The term “novel agents” has been used for the past decade to describe proteasome inhibitors and immunomodulatory drugs that are now conventionally used for multiple myeloma. However, even newer agents in development will be considered truly novel when they hit the market, as they represent new classes of drugs that have not been used before in this cancer, according to Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston. At the National Comprehensive Cancer Network (NCCN) 2013 Annual Conference, Dr. Anderson described what he considers the most promising of these investigational agents.
“We are excited about new proteasome inhibitors and [immunomodulatory drugs], but we are even more excited to have different classes of drugs. New proteasome inhibitors and [immunomodulatory drugs] are important, but their benefit is incremental. In multiple myeloma, we want a paradigm change,” he said.
“My strong feeling is that we can incorporate these investigational therapies into all stages of disease, and likely in combination, and will further improve patient outcomes,” he predicted.
Monoclonal Antibodies
Monoclonal antibodies are finally being developed for myeloma. The agents furthest along in development target CS1 and CD38 antigens. CS1 is present on all myeloma cells and on natural killer cells, and CD38 exists on myeloma cells but also on activated T cells, activated B cells, myeloid cells, monocytes, and endothelial cells.
The CS1-targeting agent elotuzumab is well tolerated but as a single agent achieves only stable disease. When combined with lenalidomide (Revlimid), however, the effect is impressive. In phase I/II studies, response rates to this combination have been 80% to 90% and progression-free survival has approached 3 years; positive outcomes have been seen even in the context of 17p deletion or other adverse cytogenetics. Two clinical trials (ELOQUENT-1 and -2) are evaluating elotuzumab plus lenalidomide/dexamethasone in the relapsed/refractory and newly diagnosed populations.
Among the antibodies targeting CD38 are SAR650984 and daratumumab. SAR650984 has multiple mechanisms of action: antibody-dependent cellular cytotoxicity and phagocytosis, complement-dependent cytotoxicity, direct apoptosis induction, and allosteric inhibition on CD38 enzymatic activity. In a phase I/II trial reported at the American Society of Hematology (ASH) Annual Meeting last year, 5 of 13 patients with a median of five prior lines of therapy achieved a minor response or better, and two complete responses were observed; 69% had received carfilzomib (Kyprolis) and/or pomalidomide (Pomalyst).1
“It is very exciting to see complete responses to this antibody alone,” Dr. Anderson commented.
Daratumumab also showed strong activity in a phase I/II study of the drug as a single-agent, where 47% of patients derived benefit, and at doses of 4 mg/kg, 66% had a minor response or better.2 The U.S. Food and Drug Administration has granted this agent breakthrough status.
“It’s very exciting as a single agent, but as with elotuzumab, it may be better in combination with [lenalidomide/dexamethasone],” he added. At doses of 4 mg or higher and in combination with lenalidomide/dexamethasone, almost all patients had a near-complete or complete drop in monoclonal protein.3
Antibody Conjugates
Also new to myeloma is the introduction of new immune-based strategies—specifically, a potent antibody-drug conjugate that targets CD138, an antigen that is highly expressed on myeloma cells. Indatuximab ravtansine (BT062) is designed to deliver the maytansinoid cytotoxic agent DM4 specifically to these CD138-expressing cells. In a phase I trial of 21 patients, stable disease or better was observed in 100% of 15 evaluable patients, including two complete responses, four very good partial responses, and five partial responses, for an overall response rate of 73%.4
HDAC Inhibitors
Dr. Anderson said he is particularly interested in the histone deacetylase (HDAC) inhibitors, due to their rational biology in myeloma and impressive preclinical activity. HDACs are implicated in bringing the proteasome protein into the alternative aggresomal autophagy system, and HDAC inhibitors block the aggresomal pathway. In preclinical studies, inhibition of both the proteasome (ie, with a proteasome inhibitor) and the aggresome (with HDAC inhibition) “has produced the most potent cytotoxicity we have ever observed,” he noted, “and if we put the HDAC inhibitor together with an [immunomodulatory drug] we block an important oncogene—c-Myc.”
However, with the current broad-acting HDAC inhibitors—especially vorinostat (Zolinza) and to some degree panobinostat—toxicity has been an issue. In the international
VANTAGE 088 trial, vorinostat led to only a 1-month benefit in progression-free survival, because side effects limited the drug’s tolerability.5 Vorinostat, therefore, is not moving forward in myeloma, but results with panobinostat are more promising, with phase III clinical trial results coming soon, he said.
Probably the best bet will be the more selective HDAC inhibitors, which are capable of overcoming toxicity presented by the broad-acting drugs, he said. The current focus is on ricolinostat (ACY-1215), which was studied in combination with lenalidomide and dexamethasone in a phase Ib study reported at the 2013 ASH Annual Meeting.6 Of 16 patients evaluable for response, 100% experienced clinical benefit and 11 (69%) had a partial response or better, including one complete response, three very good partial responses, and seven partial responses.
“Almost all these patients with relapsed/refractory disease benefited, and most importantly, ricolinostat was well tolerated,” Dr. Anderson reported. “Both broad-acting inhibitors have not been able to be combined with [immunomodulatory drugs] because of low blood counts, but this drug seems well tolerated, and so, it is excellent in combination.” Ricolinostat is moving forward in development in combination with lenalidomide/dexamethasone.
Kinesin Spindle Protein Inhibitors
Another novel class in myeloma is the kinesin spindle protein inhibitors. Inhibition of kinesin spindle protein induces aberrant mitotic arrest and rapid cell death.
The kinesin spindle protein inhibitor filanesib (ARRY-520) was studied in a phase II trial as a single agent and combined with dexamethasone, where the overall response rates were 16% and 15%, respectively.7 Better responses (24%) were observed, however, in patients who had low levels of the carrier protein α-1 acid glycoprotein (AAG), which binds the drug; duration of response in this subset was 8.6 months.
According to Dr. Anderson, “This drug is going forward in combination with bortezomib [Velcade] in the population of patients selected for low levels of AAG.”
Akt Inhibitors
The Akt inhibitor afuresertib (PKB115125) is also an interesting compound, he said, “because when we treat with a proteasome inhibitor, we activate Akt, so the principle is to block the activation and get synergistic cytotoxicity with this combination.”
In a phase I/II trial by Voorhees et al, the Akt inhibitor plus bortezomib produced impressive falls in M protein.8
Novel Combinations
“In the new world of multiple myeloma, we will be using combinations of drugs, both up front and in relapse,” Dr. Anderson predicted. “New agents are going to have to be good team players.”
Gene-sequencing studies have not revealed a predominant mutation; rather, multiple clones of cells are present from the start. When patients are followed over time, “the already-complicated genetic analysis becomes much more so,” he observed.
This means that myeloma might best be treated the way that some cancers, such as leukemia and Hodgkin lymphoma, and some infectious diseases, such as tuberculosis and human immunodeficiency virus, are already managed, he said. That is, the optimal approach might include “using combinations of effective and well tolerated agents upfront and early in the disease, treating the pathways that mediate growth and survival, attacking the marked clonal abnormalities, and anticipating mechanisms of acquired resistance.” ■
Disclosure:Dr. Anderson is on advisory boards for Celgene, Millennium, Onyx, Gilead, and Sanofi Aventis. He is Scientific Founder of Acetylon and Oncopep.
References
1. Martin TG, Strickland S, Glenn M, et al: SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies—data from a dose-escalation phase I study. 2013 ASH Annual Meeting. Abstract 284. Presented December 9, 2013.
2. Plesner T, Lokhorst H, Gimsing P, et al: Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma—data from a dose-escalation phase I/II study. 2012 ASH Annual Meeting. Abstract 73. Presented December 9, 2012.
3. Plesner T, Arkenau T, Lokhorst H, et al: Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 1986. Presented December 7, 2013.
4. Kelly KR, Chanan-Khan A, Somlo G, et al: Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: Clinical activity in len/dex-refractory patients. 2013 ASH Annual Meeting. Abstract 758. Presented December 9, 2013.
5. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicenter, randomized, double-blind study. Lancet Oncol 14:1129-1140, 2013.
6. Yee A, Vorhees P, Bensinger W, et al: ACY-1215, a selective histone deacetylase 6 inhibitor, in combination with lenalidomide and dexamethasone, is well tolerated without dose limiting toxicity in patients with multiple myeloma at doses demonstrating biolgic activity: Interim results of a phase 1b trial. 2013 ASH Annual Meeting. Abstract 3190. Presented December 8, 2013.
7. Lonial S, Shah J, Zonder J, et al: Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma patients with low α-1 acid glycoprotein levels: Results from a phase 2 study. 2013 ASH Annual Meeting. Abstract 285. Presented December 9, 2013.
8. Voorhees PM, Spencer A, Sutherland H, et al: Novel AKT inhibitor afuresertib in combination with bortezomib and dexamethasone demonstrates favorable safety profile and significant clinical activity in patients with relapsed/refractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 283. Presented December 9, 2013.
