How has your week been, myeloma world?

Summer definitely is here at Myeloma Morning Headquarters. We had temper­a­tures yesterday and today that rival those normally seen in early August.

We're not exactly sure how we feel about this devel­op­ment.

As for myeloma-related news, we have a lot of ground to cover.

We have one new myeloma research study that we summarize at length. It's about a difficult subject, namely, the impact of early relapse on the over­all survival of multiple myeloma patients. It's a difficult subject be­cause, not surprisingly, early re­lapse con­tinues to be asso­ci­ated with much shorter over­all survival – even among patients diag­nosed since the introduction of novel myeloma ther­a­pies in the mid 2000s.

After the review of the early relapse study, we discuss news that was announced early today about Ninlaro (ixazomib) and Kyprolis (car­filz­o­mib) in Europe.

The Ninlaro news, which is not so good, concerns its review for initial approval in Europe.

The Kyprolis news, which is positive, concerns its request for an expanded approval in Europe.

We then look at a study about ab­nor­mal plasma cells in the blood of multiple myeloma patients, as well as several addi­tional studies and news items on topics ranging from treat­ment-resistant bacteria, to novel stem cell mobilization regi­mens, to repurposing a drug to (possibly) treat multiple myeloma after it initially was studied as a poten­tial brain cancer treat­ment.

Overall Survival And Early Relapse After Initial Treatment

A new study in­ves­ti­gates the impact on a multiple myeloma patient's ex­pec­ted over­all survival if the patient relapses within 12 months of starting their first treat­ment after diag­nosis.

The study focuses on the ex­peri­ence of patients who were diag­nosed after it became common to use novel myeloma ther­a­pies – such as Velcade (bor­tez­o­mib), thalidomide, and Revlimid (lena­lido­mide) – in the treat­ment of multiple myeloma. The study authors find that, even with the availability of novel ther­a­pies, early relapse is typically asso­ci­ated with noticeably reduced over­all survival (abstract).

The study was carried out by researchers at the Mayo Clinic. They identified a “primary cohort” of 511 con­secu­tive newly diag­nosed multiple myeloma patients who received novel ther­a­pies during initial ther­apy at their institution between 2006 and 2014.

They also identified an “expanded cohort” of 561 multiple myeloma patients who were not necessarily diag­nosed at their treat­ment center, but who received a stem cell trans­plant at the treat­ment center. These patients also were diag­nosed in the 2006 to 2014 time period, and underwent their trans­plant within 12 months of their diag­nosis; 171 patients from the “primary cohort” were also in the “expanded cohort.”

Results For The Primary Cohort

In the pri­mary cohort, 16 per­cent of patients re­lapsed within 12 months of starting ther­apy.

The median time to relapse for all patients was 26.9 months. In the early relapse group, relapse occurred at a median of 8.0 months, compared to 30.2 months for patients relapsing late.

Early relapse was strongly asso­ci­ated with reduced over­all survival.

Median over­all survival across all patients in the pri­mary cohort was 103 months from the start of initial treat­ment. It was sig­nif­i­cantly shorter for patients relapsing early (21 months) than for those who re­lapsed late (not yet reached, but it probably will be at least 110 months).

After controlling for a range of factors that might predict early relapse, the researchers found that the only sig­nif­i­cant factors were whether or not the patient had high-risk chromosomal ab­nor­mal­i­ties at diag­nosis, and whether their serum albumin level was less 3.5 g/dL at diag­nosis.

(The researchers defined del(17p), monosomy 17, t(4;14), t(14;16), and t(14;20) as high-risk chromosomal ab­nor­mal­i­ties.)

Among the patients in the pri­mary cohort who re­lapsed early, over­all survival did not depend on how deep their response was to initial ther­apy. Median over­all survival in these patients was 24.5 months among those who reached a com­plete response, 17.1 months in those who reached a very good com­plete response, and 27.2 months in those who reached only a partial response.

Results For The Expanded Cohort

The impact of early relapse on over­all survival also was seen in the expanded cohort of patients, all of whom had an au­tol­o­gous stem cell trans­plant within 12 months of diag­nosis.

In this group of patients, 6 per­cent re­lapsed within 12 months of their trans­plant.

The median over­all survival of these early relapse patients was 23.1 months from the time of their trans­plant. For those in this cohort who did not ex­peri­ence an early relapse, median over­all survival was 122 months.

Conclusions And Thoughts On The Study From Dr. Shaji Kumar

Based on their findings, the study authors conclude that their results reinforce pre­vi­ous findings that “early relapse is likely a reflection of aggressive tumor biology, independent of commonly employed man­agement strategies in the current treat­ment landscape.”

The Beacon spoke with myeloma specialist Dr. Shaji Kumar about the results of the new early relapse study. Dr. Kumar is the corresponding author of the study and a professor of medicine at the Mayo Clinic.

We first asked Dr. Kumar what the implications of the study are for patients who ex­peri­ence an early relapse. Dr. Kumar responded that

“The early relapse should be con­sidered a sign of high-risk disease irrespective of what the patient's initial evaluation suggested. Given the early relapse, the patient's multiple myeloma should be treated as high-risk disease with com­bi­na­tion ther­a­pies. Also, par­tic­i­pa­tion in new clin­i­cal trials should be con­sidered. We are trying to develop trials that are specifically targeting this patient pop­u­la­tion.”

We also asked Dr. Kumar if patients experiencing an early relapse should con­sider an allogeneic trans­plant. He responded that

“An allogeneic trans­plant would certainly be a discussion point for the younger patients. If that route is taken, we need to first get the patient into a com­plete response, or better, before proceeding with the allogeneic trans­plant.”

Finally, we asked Dr. Kumar a very difficult question, which is what he thinks the median over­all survival is likely to be for patients who ex­peri­ence an early relapse right now, in 2016. We asked this question because a number of new myeloma ther­a­pies have been approved since the period when the patients in Dr. Kumar's study were diag­nosed, meaning patients now have more treat­ment options.

Dr. Kumar responded by noting that an earlier study carried out with patients who did not have access to novel ther­a­pies found that early relapse was asso­ci­ated with a median over­all survival of about 11 months. In the new study summarized above, early relapse is asso­ci­ated with a median over­all survival of 21 months.

So Dr. Kumar's esti­mate would be that, given the new ther­a­pies that are now avail­able, patients experi­enc­ing an early relapse in 2016 might be looking at over­all survival 9 to 12 months longer than the 21 months reported in the new study – or about 30 to 33 months from the start of initial treat­ment.

Ninlaro Gets Negative Opinion From Key European Advisory Committee

A key advisory committee has issued a negative opinion in regard to Ninlaro's appli­ca­tion for approval in Europe as a new treat­ment for multiple myeloma.

The decision by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency was announced this morning by Takeda Pharma­ceu­ticals, the com­pany that developed Ninlaro (press release).

Takeda says that it intends to appeal the opinion and request a re-examination by the CHMP.

Takeda cur­rently markets Ninlaro in the United States, where the drug was approved last November for use in com­bi­na­tion with Revlimid and dexa­meth­a­sone to treat multiple myeloma patients who have had at least one prior ther­apy (see related Beacon news).

Ninlaro's appli­ca­tion for approval in Europe is based on results of the TOURMALINE-MM1 trial. These results also were used as the basis for the drug's approval in the United States.

The European advisory committee, however, did not feel that the TOURMALINE-MM1 results were sufficient for it to recommend the drug be approved. Here is how the committee described its initial reac­tion to the TOURMALINE-MM1 trial results and the alter­na­tive approval options that were con­sidered:

“The CHMP con­sidered that the data from the [TOURMALINE-MM1] study were insufficient to dem­onstrate a benefit of Ninlaro in the treat­ment of multiple myeloma. The com­pany had proposed restricting the use of the medicine to patients whose disease is more difficult to treat and had come back after one pre­vi­ous treat­ment, and to those whose disease had come back after at least two pre­vi­ous treat­ments. However, the data in these subgroups were not compelling enough and the rationale for assuming greater effectiveness in these patients was not clear.

“Therefore, the CHMP was of the opinion that, based on the cur­rently avail­able data, the benefits of Ninlaro did not outweigh its risks and recommended that it be refused marketing authori­za­tion.”

A spokesperson for Takeda told The Beacon that the com­pany ex­pec­ts the appeal and reexamination process to take an addi­tional six months. “We will con­tinue to work closely with the CHMP and remain committed to making Ninlaro avail­able to multiple myeloma patients in Europe as soon as possible,” the spokesperson added.

Kyprolis Gets Positive European Advisory Committee Opinion

Not all of today's myeloma-related news from Europe is negative. The same advisory committee that gave a negative opinion to Ninlaro's appli­ca­tion for European approval has issued a positive opinion on an appli­ca­tion to expand the approved use of Kyprolis in Europe (press release).

The expanded use would allow Kyprolis to be used in com­bi­na­tion with dexa­meth­a­sone alone. Currently, the Kyprolis approval in Europe is for use in com­bi­na­tion with Revlimid and dexa­meth­a­sone.

If CHMP's opinion is approved by the European Commission, the drug's new approved use in Europe would read as follows:

“Kyprolis in com­bi­na­tion with either [Revlimid] and dexa­meth­a­sone or dexa­metha­sone alone is indi­cated for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy.”

Abnormal Plasma Cells In The Blood At Diagnosis And Patient Prognosis

A team of Spanish researchers has found a link between the presence of ab­nor­mal plasma cells in a multiple myeloma patient's blood and their survival prognosis (abstract).

Plasma cells are mainly found in the bone marrow. However, they sometimes can be found in the blood. Pre­vious research has found that the number of plasma cells in a multiple myeloma patient's blood at diag­nosis can be a predictor of the patient's survival (full text).

There also is research linking the presence of plasma cells in the blood of smol­der­ing multiple myeloma patients and the probability of pro­gres­sion to disease requiring treat­ment (full text, related Beacon news article).

In the Spanish study, the authors focus on abnormal plasma cells found in the blood, rather than all plasma cells – normal and ab­nor­mal – found in the blood. To determine whether a plasma cell found in the blood is ab­nor­mal, the authors rely on techniques described in a pre­vi­ous study by another group of Spanish researchers (full text; see, in particular, Table 2).

Using blood samples from 72 newly diag­nosed patients from three treat­ment centers, the authors of the new Spanish study counted the number of ab­nor­mal plasma cells and the total number of cells in each sample. They then calculated for each patient the share of all blood cells that were ab­nor­mal plasma cells.

The authors determined that patients whose share of ab­nor­mal plasma cells was less than 0.0035 per­cent had a sub­stan­tially better over­all survival than patients with an ab­nor­mal plasma cell per­cent­age greater than 0.0035 per­cent.

Three-year over­all survival was 91 per­cent in patients with a low ab­nor­mal plasma cell per­cent­age at diag­nosis, compared to 52 per­cent for patients with a high ab­nor­mal plasma cell per­cent­age at diag­nosis.

Highly Resistant Bacteria Found In The United States

Infections are a constant concern for multiple myeloma patients because their immune systems are often compromised. Thus, many of our readers may be interested in news that has just come out that a form of highly resistant bacteria has been found for the first time in someone in the United States.

Here are a few reports about this devel­op­ment from Reuters, USA Today, and the Washington Post, and here's the research article that is the basis of the news reports.

We also want to highlight, however, a report by Ars Technica, which puts these news reports into perspective. The Ars Technica report emphasizes that “Thursday’s report of a … resistant bacterial in­fec­tion in a U.S. patient is concerning, but unsurprising.”

Treanda, Etoposide, And Dexamethasone For Stem Cell Mobilization

A team of U.S. researchers has published results of a small study investigating the use of Treanda (benda­mustine), etoposide, and dexa­meth­a­sone (BED) to mobilize stem cells for harvesting prior to an au­tol­o­gous stem cell trans­plant (abstract). The researchers used the three-drug regi­men, followed by Neupogen (fil­grastim), to mobilize stem cells in 34 multiple myeloma patients planning to undergo a stem cell trans­plant.

All patients suc­cess­fully mobilized enough stem cells, and 88 per­cent of the patients required only one apher­esis session to harvest sufficient stem cells. There was one case of neu­tro­penic fever (high fever accom­pa­nied by low neu­tro­phil levels) that occurred among the patients during the mobilization process, and one mild case of reduced kidney function. The researchers con­clude, however, that “BED safely and effectively mobilizes hematopoietic stem cells.”

Galectin-1 And Multiple Myeloma

A group of mainly Italian authors have published results of a study examining the role of the protein galectin-1 in multiple myeloma (abstract). They find that suppressing the ability of multiple myeloma cells to produce galectin-1 limits the ability of the cells to proliferate and form bone tumors. This was con­firmed by laboratory studies involving myeloma cell lines in test tubes and animal models of the disease. The researchers conclude that galectin-1 is “a new poten­tial thera­peutic target in multiple myeloma”.

Iceni And Cilengitide For Multiple Myeloma

Big DNA Ltd, a pharma­ceu­tical com­pany based in Edinburgh, Scotland, has announced that it is changing its name to Iceni Pharma­ceu­ticals, and that it will be focusing in the near term on devel­op­ing the drug cilengitide (Cilcane) as a poten­tial new treat­ment for multiple myeloma. Cilengitide had pre­vi­ously been under devel­op­ment at the drug com­pany Merck Serono. Cilengitide was not successful in late stage trials testing the drug as a possible new brain cancer ther­apy, so Merck Serono sold rights to the drug to Iceni. Laboratory studies have shown that cilengitide may im­prove the anti-myeloma activity of pro­te­a­some inhibitor drugs such as Velcade. For more in­­for­ma­tion, see the related Iceni press release.

New Myeloma-Related Research Articles

1. Abdulsalam, A. H. et al., “Unusual cytological features in multiple myeloma” in the American Journal of Hematology, May 24, 2016 (abstract)
2. Alé, A. et al., “Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model” in NeuroToxicology, May 19, 2016 (abstract)
3. Amodio, N. et al., “Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma” in Molecular Cancer Therapeutics, May 18, 2016 (abstract)
4. Ashley, J. D. et al., “Dual carfilzomib and doxorubicin loaded liposomal nanoparticles for synergistic efficacy in multiple myeloma” in Molecular Cancer Therapeutics, April 19, 2016 (abstract)
5. Chalayer, E. et al., “Does the choice of thrombotic prophylactic drug depend on the known risk factors of patients with multiple myeloma in clinical practice?” in Thrombosis Research, May 7, 2016 (abstract)
6. De Haart, S. J. et al., “Comparison of intramedullary myeloma and corresponding extramedullary soft tissue plasmacytomas using genetic mutational panel analyses” in Blood Cancer Journal, May 20, 2016 (full text)
7. Green, D. J. et al., “Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma” in Bone Marrow Transplantation, May 23, 2016 (abstract)
8. Guney, T. et al., “Assessment of serum thiol/disulfide homeostasis in multiple myeloma patients by a new method” in Redox Report, May 19, 2016 (abstract)
9. Johansson, C. et al., “Structural analysis of human KDM5B guides histone demethylase inhibitor development” in Nature Chemical Biology, May 23, 2016 (abstract)
10. Krejcik, J. et al., “Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma” in Blood, May 24, 2016 (abstract)
11. Majithia, N. et al., “Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents” in Leukemia, May 23, 2016 (abstract)
12. Morrison, E. J. et al., “Employment status as an indicator of recovery and function 1 year after hematopoietic stem cell transplantation” in Biology of Blood And Marrow Transplantation, May 21, 2016 (abstract)
13. Periago, A. et al., “Circulating aberrant plasma cells allows risk stratification of patients with myeloma” in the American Journal of Hematology, May 24, 2016 (abstract)
14. Souto Filho, J. T. D. et al., “Hypoglycemia due to monoclonal anti-insulin antibody in a patient with multiple myeloma” in Annals of Hematology, May 23, 2016 (abstract)
15. Storti, P. et al., “Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo” in Leukemia, May 20, 2016 (abstract)
16. Tomasiuk, R. et al., “The evaluation of NT-proCNP, C-reactive protein and serum amyloid A protein concentration in patients with multiple myeloma undergoing stem cell transplantation” in Leukemia Research, May 24, 2016 (abstract)
17. Usmani, S. Z. et al., “Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma” in Blood, May 23, 2016 (abstract)
18. Van Keer, J. et al., “Two cases of heavy chain MGUS” in Case Reports in Oncological Medicine, April 26, 2016 (full text)
19. Všianská, P. et al., “Activity of aldehyde dehydrogenase in B-cell and plasma cell subsets of monoclonal gammopathy patients and healthy donors” in the European Journal of Haematology, May 20, 2016 (abstract)
20. Zagouri, F. et al., “Emerging antibodies for the treatment of multiple myeloma” in Expert Opinion on Emerging Drugs, May 19, 2016 (abstract)