1. Fuerst, Mark L.

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BOSTON-New targets of the Achilles heels in myeloma have led to a handful of promising strategies for the treatment of multiple myeloma. Novel therapies have been integrated into myeloma management. Some 22 therapies have received FDA approval, including proteasome inhibitors, immunomodulatory drugs (IMiDs), a histone deacetylase (HDAC) inhibitor, and monoclonal antibodies.


"All are validated and have rapidly moved into clinical trials and now are being incorporated into therapy and maintenance," said Kenneth C. Anderson, MD, Professor of Medicine at Harvard Medical School, Boston, at the American Association for Cancer Research International Meeting on Advances in Malignant Lymphoma. "People are living three times long than they did 15 years ago. In many cases, myeloma is a chronic illness. But it is still an incurable disease."


Clinicians are targeting hallmark vulnerabilities, what Anderson called the Achilles heels in multiple myeloma. This involves three areas: modulation of protein homeostasis to target protein degradation and trigger selective protein degradation; immune suppression to restore host anti-multiple myeloma immunity; and genomic abnormalities to target and overcome mechanisms of genomic instability and target genomic abnormalities and their sequelae.


Protein Degradation

Myeloma is a hallmark disease for targeting protein degradation. "We are now looking upstream of the ubiquitin proteasome pathway for inhibitors, including in the ubiquitin proteasome receptor family. If we block the pathway upstream, we may overcome proteasome resistance," said Anderson. "If you bind myeloma cells to bone marrow stromal cells, there are a variety of signals that confer resistance to treatment, including immune treatments."


Anderson has been involved in the synthesis of an HDAC6 selective inhibitor that has been used in clinical trials with a proteasome inhibitor and IMiDs. "We hope to move forward with a more favorable therapeutic index than some HDAC inhibitors," he said.


An alternative to blocking protein degradation is to trigger degradation of selective substrates with degronomids. EGFR and BTK degraders are going forward to the clinic and show great potential to overcome resistance, he noted.


Immune Suppression

Isatuximab is an anti-CD38 monoclonal antibody that triggers antibody-dependent cell-mediated cytotoxicity and lysosomal myeloma cell death. It has the usual expected immune activity plus a direct cytotoxic effect.


"It is active not only against constitutive T regulatory cells (Tregs), but also inducible cells," said Anderson. A phase I clinical trial of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma shows the combination augments T cell- and natural killer cell-mediated tumor lysis of multiple myeloma cells and decreases Tregs. The combination showed an acceptable safety profile and induced a 60 percent overall response rate. A global phase III trial is now fully accrued.


The best target in multiple myeloma is probably B-cell maturation antigen (BCMA), which is expressed on plasma cells and myeloma cells. Efforts are now underway to block agonistic signaling in multiple myeloma cells.


Another way to target BCMA circuit is an auristatin immunotoxin that induces strong anti-multiple myeloma effects. This immunotoxin in advanced multiple myeloma patients shows a response rate of 60 percent that lasts 8 months, and is going forward for fast-track FDA approval, according to Anderson.


A third way to target BCMA is through Bi-specfic T-cell engagers (BiTEs). "It's conceivable to deliver to T cells to myeloma cells by CD3 binding. Several BiTE-specific antibodies are in the clinic, and three are going forward," said Anderson.


Several classic CAR T-cell constructs also are in the clinic to target multiple myeloma specifically. A study of anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplant (ASCT) for refractory multiple myeloma found two of 10 patients had longer progression-free survival (PFS) after ASCT plus CTL019 than prior ASCT. "CD19 is really not the right target, at least alone, in multiple myeloma," said Anderson.


Another anti-BCMA CAR T-cell candidate is bb2121, which uses a 4-1BB costimulatory molecule. In a clinical trial, median PFS was 11.8 months in all patients, but "in those who received the active dose, 16 of 16 patients achieved minimal residual disease (MRD)-negativity and a median PFS of 17.7 months," said Anderson. This CAR T cell is going forward in another trial in context with a PI3 kinase inhibitor.


Others researchers are adding CD4/C8 into CAR T-cell products. An NCI study used a retroviral vector with CD28 costimulatory molecule and found 13 of 16 patients achieved a partial response or greater that lasted 31 weeks. A University of Pennsylvania study of a lentiviral vector using 4-1BB costimulator of low doses of cells alone led to a 53 percent response rate lasting 4 months.


Anderson is also excited about antigen-specific autologous anti-multiple myeloma cells. "Adoptive therapy with T cells expanded in the presence of peptides has achieved complete response in relapsed acute myeloid leukemia," he explained. "Peptide stimulated adoptive immunotherapy can be combined with vaccination. We can get memory T cells that are selective for the peptides of interest, harvest the cells, expand them, and then reinfuse them. They can be available if need be to vaccinate for memory T-cell response."



The first trial predicated on molecular profiling in multiple myeloma, called MYDRUG, is underway. It uses molecular profiling to find subgroups of myeloma that express signaling pathways, Anderson noted.


The most exciting selective drug in multiple myeloma predicated on genetic analysis is venetoclax. "In patients who have t(11:14) and overexpress the Bcl-2 protein, venetoclax plus bortezomib leads to a 90 percent response rate," he stated. "It's highly likely it will be approved by the FDA this year."


Ongoing studies are targeting the causes of genomic instability and treating the consequences of genomic abnormalities. Integrative oncogenomic analysis combining whole genome, transcriptome, and epigenome identifies altered chromatin accessibility landscape and new targets in multiple myeloma, he said.


There may be better ways to monitor the tumor other than repeated bone marrow aspiration and biopsies. Clinicians are looking at cell-free DNA. "We see copy number changes in blood based on frequency of tumor. Cell-free DNA is readily present in multiple myeloma in various stages. It can be a proxy of what's going on in the bone marrow and an earlier marker for disease progression," said Anderson.


In the future, Anderson predicted that "we will end up using combination therapies defined in preclinical studies to treat subsets of patients, defined by profiling and informed by biomarkers. We can get to MRD-negativity with novel agents with or without transplant.


"But unless we restore host anti-myeloma immunity, we will not have long-term disease-free survival and a potential cure of multiple myeloma," he concluded. "Both are required to transform this disease."


Mark L. Fuerst is a contributing writer.