New Frontiers Being Explored in Multiple Myeloma
BEFORE TOO LONG, oncologists can expect to have an entirely new arsenal in the fight against multiple myeloma. Cutting-edge therapies on the near horizon were described in a presentation by Kenneth Anderson, MD, at the 2018 American Association of Cancer Research’s (AACR’s) inaugural conference on Advances in Malignant Lymphoma in Boston.
Kenneth Anderson, MD
Dr. Anderson is the Kraft Family Professor of Medicine at Harvard Medical School and Director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, Boston. He has long been at the forefront of both laboratory and clinical research in this field and has already witnessed great advances, although he sees even brighter days ahead.
“In my lifetime, myeloma patients have gone from living just 2 or 3 months to living, in many cases, more than a decade. For many, myeloma will become a chronic illness, and they’ll have a normal lifespan,” he predicted. “But multiple myeloma is still an incurable disease, so what are the ways that we—in the scientific research world—are trying to make it better?”
Tackling Smoldering Myeloma
ONE WAY TO improve outcomes in myeloma is to prevent the disease in the first place. This means recognizing and addressing the complex genomic changes that are already present in the smoldering stage. Most likely in patients who quickly evolve to a diagnosis of myeloma, existing clones are expanding, whereas patients with more delayed disease progression are probably demonstrating clonal evolution, he said.
“As we use genotypic analysis earlier in the disease, it’s my prediction that over time we will call these rapidly progressing patients ‘early myeloma,’ and the category of ‘smoldering’ will become much smaller. We’ll be treating patients to prevent myeloma, rather than treating their complications,” Dr. Anderson said.
One emerging strategy to delay or prevent disease progression is to immunize patients with myeloma-specific peptides. Specifically, this involves cocktails of immunogenic HLA-A2–specific XBP1, CD138, or CS1 (SLAMF7) peptides to induce myeloma-specific and HLA-restricted cytotoxic T-lymphocytic responses.
“We saw that if we vaccinated patients with a cocktail of these peptides, we achieved type 1 cytokine- and tetramer-positive immune responses in all patients. To augment the response, we’ve added lenalidomide [Revlimid], and we have plans to add checkpoint inhibitors and other agents,” he said.
In myeloma, LAG3 appears to be the most commonly expressed checkpoint on memory cytotoxic T lymphocytes; anti-LAG3 enhances their proliferation and promotes a central memory phenotype. “We are excited to see if we can reproduce this in the clinic,” he said.
Targeted Sequencing Panel
NEW TREATMENTS are making molecular categories of “high risk” and “low risk” outmoded, as even some patients with the high-risk 17p deletion may respond to monoclonal antibodies and immunotherapies. Dr. Anderson and his team have developed a targeted sequencing panel of genes that are implicated in cancer.1 The panel shows that copy number and karyotype dominate the landscape of negative prognostic variables. TP53 remains, in the system, the most relevant prognostic gene, even in the era of novel therapies.
“I think this is going to help us correlate abnormalities with outcomes better than ever,” he predicted.
Achievement of Minimal Residual Disease
THE CURRENT TREATMENT algorithm recommends the use of an immunomodulatory drug, proteasome inhibitor, and steroid in newly diagnosed patients—a triplet to which virtually all patients respond and minimal residual disease negativity can be achieved. A recent study evaluated whether this triplet could prove effective with or without early stem cell transplant, and concluded that transplant still adds value in terms of progression-free, but not overall, survival.2 Minimal residual disease negativity was achieved by 65% of patients treated with the triplet and by 80% who also received transplant. The question has become whether minimal residual disease negativity portends better outcomes, he said, and “the supporting data for this are building up in newly diagnosed, and even in advanced, disease.”
In a study presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition, minimal residual disease negativity (less than one myeloma cell in a million normal bone marrow cells) was associated with increased progression-free and overall survival.3 Toward this aim, newer agents (such as the anti–CD38-targeted antibody daratumumab [Darzalex]) are achieving very deep responses, even in multiply relapsed disease. Emerging questions include whether maintenance therapy in minimal residual disease–negative patients can be discontinued and whether minimal residual disease–positive patients should be treated more aggressively.
Targeting Protein Degradation
“We’ve shown in preclinical studies that this drug has activity at low levels.... We are anxious to see whether this can also happen in the clinic.”— Kenneth Anderson, MD
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MYELOMA IS the “hallmark disease” for targeting protein degradation. Proteasome inhibitors (bortezomib [Velcade], ixazomib [Ninlaro], and carfilzomib [Kyprolis]) primarily target the beta subunit of the proteasome and block the degradation of protein.
Although the proteasome is well targeted by these current proteasome inhibitors, it may be even better to intervene upstream of the proteasome by blocking the deubiquitinating enzymes. Researchers are also looking even further upstream at what are called the ubiquitin proteasome receptors (Rpn13 and others), which are responsible for chaperoning the ubiquitinated protein to the proteasome for degradation. Rpn13 is upregulated in myeloma, and higher levels seem to be associated with decreased survival.
“If you could block this pathway upstream of the proteasome, the hypothesis is that you could overcome proteasome inhibitor resistance,” Dr. Anderson explained.
In vitro, blockade of Rpn13 with the prototype targeted drug RA190 has been shown to inhibit myeloma cell growth and induce accumulation of ubiquitinated proteins. “We’ve shown in preclinical studies that this drug has activity at low levels, including in bortezomib-resistant cell lines and patient cells. We are anxious to see whether this can also happen in the clinic,” he said.
RA190 targets the proteasome pathway but upstream of the proteasome. A second target for protein degradation is the alternative aggresome pathway, which can be blocked by the pan–histone deacetylase inhibitor panobinostat (Farydak), combined with bortezomib. They are the only two pathways for degradation of protein. Moreover, the oral histone deacetylase-6–selective inhibitor ACY241 (given with bortezomib or pomalidomide [Pomalyst] and dexamethasone) offers improved pharmacodynamics, pharmacokinetics, and efficacy over current histone deacetylase inhibitors. “We’re very hopeful it can move forward, with a more favorable therapeutic index than some of the broader pan–histone deacetylase inhibitors.”
“But perhaps the most exciting outcome of protein degradation, with therapeutic implications, is with degronimids,” he continued. Immunomodulatory drugs bind to the cereblon ubiquitin-3 ligase complex, which results in the degradation of downstream substrates. Degronomids are novel drugs that bind to this complex as well, but there is also a covalent link to the specific substrate protein targeted for degradation. In addition to cereblon, degronomids may also bind to other ligases, VHL and MDM2, to trigger selective substrate degradation.
“We now have, going forward toward the clinic, degraders of epidermal growth factor receptor, Bruton’s tyrosine kinase, and a variety of other degronomids. By ‘turning on’ degradation in a selective way, we hope to eliminate abnormal substrates and offer opportunities to overcome drug resistance, even in the context of mutations and other abnormalities. Time will tell, but I think this approach has great potential,” Dr. Anderson predicted.
Efforts are also underway to scrutinize for substrates (ie, targets) of immunomodulatory drugs other than cereblon. For instance, there appears to be a cereblon-independent mechanism for inhibiting myeloma cell growth related to the downregulation of TP53 receptor kinase. Dr. Anderson’s team and others are studying how this pathway may impact immunomodulatory drug resistance. They are also examining strategies to restore cereblon transcription levels and, by so doing, restore sensitivity to immunomodulatory drugs, he added.
Tackling Immune Suppression With Isatuximab
THE NOVEL anti-CD38 antibody isatuximab has moved from the bench to the bedside. It has the usual expected immunologic activity, but, unlike daratumumab, it also has a unique mechanism for its direct cytotoxic effect. Moreover, isatuximab is active not only against the constitutive T regulatory cells, but also against the T regulatory cells that are induced when myeloma cells move into the microenvironment. Natural killer and CD8 responses are upregulated as a consequence, ultimately providing relief of the immunosuppressive microenvironment.
Isatuximab produced a 60% response rate in relapsed or refractory myeloma in a phase I trial.4 A global phase III trial evaluating isatuximab with pomalidomide (to upregulate antibody-dependent cell cytotoxicity) is fully accrued.
“THE BEST TARGET in myeloma is not CD38 but rather B-cell maturation antigen [BCMA], which is highly expressed on myeloma cells and promotes myeloma pathogenesis. If you ‘knock out’ BCMA in a mouse model, there are no plasma cells, so this is a vital, necessary factor in myeloma,” according to Dr. Anderson.
“The best target in myeloma is not CD38 but rather B-cell maturation antigen, which is highly expressed on myeloma cells and promotes myeloma pathogenesis.”— Kenneth Anderson, MD
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The most commonly elevated ligand for BCMA is APRIL, which is made by osteoclasts and macrophages. It binds to BCMA-expressing cells and promotes myeloma growth, drug resistance, and survival. It also regulates expression of checkpoints, among them programmed cell death ligand 1, on myeloma cells. There are efforts underway to target APRIL with a humanized neutralizing antibody, which could both directly abrogate its impact on multiple myeloma cell survival and drug resistance and, coupled with checkpoint inhibitors, confer immune sensitivity.
A second way of targeting the BCMA circuit is through the BCMA auristatin immunotoxin, which is delivered via a humanized antibody, GSK2857916. In advanced myeloma, this anti- BCMA antibody-drug conjugate produced a 60% response rate, including a 43% response rate among patients previously treated with daratumumab5; median progression-free survival was almost 8 months. GSK2857916 has been granted Breakthrough Therapy designation in patients who received at least three prior lines of therapy and who are refractory to a proteasome inhibitor and an immunomodulatory drug.
A third way of targeting BCMA is with bispecific T-cell engager– based immunotherapies, analogous to those that are available (such as blinatumomab [Blincyto]) or in development. The concept is that T cells can be delivered by virtue of CD3 binding, and this can selectively deplete BCMA-positive cells. “Early data suggest that when optimal doses are reached, there are clinical responses,” he reported.
The immunotherapeutic strategy that has gained the most attention so far is chimeric antigen receptor (CAR) T-cell therapy, which has been so successful in some other hematologic malignancies. In myeloma, there have been several targets for CAR T-cell products— CD19, BCMA, kappa chains, SLAMF7, CD138, and CD38—the most encouraging of which appears to be BCMA. “This is quite exciting. You need only 222 molecules of BCMA on the surface of a myeloma cell for CAR T cells to be active,” Dr. Anderson commented.
In the phase I CRB-401 study of heavily pretreated patients, bb2121 yielded a median progression-free survival of 11.8 months.6 For 16 patients receiving the optimal dose of ≥ 150 million cells, all of them achieved minimal residual disease negativity, and their progression-free survival was 17.7 months. The KARMMa pivotal trial is underway for bb2121.
AACR LYMPHOMA CONFERENCE
- Inaugural AACR international meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application
- June 22–26, 2018, Boston
- In cooperation with the International Conference Malignant Lymphoma
- Scientific Committee Chair: Ari M. Melnick, MD, Weill Cornell Medical College, New York
The bb2121 manufacturer is also studying how the addition of a phosphoinositide 3-kinase inhibitor to T-cell culture and how a 1:1 ratio of CD4:CD8 cells might improve the product. The National Cancer Institute and the University of Pennsylvania have different anti-BCMA CAR T-cell products, which are yielding response rates of approximately 60% to 80% and prolonged responses in some patients.
Another strategy that we are exploring involves administering a CD138, XBP1, CS1, and BCMA peptide–based vaccine to generate an autologous memory cytolytic T-cell antimyeloma response. A patient’s T cells would then be harvested and expanded in the presence of these same peptides to increase memory cytolytic T cells, which would then be reinfused as adoptive immunotherapy. Finally, vaccinations could subsequently be given to maintain memory antimyeloma-specific responses. This approach may avoid some of the usual adverse effects of conventional CAR T-cell therapy, Dr. Anderson said.
Diving Deeper Into Genomics
TARGETING THE most common mutations in myeloma—NRAS, KRAS, and BRAF—has not yielded long-term benefits. A more personalized approach to genomic targeting will be tested in the Multiple Myeloma Research Foundation–sponsored My Drug trial, which kicks off in 2019 and will identify molecular alterations in functional high-risk patients. According to Dr. Anderson, this is the first trial in myeloma that is predicated upon molecular profiling.
For patients with one particular molecular profile, however, one drug has already proven effective—venetoclax (Venclexta); it targets Bcl-2, which is overexpressed in multiple myeloma with t(11;14) translocation. When the regimen of venetoclax plus bortezomib was given to patients with relapsed or refractory disease whose multiple myeloma highly expressed Bcl-2 (by Bcl-2:Bcl2L1 gene-expression ratio), 88% of patients responded, and their median time to disease progression was approximately 1 year.7
“Venetoclax is an exciting drug, and the first personalized medicine in myeloma; it’s highly likely that venetoclax will be approved [in myeloma] by the U.S. Food and Drug Administration,” he predicted.
Researchers are also seeking to uncover the underlying abnormalities responsible for the constitutive, ongoing genomic evolution in myeloma. Four processes are believed to be activated: homologous recombination, APEX nuclease activity, pan-nuclease activity, and APOBEC activity. Assays have been developed to measure these processes and identify potential inhibitors that could be employed, Dr. Anderson said.
Beyond the targeting of the genomic alteration itself, targeting of the consequences of genomic abnormalities, such as MYC amplification, may also be fruitful. Benefit may also come from the epigenetic targeting, ie, the KDM3A-KLF2-IRF4 axis, and other factors in the microenvironment.
Integrative oncogenomic analysis takes the research dive even deeper. This involves combining the whole genome, transcriptome, and epigenome, in an effort to identify the altered chromatin accessibility landscape and possibly uncover new treatment targets.
Finally, Dr. Anderson emphasized the importance of restoring host antimyeloma immunity. Although currently available novel agents may now result in minimal residual disease negativity, restoring patient immunity will be required to achieve long-term disease-free survival, he predicted. In his opinion, “Robust novel agents coupled with antimyeloma immunity will really transform this disease.” ■
DISCLOSURE: Dr. Anderson is on the advisory board of Celgene, Millennium Takeda, and Bristol-Myers Squibb; the scientific advisory board of Gilead; and is the scientific founder of Oncopep and C4 Therapeutics.
1. Bolli N, Biancon G, Moarii M, et al: Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. May 22, 2018 (early release online).
2. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.
3. Avet-Loiseau H, Lauwers-Cances V, Corre J, et al: Minimal residual disease in multiple myeloma: Final analysis of the IFM2009 trial. 2017 ASH Annual Meeting. Abstract 435.
4. Richardson PG, Mikhael J, Usmani SZ, et al: Updated results from a phase Ib study of isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma. 2017 ASH Annual Meeting. Abstract 1887.
5. Trudel S, Lendvai N, Popat R, et al: Deep and durable responses in patients with relapsed/refractory multiple myeloma treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen: Preliminary results from part 2 of study BMA117159. 2017 ASH Annual Meeting. Abstract 741.
6. Raje N, Berdeja J, Lin Y, et al: bb2121 anti-BCMA CAR T cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. 2018 European Hematology Association. Abstract S138. Presented June 15, 2018.
7. Moreau P, Chanan-Khan AA, Roberts AW, et al: Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 975.