The MM Hub were delighted to attend Clinical Advances in Myeloma 2018 on 31 January 2018, at the Hallam Conference Centre, London, UK. This was a small conference with approximately 40 attendees and gave us an opportunity to chat informally with local clinicians. The major topics discussed are summarized in an overview article that can be read here. The second session of the day addressed current and emerging treatment strategies, and below the last two talks of this session are summarized below. Some of the presentations from this day can be viewed here.
Improving the outcomes of stem cell therapy
Professor Gordon Cook from St James’s University Hospital talked about improving the outcome of stem cell therapy and the place it has in today’s treatment algorithms. He began his talk with Nordic data that displayed an improved Overall Survival (OS) in patients less than 65 years of age with transplantation. Professor Cook also gave some historical background regarding the concept of transplantation. A study, conducted by Tim McElwain and published in Lancet showed evidence for disease control in MM patients not responding to treatment, who survived following the administration of high-dose melphalan. Another more recent study, conducted by Andy Rawstron demonstrated a sequential improvement in Progression Free Survival (PFS) with log changes in Minimal Residual Disease (MRD), and a deeper response that correlated with longer maintenance.
Professor Cook reminded the audience that autologous stem cell transplantation (ASCT) is very much the standard of care internationally for MM. He then described data from various clinical trials focusing on the use of transplantation. In particular two trails showing the superior effect of lenalidomide compared to thalidomide were shown. In the Myeloma XI trial the lenalidomide, (len), dexamethasone (dex) and cyclophosphamide triplet was associated with deeper responses compared to thalidomide len-dex. There was also a higher proportion of patients with a Very Good Partial Response (VGPR) and Complete Response (CR) when treated with cyclophosphamide len-dex (CRD) in comparison to cyclophosphamide, thalidomide-dex (CTD). Following this treatment, the patients were randomized to receive either cyclophosphamide, bortezomib, and dexamethasone (CVD), or no treatment; a significant improvement was observed in PFS from 28 to 48 months for patients receiving CVD. Overall, the sequential use of novel agents prepares the patient for a better outcome post-transplant.
Using data from the Parallel Phase III Study in NDMM, Professor Cook explained that transplant still has a valid role in our current era of novel agents, driving the MRD negativity to a lower level. Data from the EMN02/H095 MM trial was then discussed, which showed that transplant gave an improved durability of response with the median PFS for ASCT patients not reached versus 42.5 months for patients treated with bortezomib, melphalan, prednisone (VMP). The upcoming Cassiopeia trial (IFM study) will examine the effect of adding daratumumab both pre- and post-transplant consolidation.
Professor Cook defined consolidation as ‘a short course of therapy designed to intensify and deepen the response following initial therapy, including ASCT’. These include second ASCT, novel agent-containing combinations, and bisphosphonates. He emphasized that whilst studies have shown an improvement in the depth of response, and an improvement in the durability of response are measured by PFS, the impact on OS has not yet been proven. However, he believed that consolidation strategies have a definite role in select patients.
Key data from a meta-analysis of tandem ASCT in MM was presented, which showed that tandem ASCT favors Event Free Survival (EFS), defined as the time from diagnosis until relapse or progression. The results of the STaMINA trial were then discussed, which showed that a second round of chemotherapy or stem cell transplant did not improve PFS or OS, compared with the current standard course of treatment, which is a single ASCT followed by lenalidomide maintenance. Professor Cook believed that a few questions could be raised from this trial, including an unconventional definition of high-risk disease, that the time of diagnosis and entry to the study was about 12 months, and that there was significant heterogeneity in how the patients were treated, as well as a limited follow-up.
The arguments for the use of maintenance in MM patients were then presented. Maintenance should be used to prolong the durability of response and could be used for patients with incurable disease whose relapse is inevitable. He purported that the ideal agent for maintenance would be effective, safe and well tolerated, as well as displaying minimal toxicity in both the short and long term. He also believed that such agents should be targeted, with a lack of negative impact on treatment at relapse. He illustrated this with two pivotal phase III studies (US Study by McCarthy and the IFM study by Attal) in which post-transplant lenalidomide gave a significant increase in the durability of response.
Following this, the role of transplant in salvage was debated. Professor Cook spoke about the recent findings from the Myeloma X trial which, showed for the first time that patients who have relapsed from their first transplant and are treated with a second high-dose therapy (HDT) plus ASCT had a longer PFS than patients who were treated with oral cyclophosphamide (19 months vs 11 months). Therefore, in this group, a second HDT plus ASCT was a more effective treatment than conventional chemotherapy.
Proportionally more transplants carried out in the UK per annum are salvage transplants, although the data from 2017 still needs to be added to this. Additionally, it was found that the phase III ACCoRd study, which assessed the role of ixazomib as an Augmented Conditioning therapy in salvage ASCT and as a post-ASCT consolidation and maintenance strategy in patients with RRMM, showed that high-risk patients were not performing very well despite an increase in the durability of response with the transplant.
Professor Cook concluded that transplantation remains a very relevant topic. So far, ASCT has shown to be both safe and effective in suitable patients. Additionally, with the use of novel agents, there is a marked improvement in disease control, although patient selection is key to the success of ASCT. In addition to this, the role of post-ASCT consolidation and maintenance still needs to be defined, and adaptive treatment delivery based on response biomarker needs defining. Finally, the position of salvage ASCT in the modern management pathway continues to evolve, therefore further trials are needed to assess these alongside ASCT. A question raised at the end of this talk requested Professor Cook’s opinion on the use of allograft transplant in MM. He responded that allograft transplant has its role in selected people and reminded us that allograft transplant only gives a cure rate of 25-30% with significant toxicity.
Emerging Immunotherapy Treatment
Dr. Parrish explained that understanding the immunomodulatory effect of the drugs used to treat the immunomodulatory effects, and indeed the magnitude of the immune effect, is paramount to enabling the most effective drug combinations to be delivered.
Dr Parrish then talked through the major immunotherapy agents currently in development for MM. Inhibitors, targeting PD1 and PDL1 checkpoints, are major targets and a study in which lenalidomide was shown to reduce PD-L1 and PD-1 expression on MM cells, as well as T cells and myeloid-derived suppressor cells, was described. Despite the recent stops put to many of the MM trials using such checkpoint inhibitors, Dr Parrish explained that there is still a strong rationale for the development of such inhibitors in MM since PD-L1 expression is strongly present on malignant plasma cells. PDL1 expression also correlates with the disease course with a downregulation of PDL1 expression in relapsed disease. The results of the Keynote-023 study were then briefly discussed. In this study, pembrolizumab (anti-PD1) was combined in dose escalation with lenalidomide, along with a constant dose of dexamethasone to treat RRMM patients. The median OS for all 50 patients was not reached with a PFS of 7.2 months. The median OS for the 37 lenalidomide-refractory patients, was 26.3 months with a PFS of 6.3 months.
The rationale for the use of CAR T-cells in MM was then described. The constructs designed and the relevant targets/antigens in use were outlined – for more information on CAR T-cells in MM, read here. The ability of CAR T-cells to identify tiny amounts of target antigen was highlighted. In particular, the suitability of B-cell maturation antigen (BCMA) in MM due to its high expression on malignant plasma cells was discussed. The results of the clinical trial for bb2121, for which it was found that the Overall Response Rate (ORR) for patients infused with 150 million T cells was 89%, and for the patients who received a higher amount of T cells had a 100% ORR, was presented. However, it was important to note that 71% of the patients suffered from Cytokine Release Syndrome (CRS), which was a major side-effect. You can read more about this study here.
Dr Parrish briefly spoke about Bi-specific T-cell engagers (BiTEs), which are a new generation antibody that combines an antigen against the tumor cell with an antigen against the T cell (usually anti-CD3) in order to bring the two into close proximity and enable killing by the T cell. The use of oncolytic viruses was also explained, as they can divide and replicate in cancer cells to harness the dysregulated growth pathway. Such oncolytic viruses are being assessed in the MUKeleven trial. He also spoke about the design of a dual-targeted CAR T-cell, which targets both BCMA and TACI, using their natural binding ligand APRIL (a proliferation-inducing ligand) conjugated to the backbone CAR-T constructs. For more information on this CAR-T construct read here.
Finally, Dr Parrish raised numerous questions regarding the use of immunotherapy in the clinic. He reminded the audience that these novel agents aim to harness particular aspects of host immunity which is compromised in MM, as well as the importance of selecting the right patients. Patients may respond differently depending on the prior treatment regimen, due to alterations in the kinetics of relapse, which needs to be further explored. Finally, he discussed daratumumab as an example for which harnessing the immune system enhances its activity, as combinations work far better than its use as a monotherapy.
Dr Parrish concluded that immunotherapy is a large topic and that a new arsenal of very effective and targeted therapies are currently being developed. He also emphasized that many questions still need to be answered for the effective use of immunotherapy, which includes the effective selection of patients for individual treatments, the delivery of treatment in the clinic and finally the management of toxicities.