We're very glad to see you again, myeloma world.

Myeloma Morning was on brief hiatus while we helped with the Beacon's article about the recently published Ninlaro (ixazomib) clinical trial results ^[1].

Now that the Ninlaro article has been published, however, it's time to get back to normal Myeloma Morning business.

And there's a lot of it. In fact, there are almost 20 items in the list of new myeloma research at the end of today's report.

We obviously have to pace ourselves a bit with such a long list of new research. So we are going to start today by reviewing two of those studies with you. We'll then share with you summaries of some of the other studies in Myeloma Mornings to be published over the weekend and early next week.

Also in today's report, we have some myeloma business news to discuss. A number of companies that develop and sell myeloma treatments issued quarterly earnings releases yesterday. We have a list of those reports and links to them.

The new research articles that we'll be summarizing in this report include:

1. A study of marizomib ^[2] (NPI-0052, salinosporamide A) by Australian researchers
2. A study by researchers in China, who investigate using osteoblast and osteoclast precursor cells as potential myeloma-related biomarkers.

Marizomib Phase 1 Clinical Trial Results

We start today's look at recent myeloma research with a study by Australian researchers. They report results of a Phase 1 trial investigating marizomib as a potential new treatment for multiple myeloma and several other cancers (full text ^[3]).

Marizomib is in the same class of drugs, known as proteasome inhibitors, as Velcade (bortezomib), Kyprolis ^[4] (carfilzomib), and Ninlaro ^[5]. The marizomib trial discussed in the new Australian study included 86 patients with various forms advanced solid tumors and blood-related cancers; 35 of the trial participants had relapsed / refractory multiple myeloma.

The objective of this trial was very similar to that of a Phase 1 marizomib trial conducted in the United States. As we mentioned in a previous edition Myeloma Morning ^[6], the goal of the U.S. trial was to determine the recommended dose for a Phase 2 trial of marizomib. Thus, numerous dose levels – and different dose schedules – were tested in both the U.S. and Australian studies.

However, all myeloma patients in the Australian study received the same dose schedule (twice weekly for two weeks in a three-week treatment cycle). All but one of the myeloma patients in the Australian study also received 20 mg of oral or intravenous dexamethasone on the day of their marizomib infusions, plus another dose of dexamethasone either the day before or the day after the marizomib infusion.

The myeloma patients in the trial were heavily pretreated, having received a median of seven prior treatment regimens. The majority of patients (80 percent) had previously received Velcade, and 20 percent were refractory to Velcade.

Patients completed a median of two treatment cycles. The main reason for treatment discontinuation was progressive disease (73 percent).

Of the 27 myeloma patients evaluable for response, one achieved a very good partial response and three had a partial response. In addition, four myeloma patients reached a minimal response and 12 had stable disease.

The most common treatment-related side effects for the dosing schedule the myeloma patients received were fatigue (37 percent) and nausea (23 percent). The researchers observed central nervous system-related side effects when marizomib was infused quickly (10 minutes), so the infusion time was extended to two hours to minimize the side effects.

The researchers state that “marizomib was generally well tolerated and demonstrated activity in heavily pre-treated relapse/refractory multiple myeloma patients, providing a rational platform for combinatorial studies in the future. This study determined the dose of marizomib to be explored in a Phase 2 trial in patients with multiple myeloma to be 0.5 mg/m² on days 1, 4, 8, and 11 in 3-week cycles, infused over 2 hours in combi­na­tion with dexamethasone given on the day before and day of marizomib dosing.”

The researchers point out that this is the same recommended dose developed during U.S. marizomib trial. It also is the marizomib doing being used in a trial investigating marizomib in combination with Pomalyst ^[7] (poma­lido­mide, Imnovid) and dexamethasone in relapsed multiple myeloma patients.

Circulating Osteoblast And Osteoclast Precursors As Disease Markers

The second new research study that we'd like to review today is by researchers based in China. It concerns osteoblasts and osteoclasts – the cells involved in the maintenance and repair of bones (abstract ^[8]).

For help in interpreting the Chinese study and its potential implications, we turned to Dr. Michaela Reagan, a myeloma researcher at the University of Maine and the Maine Medical Center Research Insitute. Dr. Reagan has a particular interest in the interaction between multiple myeloma cells and their surrounding bone en­vi­ron­ment.

Here is what Dr. Reagan told us about the study:

“One of the most devastating aspects of multiple myeloma is the accompanying bone disease. We have long known that bone cells, including the bone-forming osteoblasts and bone-degrading osteoclasts, function abnormally in the bones of myeloma patients.

“In a recent report from Dr. Shao’s laboratory at the Tianjin Medical University General Hospital, China, the researchers look at the cells that become bone cells, rather than the bone cells themselves. By examining these “precursor cells”, or cells that then mature into bone cells, the authors identified a new aspect to myeloma bone disease.

“Specifically, they found that the numbers of these precursor cells may be abnormal in multiple myeloma patients. Newly diagnosed multiple myeloma patients in the study tended to have fewer osteoblast precursors circulating in their blood compared to healthy (control) patients.

“Similarly, the same newly diagnosed myeloma patients tended to have more osteoclast precursor cells circulating in their blood compared to healthy patients.

“My analysis of the statistics used for the authors' analysis suggests, however, that these findings are not yet significant. Perhaps with data from more than 36 patients, this finding will prove correct, but due to the analysis conducted here, it cannot be concluded as of yet.

“Still, the implications of this work are that looking at circulating osteoblast and osteoclast precursors may be a novel biomarker, or a predictive marker used to study the disease course, for patients. This could be a new way to help doctors monitor bone disease or myeloma disease progression.”

Myeloma-Related Earnings Releases

Quarterly earnings updates were issued yesterday by four U.S. pharmaceutical companies involved in the development and/or marketing of myeloma treatments:

• AbbVie (earnings release ^[9]) – AbbVie co-developed Empliciti ^[10] (elotuzumab) with Bristol-Myers Squib
• Amgen (earnings release ^[11]) – Amgen markets Kyprolis as well as Epogen (epoetin alfa), Aranesp (darbepoetin), Neupogen (filgrastim), and Neulasta (pegfilgrastim)
• Bristol-Myers Squibb (earnings release ^[12]) – BMS co-developed Empliciti with AbbVie and has sole responsibility for marketing Empliciti
• Celgene (earnings release ^[13]) – Celgene developed and markets thalidomide (Thalomid), Revlimid (lenalidomide), and Pomalyst.

We have not yet reviewed the releases, although we have seen headlines about some of them. We mention the releases here, however, mainly because they can contain information about ongoing research or research planned for the near future.

New Myeloma-Related Research Articles

1. Baertsch, M. A. et al., “Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma” in BMC Cancer, April 25, 2016 (full text ^[14])
2. Beedie, S. L. et al., “In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems” in Oncotarget, April 22, 2016 (full text ^[15])
3. Christopoulos, P. F. et al., “Cadherin-11 (CDH11) expression in the peripheral blood of patients with active multiple myeloma” in the British Journal of Haematology, April 26, 2016 (abstract ^[16])
4. Das, D. S. et al., “A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells” in Leukemia, April 27, 2016 (abstract ^[17])
5. Fu, R. et al., “Clinical significance of osteoblast precursors and osteoclast precursors in earlier diagnosis and monitoring of myeloma bone disease” in Annals of Hematology, April 27, 2016 (abstract ^[8])
6. Harrison, S. J. et al., “Phase 1 clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results” in Clinical Cancer Research, April 26, 2016 (full text ^[3])
7. Lei, M. et al., “3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies” in Bioorganic & Medicinal Chemistry, April 13, 2016 (abstract ^[18])
8. Mahipal, A., Malafa, M., “Importins and exportins as therapeutic targets in cancer” in Pharmacology & Therapeutics, April 23, 2016 (abstract ^[19])
9. Moreau, P. et al., “Practical considerations for the use of daratumumab, a novel CD38 monoclonal antibody, in myeloma” in Drugs, April 25, 2016 (abstract ^[20])
10. Ninkovica, S. et al., “Engraftment syndrome manifesting as acute brachial neuropathy following high-dose chemotherapy for management of plasma cell myeloma” in Leukemia & Lymphoma, April 27, 2016 (abstract ^[21])
11. Paiva, B. et al., “Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma” in Blood, April 26, 2016 (abstract ^[22])
12. Postelnek, J. et al., “Development and validation of electrochemiluminescence assays to measure free and total sSLAMF7 in human serum in the absence and presence of elotuzumab” in The AAPS Journal, April 26, 2016 (abstract ^[23])
13. Rades, D. et al., “A predictive tool particularly designed for elderly myeloma patients presenting with spinal cord compression” in BMC Cancer, April 25, 2016 (full text ^[24])
14. Sobh, M. et al., “Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: Trends and outcomes over 25 years. A study by the EBMT CMWP” in Leukemia, April 27, 2016 (abstract ^[25])
15. Song, Y. et al., “Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma” in Leukemia, April 27, 2016 (abstract ^[26])
16. Soriano, G. P. et al., “Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes in particular in redox and energy metabolism” in Leukemia, April 27, 2016 (full text ^[27])
17. Tariman, J. D. et al., “Lack of health maintenance examinations and risk in myeloma patients” in Cancer Medicine, April 27, 2016 (full text ^[28])
18. Wildes, T. M., Campagnaro, E., “Management of multiple myeloma in older adults: Gaining ground with geriatric assessment” in the Journal of Geriatric Oncology, April 22, 2016 (abstract ^[29])
19. Yang, Y. et al., “A multicenter, retrospective epidemiologic survey of the clinical features and management of bone metastatic disease in China” in the Chinese Journal of Cancer, April 25, 2016 (abstract ^[30])