The MM Hub team were delighted to attend the 22nd Congress of the European Hematology Association in Madrid from 22nd-25th June 2017. On Saturday 24th June an Education Session on Multiple Myeloma was held from 8.00 a.m. - 9:30 a.m. The session was chaired by Adrian Alegre from the Hospital Universitario de La Princesa, Madrid, Spain, and included three talks covering immunopathology, genetics and treatment.
Immunopathology of MM
Professor Nikhil Munshi from the Dana Farber Cancer Center, USA, reviewed the immunopathology of MM, explaining how its origin is related to antigen-driven processes, such as repeated infection, chronic inflammation, and autoimmune disorders. A specific example was given of clonal immunoglobulins against lyso-glucosylceramide (LGL1) developing during the course of the metabolic condition Gaucher’s disease. Binding to this antigen was noted in a third of sporadic human monoclonal gammopathies.
The evolution of myeloma during the course of the disease was then outlined, with progression from normal PCs to MGUS, MM and extramedullary disease, described. It was noted that the myeloma cells have major interactions with the bone marrow (BM) microenvironment, which enhances growth, survival and drug resistance. A fundamental immune consequence in myeloma is the augmentation of myeloma promoting immune responses via plasmacytoid dendritic cells-pDC, myeloid derived suppressor cells-MDSC, T helper 17 and 22 cells (Th17 and Th22), and suppression of myeloma protecting immune responses. Therefore, it was proposed that targeting the immune system could provide new and effective therapeutic strategies.
Strategies to develop therapies against these immunologic targets were then described, with a study by Chauhan et al. outlined, in which targeting Toll-like receptors (on PDCs) with CpG oligodeoxynucleotides, both restored pDC immune function and abrogated pDC-induced MM cell growth. The elevated levels of Th-17 cells in myeloma was also referred to, with IL-17A leading to enhanced myeloma growth. In a study targeting IL17, the antibody secukinumab (anti-IL17A, AIN457), has been shown to effectively reduce myeloma growth, both in-vitro and in-vivo. The level of Th17 cytokines (IL6, IL-17, IL-21, IL-22) were reduced and the Th1 response inhibited. Other antibodies and small molecules targeting pro-inflammatory pathways were listed, with IL-17, IL-20, IL-22, JAK3 and IL-23 all possible targets.
In terms of suppression of myeloma protecting immune responses, it was shown that normalization of IgM post-transplant is a predictor for improved survival. The progression of MM was shown to alter B cell subsets, but were shown to improve after therapy. The discussion then turned to T cell involvement, and the production of virus-specific T cells were shown to be reduced in MM, with a poor response to in-vitro stimulation reported. Data was then shown to illustrate that at baseline, T cell immunity against the stem cell antigen SOX2, correlates with a reduced risk of progression to symptomatic MM.
Increased PD1 expression on effector cells (pDCs, MDSCs) in MM was also shown, and PD-L1 on both tumor and tumor-infiltrating cells, was found to correlate with increased risk of progression to clinical MM. Treatment with lenalidomide reduced PD1 and PD-L1 expression on RRMM BM cells, and data currently in-press (Ray et al. Leukemia), showed that anti-PDL1 monoclonal antibody induced MM-specific CD8+ CTLs and NK-cell mediated cytotoxicity in the presence of pDCs. According to data presented at EHA 2017 for pembrolizumab (anti-PD1) plus lenalidomide and dexamethasone, an ORR of 44.0%, 35% and 33.3% was achieved for all patients, those that were lenalidomide-refractory, or those that were refractory (double- or more-), respectively.
Studies to develop vaccines using single antigen targeting peptides were described, and in particular vaccines used to treat smoldering MM with the goal of preventing evolution to active disease. Finally, the use of vaccination following autologous ASCT was shown. In both cases, lenalidomide enhanced the immune responses and induced memory, possibly via decreased T cell PD-1 expression. Novel CAR T-cell therapies were also touched upon, specifically bb2121 (see previous MM Hub article for more detail of this study) as well as the role of NK and NKT cells. It was concluded that reduction of immunosuppression in MM can be achieved by drugs targeting tumor promoting cells or by enhancing anti-tumor cellular immunity and the following slide summarized the current strategies:
A question was asked regarding the percentage of patients who present with myeloma-specific T-cells, and Professor Munshi answered that, although several in-vitro studies have shown they are increased, in many cases they were not functional. When asked about the prevention of MM, Professor Munshi responded that it relies on immunotherapy.
Some of the topics discussed in this session were also covered in the immunotherapy session at ASCO, reported in a previous MM Hub article.
Genetic classification of myeloma for prognostication and Treatment selection
The second presentation was given by Professor Hervé Avet-Loiseau from the University Cancer Research Center of Toulouse, France. Professor Avet-Loiseau explained that genetic analyses are mandatory at the time of diagnosis, and probably also at relapse in order to define prognosis. Several mutations are known to strongly correlate with a reduction in OS: t(4:14)(p16;q32) (12-14%) of patients, Del(17p) (7-8%), 1q gains (30%), Del(1p32) (7-8%). By studying the survival curves for these patients, compared to those without the corresponding genetic abnormality, the question was posed as to whether short or long survivor outliers could be identified.
Currently, risk stratification in MM is predominantly based on ISS/FISH and gene expression profiling (GEP), although the mutational landscape in MM, mainly based on whole exome sequencing, is now known to be highly heterogeneous, with no specific common mutation and only a limited set of genes is recurrently mutated in MM. The most frequent mutations have no prognostic impact (KRAS, NRAS, DIS3, BRAF, FAM46C), but mutations in TP53, for example, appears to have some prognostic impact, but as it is a fairly rare mutation it has limited potential as a target. Many other mutations are so rare they are unlikely to be of any prognostic value.
The use of targeted exome sequencing was discussed. The panel of tests used in Professor Avet-Loiseau’s group include 246 genes recurrently mutated, 2548 SNPs for copy number changes and whole IGH sequences for 14q32 translocations, allowing assessment of copy number change (17p, 1p32, 1q gains, trisomies), all 14q32 translocations (4-14, 14-16, 14-20, 11-14) and mutations (especially TP53).
The identification of high-risk abnormalities is important for prognosis, but whether such genetic information can be used to propose specific drug targets is still a matter of debate. However, several specific examples of drugs that have been shown to give improved results in high-risk patients (specifically t(4;14) and del(17p)) were shown. The combination of a PI (such as bortezomib, carfilzomib, and ixazomib) and an IMiD appears to improve PFS; improved PFS was also see with tandem HDMEL, indicating that risk-adapted therapy is a real possibility. However, the question remains as to whether this improved PFS is true for newly diagnosed patients, and also what the role of therapeutic antibodies might be.
The next question is whether we are we ready for genomic adapted therapy, or individualized targeted therapy. More than 800 MM genomes/exomes have been sequenced, and have revealed a highly heterogeneous genetic landscape for MM, with only a small set of genes recurrently mutated, namely KRAS, NRAS and BRAF. A specific example described was the activating V600E mutation that occurs in BRAF kinase. Patients with this mutation were found to be refractory to all other therapeutic options, but responded rapidly and durably to low doses of the inhibitor vermurafenib, which specifically interrupts the BRAF/MEK interaction if BRAF has the V600E mutation.
It was concluded that there are several “drugable” molecular targets and that the BRAF mutational profile represents a proof of concept, but that the specific target has to be clonal. In contrast to oncology, genetic classification of myeloma for treatment selection is not yet used.
New approaches to myeloma treatment in 2017
The final talk was given by Professor Jesús San Miguel from the Clínica Universidad de Navarra, Spain, who began with the statement that ‘the goal of therapy in MM should be to search for an appropriate balance between treatment efficacy, toxicity and cost’. In order to assess this, he discussed how depth of response is best correlated with survival and advocated that ‘MRD is the best biomarker to predict outcome’. He then posed the question of whether all MM patients should be treated and was of the opinion that smoldering MM (patients with MC>3g/dl and/or PC>10%, with no CRAB) should not be treated. (To listen to both sides of a Clinical Debate on this topic, you can read the MM Hub article here). However, he discussed the transformation from SMM into symptomatic MM, illustrating how patients could be separated into high-risk and low-risk based on the percentage of aberrant PCs by immunophenotype plus immunoparesis.
The revised International Myeloma Working Group (IMWG) diagnostic criteria was then discussed, with the new biomarkers of malignancy (≥60% PC in BM, a serum free light chain ratio ≥100 and ≥1 focal lesion by MRI) making early intervention possible, and opening up new therapeutic strategies. Therefore, this criteria, along with the concept of MRD, should contribute to individualized treatment based on highly sensitive methods for monitoring treatment efficacy.
Treatment of the different patient subsets was then addressed. For newly diagnosed transplant candidates (generally young), response to induction treatments was shown to translate into prolonged PFS. The combination of a monoclonal antibody plus a triplet based on a PI-IMiD-Dex regimen, could be the future standard of care (SOC) for induction. However, the timing of ASCT (early – upfront vs. late – delayed until relapse) was then addressed. Currently, intensification with ASCT is still SOC for this subset, to enhance response rate and prolong PFS and OS. In a pooled analysis of two trials (IFM-DFCI 2009 and EMN 02/HQ95 trials), early ASCT gave better results than late ASCT: 44% vs. 26% 4-year PFS and 84% vs. 70% 4-year OS, respectively. In patients with high-risk cytogenetics and failure in CR after bortezomib-based induction, double ASCT yielded better results than single ASCT, suggesting this is still a viable option.
Consolidation therapy was defined as a means by which to improve response/deeper therapy, by administration of treatment for a limited period, and maintenance is required to ‘maintain’ a response following therapy, by administration of treatment for a prolonged period. Maintenance therapy with lenalidomide is commonly used following two trials that compared lenalidomide versus placebo post-ASCT (IFM 2005-02, CALGB 100104) and resulted with a markedly improved PFS and OS. The STAMINA trial comparing three modes of treatment: consolidation, double ASCT and maintenance alone, is ongoing, but initial data suggest that the addition of lenalidomide/bortezomib and dexamethasone (RVD) consolidation or a second ASCT, provided no extra benefit when compared to a single transplant followed by lenalidomide maintenance. It was mentioned that the role of Allo-RIC should be revisited in the era of novel drugs, by means of “integrated programs”.
Strategies for patients non-eligible for transplant were then presented. The triplet regimen commonly used is MPT, based on data from 6 randomized trial to compare MPT versus MP: PFS = 20.4 vs. 15 months; HR = 0.67 and OS = 39.2 vs. 33 months; HR = 0.82. Substituting bortezomib for thalidomide (VMP) was also superior to MP alone, with a 13.3-month benefit in OS observed in one trial; although only a marginal benefit in PFS was observed for carfilzomib plus MP (KMP): 22.3 vs. 22.1 months. Positive data from the FIRST trial was shown, showing that continuous lenalidomide (Rd) was superior to MPT alone, and data from the SWOG S0777 study indicated an improved PFS and OS with the addition of bortezomib to Rd.
Finally, strategies in the relapsed setting were covered and it was emphasized that the choice must take into account disease-related factors such as type of relapse, cytogenetic risk, and, extramedullary disease, as well as the efficacy and safety of previous treatments (second ASCT if PFS>3 yr), and patient-related factors (age, comorbidities, frailty). The options for treatment at relapse now include immunotherapy strategies, such as checkpoint inhibitors (eg. pembrolizumab), monoclonal antibodies such as anti-CS1 and anti-CD38, deacetylase inhibitors, BCL-2 inhibitors, XPO1 inhibitors, as well as anti-BCMA CAR-T cell modalities, and many other promising investigational drugs. Several case studies were presented:
Lastly, the four major targets for immunotherapy were outlined: direct targeting of surface tumor antigens (using monoclonal antibodies), boosting immune effectors (using adoptive T-cell therapy), activating tumor specific immunity (using vaccines), and overcoming inhibitory immune suppression (IMiDs and checkpoint inhibitors), and data was shown from the pembrolizumab trial and BCMA CAR T-cell studies.
MM was heralded a model for scientific and clinical success and progress. The advances in our understanding of MM cell biology has allowed us to identify prognostic factors and myeloma subtypes, and new drugs have been discovered with singular mechanisms of action. All this now enables us to define more efficiently individualized and tailored treatment strategies.