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Oncology Times:
doi: 10.1097/01.COT.0000440852.34423.2f
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Myeloma: Promising Treatment Updates for Patients with Relapsed/Refractory Disease

Carlson, Robert H.

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NEW YORK—The audience here at the Lymphoma & Myeloma International Congress was quite familiar with lenalidomide, bortezomib, pegylated doxorubicin, and the newer drugs pomalidomide and carfilzomib—all approved regimens for relapsed/refractory multiple myeloma and briefly mentioned in a presentation by Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute. Because of these drugs, he said, prospects for patients with myeloma are bright, with survival times doubling or tripling over the past decade.

But it was the “defined, urgent, and so far unmet need” for new treatments for patients with relapsed/refractory disease, that Anderson wanted to focus on, as he discussed new antibodies, vaccines, targeted agents, and genomic analysis that might help fill that need.

He noted that elotuzumab, which targets CS1, has produced remarkable response rate of 80 to 90 percent, and progression-free survival times so far of 33 months in patients with relapsed myeloma when combined with lenalidomide-dexamethasone, but it had very little activity as a single agent. Randomized Phase III trials of elotuzumab are now ongoing.

And daratumumab, which targets CD38, also had a high overall response rate in relapsed/refractory myeloma when combined with lenalidomide-dexamethasone—82 percent in one Phase II trial, and up to 91 percent in patients with only one prior therapy.

As reported at the 2012 American Society of Hematology Annual Meeting, a study of single-agent daratumumab, showed that 15 of 32 patients (47%) benefited (Plesner et al: ASH 2012, Abstract 73), and earlier this year that drug received Breakthrough status from the Food and Drug Administration for the treatment of double-refractory multiple myeloma.

Anderson said vaccines are now being developed at Dana-Farber that fuse myeloma cells with dendritic cells. “Even in the context of relapsed/refractory and advanced myeloma, the data show an immune response both humoral and cellular, and about 70 percent of patients had stabilized disease,” he said, adding that a more appropriate context would probably be in patients with minimal residual disease.

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Checkpoint Inhibitors

He said there has been some exciting news about checkpoint inhibitors in melanoma, kidney, lung, and other solid tumors, and this is starting to happen for hematologic malignancies as well: The immune checkpoint receptor PD-1 (programmed cell death 1) is a key receptor expressed on activated T-cells, and its ligand, PD-L1 is strongly expressed on myeloma cells.

PD-1 binding to PD-L1 results in suppression of the immune response. “If you block either an antibody to the ligand or to the receptor, you take the brakes off the immune system,” he said.

Checkpoint inhibition has already been done post-transplant by administering an anti-PD-1 antibody, which induced an immune response against myeloma cells, he noted. “Our next study is to combine the [myeloma cell-dendritic cell] vaccine with the antibody to PD-1 to not only increase the response but also do it in an exciting way. I think the future here is in combination immune therapies, even in the setting of high-risk cytogenetics.”

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Upstream DUBs

He and other researchers are also exploring the ubiquitin-proteasome cascade, hoping to hit the so-called deubiquitylating (DUB) enzyme upstream.

Anderson said he is excited about the DUB inhibitor P5091 because it is active in bortezomib-resistant myeloma patient cells and in myeloma cell lines resistant to bortezomib. Another DUB inhibitor in development is the orally bioavailable MLN970/MLN 2238, also active against myeloma cell lines and in Phase I trials.

Opromazib (ONX 0912) is the “son” of carfilzomib, Anderson said, an oral chymotryptic inhibitor active against myeloma in vitro, with Phase I/II studies ongoing.

And marizomib (NPI-0052) is a non-peptide proteasome inhibitor that produces broad, prolonged inhibition of the chymotryptic, tryptic, and caspase-like activity of the proteasome whereas all the others are primarily chymotryptic inhibitors, he said.

MarizoIt is active in bortezomib and IMiD-resistant myeloma preclinically but without the toxicities associated with bortezomib. Early data show responses in patients whether or not they had prior bortezomib or lenalidomide. “We simply do not know whether it is better or not to be more selective or less selective in inhibiting the proteasome, but studies with marizomib may help us understand,” he said.

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New Drug Classes

Anderson said the BTK (Bruton's tyrosine kinase) inhibitor PCI-32765 is of interest, because BTK is involved in osteoclastogenesis. “In a preclinical model we can maintain the integrity of bone disease by using the BTK inhibitor ibrutinib,” he said. “There is also evidence in in-vivo models of anti-myeloma activity, and a clinical trial is ongoing.”

KENNETH C. ANDERSON, MD
KENNETH C. ANDERSON, MD
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In addition, Anderson noted, BET bromodomain inhibition has been shown to suppress the expression of c-myc, known to be important in myeloma, Burkitt's lymphoma, and other cancers. Inhibition of BET bromodomain triggers anti-myeloma activity. Selectively inhibiting bromodomain 4 downregulates c-myc expression totally and inhibits myeloma cell growth in vitro and in animal models.

BTK inhibitors and bromodomain 4 inhibitors are already or will soon will be in clinical trials in multiple myeloma, he said.

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Combinations May Block Protein Degradation

Proteosome inhibitors block the degradation of ubiquitinated proteins but it has to be done more completely, Anderson said. “If it turns out that histone deacetylase [HDAC] inhibitors like the broad-acting vorinostat or the more selective AC1215 can block the aggresomal degradation of protein, then combining proteasome inhibitors with HDAC inhibitors could block the entire mechanism of protein degradation.”

This regimen is already in the clinic, Anderson said, citing the randomized, placebo-controlled VANTAGE 088 study trial led by Meletios Dimopoulos that tested bortezomib with or without vorinostat in myeloma and for which Anderson was senior author (Lancet Oncology 2013;14:1129-1140).

“This was a positive trial, with an overall response rate of 54 percent for the combination vs. 41 percent for placebo, but the progression-free survival difference was only one month—7.63 vs. 6.83 months—because the broad-acting HDAC inhibitors caused fatigue, diarrhea, and cytopenia,” Anderson said.

A more selective oral HDAC-6-directed inhibitor, ACY 1215, which directly impacts the pathway and shuttling of protein into the aggresome is now progressing and is proving to be very well tolerated, he said.

The concept is to block both the proteasomal and aggresomal degradation of protein. Phase I and II clinical trials combining ACY 1215 with bortezomib, lenalidomide-dexamethasone, pomalidomide, or carfilzomib are underway or planned, Anderson said.

“We have to identify the most important pathways in myeloma, activated by mutation or otherwise, so we can target them using combination therapies, as our colleagues in lymphoma, HIV, and other diseases are doing. And then go in early—rather than letting mechanisms of relapse occur, we should try to prevent them from occurring.”

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Mutations Change Over Time

Whole genome sequencing is uncovering some fascinating anomalies caused by genomic instability, such as frequent mutational changes in myeloma cells over time, he said.

For example, there is evidence that new mutations appear that were not seen at diagnosis, copy numbers change in chromosomes, sometimes extra copy numbers or increased copy numbers appear, and even translocations present at diagnosis can be gone at the time of relapse.

“When we implement the genetic signature and therapy is predicated on upon it, it has to be at a given point in time,” he said. “Given this degree of genetic heterogeneity, it is incumbent on us to define the abnormalities that exist at the time of diagnosis, try to anticipate the abnormalities that can account for relapse, and use combinations of therapies early.”

Wolters Kluwer Health | Lippincott Williams & Wilkins

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