General MM

ASH 2017 all wrapped up

The 59th ASH Annual Meeting and Exposition was held in Atlanta, US, from 9–12 December, and although the initial buzz from the data has dissipated, the content presented has paved the way for 2018, and will potentially bring about changes in clinical treatment. In this article, I have attempted to curate the sessions covered by the MM Hub, in order to give our readers a flavor of the themes and topics discussed as it unfolded. Using both written articles and video interviews, we managed to cover almost all of the sessions relevant to multiple myeloma (MM) and I hope this coverage will paint a picture of some of the major strides made in MM treatment and research in 2017. Only a month on, we are already seeing changes to drug approvals and guidelines based on some of the data presented.

Three of the major themes that emerged from ASH 2017 in the field of MM include Genomics, Precision Medicine, and Biologics, although these three themes are also intrinsically intertwined. Data for these themes spanned the entire patient spectrum of MM, from early-stage precursor states of smoldering myeloma (SM), monoclonal gammopathy of undetermined significance (MGUS), through to symptomatic MM and that of Relapsed and Refractory MM (RRMM).

Saturday - kicked off with genomics

Genomics dominated the conference and was the focus of many of the talks on the first day, which kicked off with a session on transcriptional regulatory circuitries in MM: Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Transcriptional Regulatory Circuitries of Multiple Myeloma. Catherine Deceunynck chaired this session and highlighted the key areas covered – listen here. Gareth J. Morgan discussed efforts to identify novel oncogenes and tumor suppressor genes in newly diagnosed (ND) MM patients – listen here and read here. Professor Morgan explained that by defining the mutational landscape for MM we can identify new targets that can be modulated therapeutically, such as the Ras/MAP Kinase and NFĸB pathways.

Professor Morgan also explained how genetic profiling can enable segregation of patients into therapeutically targetable subtypes, with differential prognosis. In particular, a group of ‘double hit’ patients that have a poor outcome are key candidates for the latest therapies (such as monoclonal antibodies and CAR T-cells) and can now be easily identified. In the same session, David Melnekoff (abstract 62) presented data from a study that used single-cell RNA sequencing and revealed that myeloma cells in relapsed MM patients form transcriptionally distinct clones. This suggests that therapy should be personalized in order to overcome this clonal heterogeneity.

Several pre-clinical studies were also presented on Saturday during Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: New Insights into the Role of the Immune Microenvironment of Multiple Myeloma – read here, along with studies to examine immune suppression, surveillance and homing mechanisms – read here. These studies examined how the different therapies influence the bone marrow (BM) microenvironment, with the aim of circumventing drug resistance and understanding/modulating immune mechanisms. Saturday afternoon saw Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Mechanisms of Resistance and Prognosis take place, and is summarized here.

Another session on Saturday was entitled: The Yin and Yang of Myeloma: Understanding and Harnessing Normal Plasma Cell Biology to Better Treat Myeloma, which was summarized by Rafael Fonseca – listen here. He explained how plasma cells commit to becoming professional protein production factories and that in MM, such alterations in metabolic commitments can be targeted.

Sunday - more genomics and clinically relevant abstracts

Sunday’s sessions included more genomics with Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomics, in which data from the MMRF Commpass study was presented (abstract 325) and clonal evolution was discussed by Alessandro Lagana. The genetics of progression from SM to symptomatic MM was a topic underpinning many of the abstracts and was covered in Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomics of The Pathogenesis and Progression of Multiple Myeloma – read here.

Ankit Dutta shed light on subclonal tumor evolution associated with MM transformation and progression, with relevance to earlier stratification of patients and tailored treatment regimens. Mark Bustoros presented data from a study using next-generation sequencing (NGS) to identify high-risk SM patients and can be used to predict prognosis. In addition, Niamh Keane presented data to show that MYC translocations are a strong predictor of progression to MM and are found in MGUS and SMM patients with a shorter than average time to progression. The talks from the second half of this session, covering genomics and molecular profiling, are summarized here.

Nikhil Munshi talked in interview about the genomic landscape in MM and its relevance to treatment – listen here. Professor Munshi explained that the rationale for such studies is to provide an improved understanding of myeloma in terms of how patients progress to MM and how myeloma cells change during progression and that with this information, we can now look for specific targets. One of the key findings discussed was the fact that as MM progresses it acquires new mutations, necessitating ongoing analysis in order to stay one step ahead. Professor Munshi described how whole genome sequencing, transcriptome profiling, and epigenome analyses are being combined for a so-called oncogenomic analysis, in order to form a three-dimensional picture allowing a clearer understanding of the biology and 'targetable dependencies' – see the presentation by Raphael Szalat (abstract 328).

Sunday afternoon saw a move towards more clinically relevant abstracts with Session: 653. Myeloma: Therapy, excluding Transplantation: Upfront Therapy for Multiple Myeloma: Induction and Maintenance. The first talk in this session was presented by Sonja Zweegman, with an updated analysis of the Dutch HOVON trial to assess ixazomib, thalidomide, and low-dose dexamethasone in patients not eligible for transplant – read here. This talk was followed by a presentation of data from a Japanese phase II study to assess the efficacy of elotuzumab with lenalidomide and dexamethasone in NDMM patients – read here. The final analysis of the important IFM2009 trial was presented by Herve Avet-Loiseau (abstract 435), which confirmed that sequencing-based measurements of minimal residual disease (MRD) are more sensitive in determining PFS than flow cytometry. Krina Patel presented more data with ixazomib, this time in the post-transplant setting – read here.

In the final talk in this session, Dr. Branagan showed that two-doses of a high-dose influenza vaccine was better than one for most MM patients, and led to seropositivity that lasted the flu season, compared to the SOC vaccine methodology which resulted in low antibody titers within 30 days post-vaccination – read here. Another study along this theme was presented in abstract 903, which examined antibiotic prophylaxis in 977 patients. The study: Tackling Early Morbidity and Mortality in Myeloma (TEAMM), showed that levofloxacin was effective in tackling infection when taken for 12 weeks, with the placebo group presenting with 134/488 patients (27%) with infection compared to 95/489 (19%) of patients taking levofaxacin, and with differences between the two groups emerging after just 4 weeks. 

On Sunday afternoon, 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy in Myeloma and Amyloid took place with several exciting talks. Suzanne Lentzsch summarized the findings from her phase Ib study with a new antibody targeting the amyloid – listen here. In the same session, Craig C. Hofmeister presented data from the Centaurus phase II study to assess daratumumab as a monotherapy for patients with intermediate or high-risk SM (abstract 510).

Sunday evening saw several pre-clinical studies presented, with Session 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Novel Immunotherapeutic Strategies in Multiple Myeloma. Dr. Charlotte Pawlyn described some of the topics discussed in this session ­– listen here. In particular, she talked about the development of ‘off-the-shelf’ or universal CAR T-cells (as opposed to autologous CAR T-cell products) and explained that the challenge ahead is to ensure that these products aren’t rejected in the patient being treated. Another pre-clinical session was held on Monday: Session 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Emerging New Targets and Mechanisms of Resistance, and was summarized by Dr. Nicola Lehners ­–  listen here. This session taught us that myeloma cells scavenge mitochondria from the stromal cells in the bone marrow microenvironment via a CD38 dependent mechanism; several new targets were also revealed, as well as ways to overcome drug resistance.

Monday - biologics entered the fray

Monday saw some of the most talked about abstracts presented, with biologics making their entrance on the stage. One scientist was quoted as saying: ‘CAR-Ts are so hot they might melt the snow’, and in particular a quote on Twitter from Keith Stewart stood out: ‘If you are a myeloma cell winter is coming: the night is dark and full of CAR T-cells.’ Clearly, the data presented was highly promising, with Jesus Berdeja and James N. Kochenderfer’s updated data from the bb2121 trial (anti-BCMA CAR T-cell) making waves. In addition, Adam D. Cohan’s data was also highly promising – read both studies here, along with a summary of two other abstracts from Sunday’s Session 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy in Myeloma and Amyloid, describing biologics targeting BCMA. An interesting approach taken in a Chinese study used dual targeting with infusion of both BCMA and CD19 CAR T-cells – read here, with preliminary data indicating that this was both safe and effective. BCMA was also the chosen target for GlaxoSmithKline's antibody-drug conjugate, which recently received both Priority Medicine's (PRIME) and breakthrough therapy designation – read here; this paves the way for such technology to be used with other drug conjugate combos, which will be an exciting area to see develop.

Triplet regimens were a focus on Monday, with updated data presented from the ASPIRE clinical trial to assess carfilzomib with lenalidomide and dexamethasone in RRMM patients – read here, and listen here to a summary from Dr. David Siegal. This was followed by a presentation with data on the impact of bortezomib-based induction therapy on high-risk transplant-ineligible patients enrolled in the Ginema-MM-03-05 and EMN01 trials – read here. Daratumumab (dara) was also a key character on Monday’s stage, with the updated data from the POLLUX study to examine efficacy in RRMM patients in combination with lenalidomide and dexamethasone, presented by Meletios Dimopoulos – read here and listen here. Indeed, January has already seen the approval of daratumumab for the treatment of RRMM patients in England and Wales on as a fourth line regimen.

Daratumumab has also entered the fray as a frontline regimen, with data from an interim analysis of the pivotal ALCYONE trial presented as a late-breaking abstract by Maria Mateos – read here, the data for which was also recently published in the New England Journal of Medicine. Success was also achieved with subcutaneous administration of dara – read here, which was exciting news for patients as it allows more convenient self-administration and will limit the time spent in clinics. Several other studies addressed mechanistic questions as to how daratumumab works in combination with other treatments. In particular, Professor Hermann Einsele explained the rationale for combining daratumumab with histone deacetylase (HDAC) inhibitors – listen here.

Clinical abstracts covering RRMM continued into Monday afternoon, with Session 653. Myeloma: Therapy, excluding Transplantation Studies in Relapsed and Refractory Multiple Myeloma excluding transplantation. Data was presented from several abstracts that examined second-line therapeutic options. The first talk covered the phase II MUK five study, to assess carfilzomib, cyclophosphamide, and dexamethasone in first relapse – read here. This was followed by a second study comparing the efficacy of bortezomib, cyclophosphamide, and dexamethasone, with lenalidomide, cyclophosphamide, and dexamethasone – read here, followed by data from another phase II study to examine pomalidomide after lenalidomide first-line therapy – read here. A talk about genomic predictors for PFS in patients enrolled in the ENDEAVOR trial was presented by Dr. Robert Pelham, who revealed a set of genes that can be used to identify and stratify RRMM patients who may achieve enhanced benefit from carfilzomib/dexamethasone therapy – read here. Finally, preliminary data was presented from a phase II study conducted by Robert Orlowski’s group to assess the efficacy of lenalidomide and elotuzumab maintenance therapy post autologous stem cell transplant (ASCT) – read here.

Other Key Messages

Clinical abstracts continued on Monday evening with Session 653. Myeloma: Therapy, Excluding Transplantation II, and covered treatment strategies for patients not eligible for transplant – read here. The clinical landscape for NDMM patients was summarized by Dr. Nina Shah – watch here, and the take-home messages for transplant-eligible MM patients were delivered by Professor Philip McCarthy – listen here.

Possibly the most talked about drug in precision medicine for RRMM is venetoclax which has been shown to specifically target patients with the t(11;14) translocation. A clinical trial with an expanded cohort to assess venetoclax in combination with dexamethasone in heavily pre-treated t(11;14) patients, was outlined by Professor Jonathan Kaufman – listen here. This proved to be a safe and well-tolerated regimen with a 65% response rate. Dr. Kaufman concluded by saying that venetoclax illustrates how finding new drugs for new targets can influence how we treat the disease, and indeed venetoclax has been touted to be the next drug approved for MM. The key highlights from ASH in terms of RRMM were summarized by Professor Sagar Lonial – listen here

Key Controversies

The key controversies in MM were discussed by Ola Landgren – listen here. He outlined the ongoing debate regarding when to start treatment with two opposing schools of thought supporting either high-risk SM and symptomatic MM. Therefore, the definition of such high-risk patients is also an area for debate, as well as how and when to assess high-risk. In particular, the value of MRD negativity was a key area of discussion, in terms of how better to define MRD assays and to increase sensitivity. Professor Landgren commented that new technologies, imaging and lab-based methods to measure MRD will impact how patients are treated. In relation to this, Dr. Bruno Paiva discussed using NGF for MRD monitoring – listen here and Professor Irene Ghobrial talked about the impact of NGS in the management of SM – listen here. Another controversy touched upon was MRD might be used to tailor the duration of therapy, as well as whether patients should be given fixed duration or continuous treatment regimens. Dr. Landgren concluded that much of this is difficult to answer, as it will depend on disease subtype and patient class. However, the ongoing spirit of debate is sure to bring us towards some consensus, and at the forefront of all of this is improved quality of life for patients. Professor Heinz Ludwig discussed whether novel MM agents have improved quality of life in patients - listen here.

Conclusion

Overall, the outlook for patients with MM is improving every day, with novel agents changing the way in which we treat and manage patients. What was evident from ASH was that it is not only the new agents that will change the way we treat but also the technology and means by which we administer them. Precision medicine is close to becoming a reality in MM, with biomarkers and genomics guiding risk stratification as well as prognostics and drug susceptibility. With more and more therapeutic combinations on offer, the challenge for doctors will be keeping one step ahead so that the right choices can be made for the right patient, at the right time. ­

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