Hello again, myeloma world.

Today's review of myeloma-related research and news covers a particu­larly wide range of topics.

We start our review with a quick look at a new study related to Pomalyst and its use in heavily pretreated multiple myeloma patients. (The Beacon published a separate article ^[1] about this study earlier today.)

Next, we report on changes the U.S. Food and Drug Admin­istra­tion has made in the procedures for “com­passion­ate use” access to unapproved drug treat­ments, including potential new myeloma therapies.

We then turn to discussion of a European study about the use of umbilical cord blood transplantation in multiple myeloma patients.

The next research article we summarize could be challenging for many readers because it deals with a topic we don't discuss very often here at The Beacon – epigenetics. Thus, we take some time in our summary to describe what epigenetics is and provide additional background information related to the research.

Other topics covered in today's report include full-dose versus lower-dose melphalan during stem cell trans­plantation, a new “p110-δ inhibitor” that may be active against multiple myeloma, and the characteristics of multiple myeloma patients in Pakistan.

Pomalyst And Low-Dose Dexamethasone In Heavily Pretreated Multiple Myeloma

The Beacon earlier today published a separate article ^[1] on the recently published results of the STRATUS (MM-010) trial. The STRATUS study is a single-arm Phase 3 trial investigating Pomalyst ^[2] (pomalidomide, Imnovid) and lower-dose dexamethasone in heavily pretreated multiple myeloma patients.

The results of the STRATUS study are important because the trial is large – it involves more than 650 patients – and the efficacy and safety outcomes are in line with what has been observed for the two-drug combination in smaller previous trials (abstract ^[3]).

New Process for Expanded Access (Compassionate Use) Of Investigational Drugs

The U.S. Food and Drug Administration (FDA) today announced that it is implementing a streamlined pro­cess for physicians and patients to request com­passionate use access to investigational drugs – that is, drugs that are not yet approved by the FDA (FDA announce­ment ^[4]).

Compassionate use access to investigational drugs is generally the only way for patients to be treated with an investigational drug if they do not qualify – or for other reasons cannot participate in – clinical trials testing the drug.

The cornerstone of the new FDA compassionate use process is a significantly shorter application form for compassionate use access. The agency also has published a question-and-answer document ^[5] about com­passion­ate use and guidance for the pharmaceutical industry ^[6] about what it can charge for com­passion­ate use of investigational drugs.

Unrelated Umbilical Cord Blood Transplantation For Multiple Myeloma

A team of European researchers has published a retrospective study of unrelated umbilical cord blood transplants in multiple myeloma patients (abstract ^[7], full-text PDF ^[8]).

The blood from umbilical cords has many stem cells. Thus, umbilical cord blood transplantation is a special form of allogeneic (donor) stem cell transplantation, where the source of the stem cells is cord blood.

After a search of a European transplantation registry, the study authors identified 85 multiple myeloma and 10 plasma cell leukemia patients who received either a single or double unrelated cord blood transplant between 2001 and 2013. The median age of the patients at the time of their cord blood transplant was 53 years, and they had their transplant a median of 3.5 years since initial diagnosis.

Nearly all patients (96 percent) had at least one autologous stem cell transplant prior to the cord blood transplant, and almost half the patients (46 percent) had 2 or more autologous stem cell transplants prior to the cord blood transplant.

Three-year progression-free survival among the patients was 24 percent, and three-year overall survival was 40 percent.

About a quarter of the patient were given anti-thymocyte globulin (ATG) to prevent serious graft versus host disease (GVHD), a potential life-threatening complication that can arise during donor stem cell transplants. The use of ATG, however, had a statistically significant negative effect on patient overall survival.

The risk of non-relapse mortality at some point during the first three years following the cord blood transplant was 29 percent. Non-relapse mortality is a measure of how dangerous a treatment procedure is. It is some­times described as “treatment-related mortality.”

Patients who were given ATG for GVHD prevention were statistically more likely to experience non-relapse mortality.

Epigenetic Modifier Mutations In Multiple Myeloma

A joint U.S.-U.K. team of myeloma researchers has published results of an investigation into multiple myeloma cell mutations that affect the production of “epigenetic modifiers” (abstract ^[9], full text PDF ^[10]).

Epigenetic changes in a cell are changes that do not affect the cell's DNA, but which nevertheless affect the cell's production of different proteins. Epigenetic changes are believed to play an important role in the devel­opment of a number of cancers, including multiple myeloma.

Epigenetic modifiers are molecules – often proteins – that cause epigenetic changes in cells. The modifiers may be produced outside a patient's body and introduced into the body through various means. The modi­fiers also may be produced within the body – even in a patient's own myeloma cells.

The authors of the current study analyzed genetic data for 463 newly diag­nosed multiple myeloma patients and 156 previously treated multiple myeloma patients.

Using these data and a comprehensive list of epi­genetic modifiers, the researchers identified several muta­tions in multiple myeloma cells that may be causing them to produce epi­genetic modifiers. The modifiers, in turn, may be causing epi­genetic changes in the cells, making them more resistant to treatment.

Having knowledge of these mutations will help future researchers develop strategies to counteract their effect, reducing the ability of myeloma cells to become treatment resistant.

Blood levels Of VCAM-1 and ICAM-1 And Multiple Myeloma

Greek researchers have published results of a study investigating two proteins, known as VCAM-1 and ICAM-1, that affect the interaction of multiple myeloma cells and other cells in the body (full text ^[11]). In particular, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) affect how well myeloma cells are able to “stick” to other cells around them. The “stickier” the myeloma cells, the more the disease is likely to have an impact.

The Greek researchers found that levels of VCAM-1 and ICAM-1 in the blood of newly diag­nosed multiple myeloma patients were higher than the levels found in patients with smoldering multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS).

Also, relapsed multiple myeloma patients had higher levels of ICAM-1 in their blood than newly diag­nosed myeloma patients, and the relapsed patients had higher levels of VCAM-1 than smoldering or MGUS patients.

Finally – and perhaps most importantly – the study authors found that the level of VCAM-1 in a newly diag­nosed multiple myeloma patient's blood had a statistically significant impact on the patient's overall survival prognosis, independent of other factors that can affect prognosis. Patients with above-median levels of VCAM-1 at diagnosis had a median overall survival of 43 months, versus 75 months for patients who had below-median levels of VCAM-1 at diagnosis.

This suggests that developing drugs that reduce the level of VCAM-1 in a myeloma patient's body could lead to more effective treatment of the disease.

Full-Dose Versus Lower-Dose Melphalan During Autologous Stem Cell Transplantation In Multiple Myeloma

University of Florida researchers have published results of a small retrospective study investigating the efficacy and safety of full-dose (200 mg/m2) versus lower-dose (140 mg/mg2) melphalan during stem cell transplantation in multiple myeloma patients.

The results of the study are based on data for 33 patients who received lower-dose melphalan (“MEL140”) and 96 patients who received full-dose melphalan (“MEL200”) during transplants at the authors' treatment center from 2001 to 2010 (abstract ^[12]).

Patients in the study generally were given lower-dose melphalan if there were concerns about the patient's general health (“performance status”), heart health, or kidney health.

The study authors find that there were “no significant differences in [the] incidence of treatment-related mortality and morbidity” between the two groups of patients. They also note that “multiple myeloma patients who received MEL140 had similar long-term outcomes to MEL200 patients despite their older age and co-morbidities.”

Potential New p110-δ Inhibitor To Treat Multiple Myeloma

A pair of researchers at two Ohio universities have identified a drug that may improve the effectiveness of Velcade in the treatment of multiple myeloma (full text ^[13]).

The drug, which the researchers designate DT97, is a “p110-δ inhibitor.” Another p110-δ inhibitor, Zydelig (idelalisib), is approved by the FDA as a treatment for certain kinds of leukemia and lymphoma. Zydelig also has been investigated as a potential new multiple myeloma therapy, but it is “not effective in treating multiple myeloma and can generate numerous severe, adverse effects,” the authors write in their paper.

The Ohio researchers isolated DT97 as a potential myeloma therapy after conducting a broad search for p110-δ inhibitors that might be effective in myeloma patients. The researchers then carried out several laboratory investigations into DT97's activity as an anti-myeloma agent, finding in both test tube and animal studies that the drug enhances the anti-myeloma activity of Velcade.

The authors conclude that DT97 “holds promise for lead compound optimization, pharmacokinetic studies, and early phase clinical trials.”

Characteristics Of Multiple Myeloma Patients In Pakistan

Two recently published research articles describe the characteristics of multiple myeloma patients diagnosed and treated at a single treatment center in Pakistan (abstract 1 ^[14], abstract 2 ^[15]). The authors of the studies find that multiple myeloma patients at the treatment center are younger, much more likely to be male, and more likely to be diagnosed with later-stage disease than multiple myeloma patients in western countries.

Some of these findings, the authors note, correspond to findings of other research examining the charac­ter­istics of multiple myeloma patients in select non-western countries. Patients in such countries, for example, generally are younger than patients in western countries.

Quickly Noted

• HDAC inhibitors and multiple myeloma - A trio of Mayo Clinic researchers has published a review of histone deacetylase (HDAC) inhibitors and their use for the treatment of multiple myeloma (full text ^[16]). One HDAC inhibitor, Farydak ^[17] (panobinostat), is currently approved in the United States and elsewhere for the treatment of multiple myeloma. Other HDAC inhibitors that have been investigated as potential myeloma therapies include Zolinza ^[18] (vorinostat) and ricolinostat ^[19] (ACY-1215).
• Blood clots in multiple myeloma – A group of European researchers has published a review article about blood clots (venous thromboembolism) in multiple myeloma patients, including when they are likely to occur and strategies for preventing them (abstract ^[20]).

New Myeloma-Related Research Articles

1. Bhatti, S. et al., “Clinical and prognostic utility of cardiovascular magnetic resonance imaging in myeloma patients with suspected cardiac amyloidosis” in European Heart Journal - Cardiovascular Imaging, May 25, 2016 (abstract ^[21])
2. Chen, W. et al., “Cost-effectiveness of bortezomib for multiple myeloma: a systematic review” in ClinicoEconomics and Outcomes Research, May 3, 2016 (full text ^[22])
3. Dimopoulos, M. A. et al., “Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma” in Blood, May 25, 2016 (abstract ^[3])
4. Fotiou, D. et al., “A review of the venous thrombotic issues associated with multiple myeloma” in Expert Review of Hematology, May 27, 2016 (abstract ^[20])
5. Gorsane, I. et al., “Renal impairment in multiple myeloma: A single center experience” in the Saudi Journal of Kidney Diseases and Transplantation, May 13, 2016 (full text ^[23])
6. Jakubowiak, A. J. et al., “Cost-effectiveness of adding carfilzomib to lenalidomide and dexamethasone in relapsed multiple myeloma from a US Perspective” in Journal of Medical Economics, May 25, 2016 (abstract ^[24])
7. Janssen, S. J. et al., “Complications after surgical management of proximal femoral metastasis: a retrospective study of 417 patients” in Journal of the American Academy of Orthopaedic Surgeons, May 25, 2016 (abstract ^[25])
8. Katragadda, L. et al., “Effect of melphalan 140 mg/m² versus 200 mg/m² on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation - A single center experience” in Clinical Transplantation, May 24, 2016 (abstract ^[12])
9. Kryukov, F. et al., “Centrosome associated genes pattern for risk sub-stratification in multiple myeloma” in International Journal of Dermatology, May 28, 2016 (full text ^[26])
10. Lee, Y. J. et al., “Lymphomatoid papulosis associated with multiple myeloma” in International Journal of Dermatology, May 27, 2016 (abstract ^[27])
11. Malek, E., Driscoll, J. J., “High throughput chemical library screening identifies a novel p110-δ inhibitor that potentiates the anti-myeloma effect of bortezomib” in Oncotarget, May 24, 2016 (full text ^[13])
12. Paviglianiti, A. et al., “Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the European Society for Blood and Marrow Transplantation” in Haematologica, May 26, 2016 (abstract ^[7], full text PDF ^[8])
13. Pawlyn, C. et al., “The spectrum and clinical impact of epigenetic modifier mutations in myeloma” in Clinical Cancer Research, May 27, 2016 (abstract ^[9], full text PDF ^[10])
14. Ryu, D. et al., “Comprehensive genomic profiling of IgM multiple myeloma identifies IRF4 as a prognostic marker” in Oncotarget, May 19, 2016 (full text ^[28])
15. Sultan, S. et al., “International scoring system in symptomatic multiple myeloma: experience from a tertiary care center” in Asian Pacific Journal of Cancer Prevention, May 2016 (abstract ^[14], full-text PDF ^[29])
16. Sultan, S. et al., “Multiple myeloma: a retrospective analysis of 61 patients from a tertiary care center” in Asian Pacific Journal of Cancer Prevention, May 2016 (abstract ^[15], full-text PDF ^[30])
17. Tandon, N., Ramakrishnan, V., Kumar, S. K., “Clinical use and applications of histone deacetylase inhibitors in multiple myeloma” in Clinical Pharmacology: Advances and Applications, May 6, 2016 (full text ^[16])
18. Terpos, E. et al., “Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment” in Blood Cancer Journal, May 27, 2016 (full text ^[11])