinical trials and how the various definitions of response relate to the biochemical measurements and complete workup data. Professor Bladé also spoke about monitoring patients both under active therapy and during treatment-free periods. Elena Zamagni detailed novel imaging techniques and the role they play in MM both at diagnosis in terms of staging, and throughout the treatment journey for continued assessment and as a means of monitoring treatment response. Dr Zamagni explained, “Ideally we should use the same technique at baseline and for treatment assessment”. Jill Corre then explained the differences between the use of NGS and NGF for measuring MRD, in terms of the pros and cons of technical application and clinical sensitivity. Finally, this session was concluded by Vincent Rajkumar who eloquently talked us through how smoldering myeloma (SMM) was originally defined, how we currently define it, and when to treat.

Session 6: Choice of therapy for first relapse after autologous transplant

The first debate of the congress addressed the topic of relapse after autologous stem cell transplant (ASCT). Saad Usmani took to the stand presenting the case for monoclonal antibodies, and summarized the true sentiments of such a debate: “This is not a debate between myself and Sagar…this is a debate each of us has with ourselves when treating patients”. Nevertheless, he presented a compelling argument for the use of triplet regimens with novel monoclonal antibodies at first relapse in cases of high-risk disease and fast or aggressive or slow, biochemical relapse. Sagar Lonial presented the counter-argument with the case in favor of second-generation proteasome inhibitors (PIs) as the optimal choice for salvage therapy. Professor Lonial focussed on the definition of ‘best’, urging caution in falling victim to fad treatments with data from only short-term follow-ups and emphasized the necessity to look at, and wait for, overall survival (OS) data. He concluded that antibodies could be equally effective in first and later relapse, and could, therefore, be saved for later use.

Session 7: Treatment guidelines for elderly patients

After lunch, Mohamad Mohty provided some light relief from debate with an interactive case study. It was interesting to see via a show of hands how disparate the treatment decisions were, although to some degree this may be due to worldwide differences in drug availability. Nevertheless, it was a telling sign that clinicians worldwide are managing their patients quite differently. In addition, assessment of frailty seemed to be limited, and therefore the subsequent talk by Alessandra Larocca was highly relevant, as she explained the relevance of assessing frailty in order to guide treatment decisions, emphasizing that “all elderly are not equal”. It was clear that understanding frailty in terms of application to treatment choices has a long way to go. Following this, practical considerations for the management of frail patients were outlined by Cyrille Hulin who explained how dosing can be adjusted with increased age and how to manage adverse events in these patients.

Kwee Yong took on Thierry Facon in a debate regarding the use of ‘Alkylating agents as part of frontline therapy in the elderly’. Professor Yong proposed that the use of melphalan and cyclophosphamide frontline are still valid options, in particular as partners for bortezomib, arguing that lenalidomide and dexamethasone, in combination, have yet to prove affordable and safe for long-term use. Professor Facon showed data in favor of removing melphalan from upfront regimens, with the high occurrence of secondary primary malignancies (SPMs) a major consideration.

Session 8: Management of special situations

A second debate took place on the topic of Allogenic stem cell transplantation (SCT) for high-risk cytogenetics frontline, with Hermann Einsele tasked with defending this treatment approach and Fredrik Schjesvold tasked with outlining the problems. Professor Einsele concluded that allogenic SCT may still play a role for young, fit patients with ultra-high-risk MM (such as del(17p), plasma cell disease (PCD) and extramedullary disease (EMD)) and that incorporating novel agents into this regimen may further improve outcomes. Dr Schjesvold argued that new regimens gave a greater survival benefit than allogenic transplant and that graft versus host disease (GvHD) is a major implication, but CAR T-cells will undoubtedly “change the playing field”.

Sagar Lonial then took to the podium again to outline the latest results of immunotherapy, providing insights into how immunomodulatory drugs (IMiDs) act to enhance many other therapies and elaborated on how checkpoint inhibitors, monoclonal antibodies, peptide vaccines and CAR T-cells fit into the current MM landscape. Torben Plesner then addressed the topic of ‘Practical considerations when using anti-CD38 antibodies’, a very relevant topic with daratumumab fast making its way into clinics worldwide. Dr Plesner spoke about the management of infusion-related reactions (IRRs) as well as daratumumab interference in both blood tests and MRD analysis to assess CR, emphasizing the need to communicate the inclusion of daratumumab in a patient’s regimen to the blood bank. Francesca Gay provided a current definition of plasma cell leukemia (PCL) explaining in detail how it differs from MM, along with treatment approaches to improve patient survival and future directions. Niels van de Donk followed with an overview of high-risk disease, defined as the following cytogenetic abnormalities: t(4;14), del(17p), t(14;16), amp1q and del1p, and recommendations for induction, consolidation and maintenance regimens.

Session 9: Special lectures - COMy Multiple Myeloma Excellence Award

The final session of the day began with the presentation of the COMy Multiple Myeloma Excellence Awards, which were awarded to Irene Ghobrial and Philippe Moreau, in recognition of innovative research and a significant contribution to progress in the field of MM, “making a true difference from either a clinical or biological perspective”.  Dr Ghobrial’s research focuses on mechanisms of progression from soldering myeloma to MM. Dr Ghobrial was described by Thierry Facon as “very special” having had many of his key researchers journey through the Ghobrial research lab, returning to France with valuable expertise. Dr Ghobrial spoke about ways in which she hopes that early screening might prevent progression to overt MM, detailing some of the innovative techniques that her research team has established. This included the use of liquid biopsies for cytogenetic profiling, single-cell RNA sequencing of the BM microenvironment and the PROMISE trial (Predicting progression of developing Myeloma in a High Risk screened population). Dr Ghobrial thanked her family, friends and many mentors, and concluded by sharing her motto, based on a Martin Luther quote: ‘The fierce urgency of now’, adding, “Every day counts for us to make a difference to our patients. It is truly an honor to work in myeloma”.

Irene Ghobrial receiving her award

Mohamad Mohty presented the award to Philippe Moreau, explaining how he has made significant contributions to the treatment of transplant-eligible patients and the younger population, as well as bringing novel drugs to the relapse setting. Professor Moreau used his time at the podium to talk about ‘25 years of progress’, which was an informative history lesson detailing how many of the early therapies were established and how current regimens have built on these. In particular, Professor Moreau described the many initiatives driven by the IFM (Intergroupe Francophone du Myelome) concluding with details of the Cassiopeia trial to assess daratumumab in newly diagnosed transplant-eligible patients, in combination with VTD (bortezomib, thalidomide, and dexamethasone) versus VTD alone, as part of the induction and consolidation regimen; patients will be randomized again post-transplant to receive daratumumab maintenance.    

Philippe Moreau receiving his award

Saturday 5 May
Session 10: How I manage myeloma

After being slightly detained on account of a slow hotel lift, Bart Barlogie’s arrival was applauded by a full auditorium. Not satisfied with delivering only management and palliative strategies, Professor Barlogie is well-known for his lifelong pursuit of a cure for MM. The title of his talk: ‘The road to cure in a transplant-eligible patient: a practical example’, was, therefore, no big surprise, but nevertheless eagerly anticipated. Professor Barlogie began by defining the concept of a cure and provided examples of successful treatment after relapse. In particular, he emphasized the need for long-term follow up in the region of 15 years or longer, with overall survival (OS) the gold standard endpoint, and concluded that “MM has finally joined the ‘club’ of curable cancers”. The next talk was presented by Lalit Kumar who spoke about ‘Optimal management of myeloma in countries with limited resources’. Practicing medicine in India, Professor Kumar talked about two phase III trials comparing thalidomide-dexamethasone with lenalidomide-dexamethasone as an induction regimen, and bortezomib, lenalidomide and low-dose dexamethasone (VRd) with lenalidomide and low-dose dexamethasone, as well as transplant studies and maintenance strategies. Herve Avet-Loiseau concluded this session with a talk entitled ‘MRD clinical applications: more questions than answers’. Professor Avet-Loiseau concluded that MRD should not currently be used in routine practice, that MRD must be included in all upcoming trials, and that more trials are warranted to address the many open-ended issues.

Session 11: Management of relapsed/refractory myeloma

Arnon Nagler spoke about salvage (second) ASCT in terms of at which point in the treatment journey it is best used, providing a set of prediction factors for success, in particular, a first remission duration of at least 18 months. Meral Beksac followed with a presentation on the topic of IMiDs and PIs in relapse and refractory patients, talking through various clinical trials to compare the efficacy of PIs with newer PIs emerging as less toxic, and showing value overcoming high-risk disease, although limitations to these studies exist and must be evaluated. Xavier Leleu then spoke about the optimal sequencing of therapy, talking through the different trial data for triplet regimens and explaining how continuous use until disease progression may be necessary. He also detailed the study design for many of the upcoming trials, including phase Ib PAVO, phase III ELOQUENT-2, phase III HD-6, MUK9 Trial: OPTIMUM, GEM2017FIT Pethema study, as well as those planned by the IFM.   

Session 12: Novel therapies/approaches

Maria-Victoria Mateos presented an excellent overview of new drugs in the pipeline for MM, showing in a timeline how we have moved from the chemotherapy era to targeted therapy. She then talked through the various mechanisms of action of several new agents; alkylators (eg. Melflufen and EDO-S101), filanesib, venetoclax, selinexor, BCMA-ADC (GSK2857916), and BCMA CAR-T’s. Professor Mateos’ drive to keep working towards a cure was evident with her concluding statement: “Maintain hope and keep working so we can advance in the next 5-10 years as much as we have done in the last years”. Expertise on how to treat extramedullary disease (EMD) was then shared by Saad Usmani, who explained that EMD still carries a poor prognosis even with the use of novel agents as well as what tests to carry out for suspected EMD, and that exclusion of EMD patients from clinical trials is a big unmet need, in particular, those with CNS involvement. He concluded that some agents with novel mechanisms of action do however offer hope, suggesting BCL-2 and XPO1 inhibitors, next-generation IMiDs, and monoclonal antibodies, as possibilities.

Mohamad Mohty spoke provided a detailed analysis of the pros and cons of chemotherapy-based stem cell mobilization. Professor Mohty mentioned the finding that lenalidomide can inhibit stem cell mobilization, but explained that the mechanism for this remains unclear. He touched on the study scheme of the Cassiopeia trial to test daratumumab in the induction regimen, before focussing on the benefits of using plerixfor (Mozobil) for stem cell mobilization in the place of chemotherapeutic regimens, which lead to increased infection, transfusion and the need for hospitalization, adding to treatment costs.

Maria-Victoria Mateos took to the stand yet again to open the debate in favor of treating smoldering MM, arguing that we do not wait for symptomatic disease in any other cancer. The risk of progression to MM was explained, and the importance of identifying the individual risk for each new patient with modern methods now able to identify a subgroup of patients with a 50% chance of progression at 2 years, and the possibility of an international staging system for SMM in the future. Professor Mateos concluded that she would treat every patient with high-risk SMM, arguing that if we were using older definitions/classifications, these patients would have been considered as having MM. Xavier Leleu fought back with the opposite viewpoint, explaining that toxicity of many of the regimens was a key factor, concluding that we still need data from randomized clinical trials to prove substantial benefits. He referred to both the Centaurus study and the GEM-CESAR study, which are currently in progress and will hopefully provide insights into the possible benefits of such early intervention, but that until these come to fruition “observation remains the standard of care in SMM”.

Non-profit symposium

As part of a non-profit symposium sponsored by the Association for Training, Education, and research in Hematology, Immunology, and Transplantation (ATERHIT) and the International Academy for Clinical Hematology (IACH). The topic of CAR T-cells in myeloma was presented by Ibrahim Yakoub-Agha who provided the rationale for CAR T-cell therapy in MM in terms of redirecting the TCR towards tumor antigens, overcoming HLA restriction and boosting the number of high-affinity T cells. Data from several of the CAR T-cell trials was for BCMA (U-Penn, bluebird, and NCI) and CD19 constructs presented, along with mention of a number of other promising antigens, including SLAMF7, CD138 (syndecan-1) and ĸ-light chain. Of note, he outlined plans for the CARAMBA Horizon 2020 project, in which SLAMF-7 CAR T-cells will be prepared using the Sleeping Beauty gene transfer system. The second lecture of this symposium was presented by Karthik Ramasamy on the topic of ‘Incorporating patient perspectives during therapy’. Dr Ramasamy spoke about the challenge of communicating relevant treatment options effectively, as well as maintaining a dialogue with patients with regards to the rationale behind certain decision-making. Examples included a lack of supportive care to enable transplant and geographical distance making administration of certain therapies problematic, highlighting the additional factors that need to be considered for patients ‘living with myeloma’ taking into account both physical and emotional effects equally. He emphasized the conflict between the benefit of continuous therapy and a patient’s desire to have treatment free periods. He also highlighted the need to capture more information from clinical trials about quality of life (QoL), noting that the tools to assess QoL also need revision with increased emphasis on supportive factors.

Session 13: Hot debates

Thierry Facon took on Jean-Luc Harousseau to discuss the topic of continuous therapy as a standard of care. Professor Facon put forward the case for use of continuous [maintenance] therapy, in particular following ASCT in order to drive sustained responses. He concluded that “continuous therapy should be the rule, fixed duration treatment is associated with a greater risk of providing a suboptimal outcome to patients and the role of the myeloma community is to investigate stopping rules”. Professor Harousseau’s counter-argument focussed on the need for randomized studies to assess optimal duration potentially using MRD assessment, alongside improved induction and consolidation regimens.

The next debate focussed on whether autologous transplant should be considered frontline in the elderly. Mohamad Mohty explained how the historical cut-off for transplant was originally set at 65, which was the retirement age in most countries, as well as being an arbitrary age to enable comparisons between trials. However, he argued that age alone is no longer sufficient to define a treatment approach, that many of the emergent complications associated with ASCT were not confined to just the elderly, and that patients should be considered on a case by case basis. Joan Bladé fought back with the counter-argument using the high rate of comorbidities in this population as a valid reason for a cut-off, concluding that “only very fit elderly patients with MM can benefit from high-dose melphalan’.

The next debate was the pros and cons of MRD driven therapy. Philippe Moreau argued the case against the use of MRD in current clinical practice talking us through both the validated points for MM, including MRD negativity acting as a surrogate for PFS and that it is useful to compare treatment options. However, he explained that several open issues remain: it is not yet standardized by PET-CT, the time interval to define sustained MRD negativity is unknown as is the definition of loss of MRD –negative status, as well as optimal timing for assessment and the meaning of MRD-negativity in specific subgroups. He was emphatic that MRD status should not be shared with patients or used to later therapy until we fully understand the impact. Jesus San Miguel argued in favor of MRD-driven therapy using examples to illustrate its value and relevance as an endpoint, and finishing with the question: “If MRD is the most relevant prognostic factor, why do we not use MRD to drive therapy?”.

Session 14: Special lecture

The congress concluded with two special lectures and one of the most awaited talks of the congress presented by Vincent Rajkumar and entitled: ‘Affordable and effective strategies in young patients: do they exist?’. With the well-publicized ASCO debate on the topic of ‘Value and Cost of Myeloma Therapy’ pinned for 3 June between Professor Rajkumar arguing that we cannot afford it, and Rafael Fonseca arguing that we can, many of us were keen for a sneak preview. Professor Rajkumar gave the cost of many of the key therapies in the US, explaining how drug prices have risen astronomically in the last 20 years. He presented many of the issues related to cost, which are unique to the USA, but it was an eye-opener for many of us that had not understood the limitations of this system. There was an emotional charge in the message that we have a responsibility “to choose the best possible option for patients [ie. not necessarily the most expensive one], to recognize that US drug prices matter worldwide [the US market represents almost half of global spending in cancer drugs], and to generate careful, powerful guidelines”. He expanded on this by explaining that what we [as physicians] say matters and that physicians worldwide will build on what is said on these platforms, potentially adapting clinical practice; he, therefore, cautioned the liberal use of terms such as ‘standard of care’.

The mantle for the final talk was handed to Kenneth Anderson who, armed with a lifetime of knowledge, was well-positioned to look forward in terms of where we will be in ‘Myeloma in 2025’. Professor Anderson envisions a future whereby combination therapies will be used to treat patients defined by profiling and biomarkers, leading to “smaller trials, less cost and more rapid approval of novel agents”. Collaborative efforts between academia, biotech/pharma, and government institutions will facilitate continued advances, and achieving long-term disease-free survival and a potential cure will depend on sustained MRD-negativity and restoration of host immunity.

And finally…

Overall, there was a general feeling of excitement during the congress as old friends and colleagues gathered together, with discussion and healthy debate at the heart of the agenda. It is clear that there is both genuine passion and dedication to the cause in the MM community, amongst researchers and clinicians alike, and this commitment was evident in many of the topical debates. The true spirit of such debate was summed up by Mohamad Mohty quoting Joseph Joubert: “It is better to debate a question without settling it than to settle a question without debating it”. Therefore, whilst there may appear to be more questions than answers in MM, with a number of controversies fueling debate, it is heartening to know that the community is working together to educate, inform and communicate their differing viewpoints, with the best outcome for patients very much the end goal. 

The MM Hub will be writing about many of the individual talks in the coming weeks.

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