Multiple Myeloma: Researchers Are Digging Deeper Than Ever


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Researchers are tackling multiple myeloma from many angles, and the result could be a flood of novel approaches soon within the oncologist’s reach, according to Kenneth C. Anderson, MD. At the 2017 Debates and Didactics in Hematology and Oncology Conference at Sea Island, Georgia, Dr. Anderson described the latest thinking about the mechanisms underlying this tumor and how its various components can be effectively attacked. The strategies go beyond anything yet in the clinic.

Dr. Anderson is Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, the Kraft Family Professor of Medicine at Harvard Medical School, and Vice Chair of the Joint Program in Transfusion Medicine at Dana-Farber Cancer Institute, Boston. He is also President of the American Society of Hematology. 

“Future therapies will target the hallmark vulnerabilities in myeloma,” Dr. Anderson said. These approaches include novel ways to modulate protein homeostasis, ameliorate immune suppression, as well as target and overcome genomic abnormalities. 

“I’m discussing what I hope will happen in the future,” he told attendees at the Emory University–sponsored conference.

Achieving MRD Negativity

Cutting-edge technology with flow cytometry and gene sequencing can now determine the presence of minimal residual disease (MRD), detecting as few as one myeloma cell among a million normal cells. MRD-negative status has been associated with prolonged remissions and, according to recent findings, can be achieved even in patients with relapsed disease. At the 2017 European Hematology Association, researchers reported that treatment with daratumumab (Darzalex) plus lenalidomide (Revlimid) or bortezomib (Velcade) and dexamethasone produced MRD-negative status even in relapsed patients with high-risk cytogenetics.1 


By intervening very early with effective combinations, we may be able to produce long-term remissions.
— Kenneth C. Anderson, MD

“How can we make this better? By combining other drugs with monoclonal antibodies,” Dr. Anderson said. For example, the histone deacetylase (HDAC) 6 inhibitor ACY241 both upregulates daratumumab’s target, CD38, and augments effector T cells, thereby enhancing myeloma cell cytotoxicity. Future studies will evaluate the combination of HDAC inhibitors and monoclonal antibodies to increase and extend MRD-negative responses.

“By intervening very early with effective combinations, we may be able not only to achieve MRD negativity, but also to produce long-term remissions,” he predicted. “It won’t necessarily be enough to get to MRD negativity unless the host has a good immune repertoire. And for this—restoring the immune repertoire—we will also develop novel strategies.” 

Modulation of Protein Homeostasis

In addition to inhibiting the proteasome with current agents, he said, an additional impact might come from intervening upstream of the proteasome—blocking the deubiquitinating enzymes, a group of proteases that cleave ubiquitin from proteins and other molecules.

In preclinical studies, the deubiquitinating agent P5091, targeting USP-7, can overcome bortezomib resistance in myeloma cell lines and patient cells. This has led to a first clinical trial of the deubiquitinating enzyme inhibitor b-AP15, targeting USP14/UCHL5 to overcome proteasome-inhibitor resistance.

OF NOTE

  • Interim results from the KEYNOTE-183 and KEYNOTE-185 trials demonstrated an increased risk of death for patients with multiple myeloma receiving pembrolizumab combined with an immunomodulatory agent.
  • Based on these data, the U.S. Food and Drug Administration required that all patients in these trials be discontinued from further investigation with pembrolizumab.

In terms of protein degradation, the immunomodulatory drugs work by binding to the protein cereblon that is part of the ubiquitin 3 ligase complex; this triggers the degradation of the transcription factors IKZF1/3, as well as downstream proteins such as IRF4 and Myc. 

Researchers are testing a new-generation immunomodulatory drug, CC-220, which binds to the protein cereblon and triggers protein degradation. Compared to standard immunomodulatory drugs, CC-220 has more potent direct antimyeloma effects and enhanced immune-mediated killing and T-cell activation. “Time will tell whether this new more potent [immunomodulatory drug] actually translates into more clinical activity,” Dr. Anderson commented. 

His own research team has been involved in making degronimids—“drugs that sometimes look like [immunomodulatory drugs] and sometimes don’t but, importantly, bind to cereblon or other ubiquitin 3 ligases and put the ubiquitin tag on the protein that you want to degrade,” he said. “So instead of blocking protein degradation with a proteasome inhibitor or a deubiquitinating inhibitor, in this case we are “turning on” the degradation of selective substrates. This may prove useful not only in cancer, but also in inflammatory and infectious diseases.” 

Restoring and Mediating Antimyeloma Immunity 

There is hope that checkpoint inhibition will ultimately prove effective in myeloma, based on the presence of programmed cell death ligand 1 (PD-L1) on myeloma cells and programmed cell death protein 1 (PD-1) on effector immune cells. Importantly, PD-L1 is also expressed on “accessory cells,” such as plasmacytoid dendritic and myeloid-derived suppressor cells; these accessory cells promote tumor cell growth, tumor survival, and drug resistance, as well as suppress the immune system.

“Checkpoint inhibitors could therefore not only take the brakes off the immune system and trigger a response, but also may abrogate the effects of these accessory cells,” Dr. Anderson said. 

Treatments Under Investigation in Multiple Myeloma

  • HDAC 6 inhibitor ACY241
  • Deubiquitinating enzyme inhibitor b-AP15
  • Immunomodulatory drug CC-220
  • BCMA antibody auristatin immunotoxin
  • BCL-2 inhibitor venetoclax

The combination of anti–PD-1/PD-L1 agents and lenalidomide yields far greater myeloma cell killing than lenalidomide alone.2 This promising preclinical activity led to clinical investigations of pembrolizumab (Keytruda) plus lenalidomide or pomalidomide (Pomalyst) plus dexamethasone, where responses were observed in at least half the relapsed/refractory patients. These studies were recently halted due to significant safety issues (see note). 

“We will have to determine whether checkpoint inhibitors can be used safely in combination with [immunomodulatory drugs] in appropriate doses and schedules,” he commented.

Targeting B-cell maturation antigen (BCMA), a selective plasma cell antigen, may be one of the most effective strategies since BCMA is expressed uniformly on myeloma cells and not normal cells. “It’s probably the best target in myeloma. I think it will be better than SLAMF7 and CD28 [the targets of elotuzumab (Empliciti) and daratumumab, respectively]. Certainly, it’s more selective,” he noted. 

Strong antimyeloma effects have been observed with BCMA auristatin immunotoxin—a BCMA antibody that is bound to an immunotoxin and maintains immunologic activity. Another BCMA-targeted approach now entering clinical trials is a bispecific T-cell engager (BiTE) antibody–based immunotherapy that attempts to localize the response of T cells against BCMA-expressing myeloma cells. A BiTE antibody for acute lymphoblastic leukemia, blinatumomab (Blincyto), is already approved by the U.S. Food and Drug Administration.

At present, however, the most promising immunotherapeutic strategy is chimeric antigen receptor (CAR) T-cell therapy. Several products targeting BCMA and CD19 are in clinical trials. Virtually every myeloma patient responds to anti-BCMA CAR T cells when dosed optimally, and heavily pretreated patients have achieved MRD negativity, he reported. 

Yet another approach targets other factors in the immune landscape, one being the APRIL/BAFF cytokine network. A humanized anti-APRIL antibody is in development to “hopefully abrogate these direct effects of APRIL on the myeloma cell, as well as enhance immune sensitivity,” Dr. Anderson reported.

Targeting Genomic Abnormalities

“Multiple myeloma is genomically complicated, even at diagnosis,” he continued. “Patients can have thousands of deletions, substitutions, and rearrangements, and as you follow them over time, you see that they only get worse. This is not meant to be negative but to be sanguine about the enemy with which we are dealing.” 

Targeting of mutations has been less fruitful in myeloma than in solid tumors. Drugs targeting the most aberrantly mutated pathway—RAS/RAF/MAP kinase—alone or in combination, have so far only achieved transient responses. 

More promise has come in the form of a drug that targets BCL-2, especially in the subset of myeloma patients with t(11;14) disease. “Venetoclax [Venclexta] is the first real personalized medicine in myeloma,” Dr. Anderson stated. 

In a study by Kumar et al, the response rate in patients with t(11;14) myeloma and overexpression of BCL-2 approached 90%.3 The combination of venetoclax (to block BCL-2) and bortezomib/dexamethasone (to abrogate MCL1) is being evaluated in a phase III registration trial.

Targeting the consequences of the many genomic abnormalities is another approach. For example, amplification of c-Myc in myeloma cells is associated with a poor prognosis; however, c-Myc–induced cell proliferation leads to high levels of replicative stress and oxidative stress, which makes these malignant cells more vulnerable. 

“We try to put them over the edge,” Dr. Anderson said. “We inhibit their replicative stress response on the one hand, and give drugs such as bortezomib to increase reactive oxygen species on the other. The cells can’t deal with this additional stress, and they die.”

Finally, researchers are also searching for ways to inhibit the causes of genomic instability in myeloma, which may be related to abnormalities in homologous recombination, APEX nuclease activity, pan-nuclease activity, and APOBEC activity. These four processes are implicated both in myeloma’s constitutive abnormalities and ongoing DNA damage. 

“Since myeloma is so heterogeneous from the start, and ongoing damage and genetic evolution occur, we are thinking about treating the underlying causes rather than being like the little Dutch boy, reacting and putting his finger in each hole in the dyke,” he said. In vitro assays can measure these four processes, and new drugs are under development to block them. “We may be getting closer to addressing the hallmark abnormalities in myeloma.” ■

DISCLOSURE: Dr. Anderson is an advisor for Millennium Takeda, Gilead, and Bristol-Myers Squibb and scientific founder of Oncopep, C4 Therapeutics.

REFERENCES

1. San-Miguel J, Weisel K, Cook G, et al: Efficacy by cytogenetic risk status for daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone in relapsed or refractory multiple myeloma. 2017 European Hematology Association Congress. Abstract S101. Presented June 23, 2017.

2. Gorgun G, Samur MK, Cowens KB, et al: Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res 21:4607-4618, 2015

3. Kumar S, Vij R, Kaufman J, et al: Venetoclax monotherapy for relapsed/refractory multiple myeloma: Safety and efficacy results from a phase I study. 2016 ASH Annual Meeting. Abstract 488. Presented December 4, 2016.



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