A belated good morning to you, myeloma world.

How has your Friday been so far? Has April Fools' Day brought joy, con­ster­na­tion, or a bit of both to your life?

We were caught off guard this morning by some news that came out just as we were about to wrap up this edition of Myeloma Morning. But the news, which con­cerns Darzalex, is good, so we definitely won't be com­plaining.

Here are today's myeloma-related headlines.

First, Darzalex (daratumuab) is a big step closer to being approved as a new myeloma treat­ment in Europe. A pos­i­tive opinion from a key European advisory committee means the drug probably will be approved in Europe to treat myeloma patients within the next two months.

Second, a new study by Dutch researchers reports on long-term out­comes of allo­geneic (donor) stem cell trans­plan­ta­tion in multiple myeloma patients. The researchers draw on data for almost 150 patients at a single treat­ment center. They find that allo­geneic trans­plan­ta­tion as part of a patient's initial myeloma ther­apy can lead to very long survival times. In contrast, the ther­apy is much less suc­cess­ful in patients who undergo it after their myeloma relapses.

We have more on these devel­op­ments – as well as other news – in the rest of this article.

Darzalex A Lot Closer To European Approval

Janssen, the Johnson & Johnson sub­sid­i­ary that mar­kets Darzalex, announced this morning that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a pos­i­tive opinion on the appli­ca­tion to have Darzalex approved in Europe as a new treat­ment for multiple myeloma (press release).

A pos­i­tive opinion from CHMP is not a regu­la­tory approval. Instead, it is an assess­ment that is passed on to the European Com­mis­sion, which ultimately decides whether or not to approve a new drug in Europe.

That said, it is very rare for the European Com­mis­sion to decide not to approve a drug if it has received a pos­i­tive opinion from CHMP. So today's news means it is very likely Darzalex will be approved in Europe. The final approval de­ci­sion can be ex­pec­ted within two to three months.

According to Janssen's press release, the approved use for Darzalex is ex­pec­ted to be as a single agent in adults with re­lapsed and refractory multiple myeloma, who have been pre­vi­ously treated with a pro­te­a­some inhibitor and an immuno­modu­la­tory agent, and who ex­peri­enced disease pro­gres­sion on their last ther­apy.

Note that the pro­te­a­some inhibitors class of drugs in­cludes treat­ments such as Velcade (bor­tez­o­mib) and Kyprolis (car­filz­o­mib), and the immuno­modu­la­tory class of drugs in­cludes treat­ments such as Revlimid (lena­lido­mide), Pomalyst (poma­lido­mide, Imnovid), and thalido­mide (Thalomid).

The proposed approved use in Europe is dif­fer­en­t than Darzalex's approved use in the United States. There, the approved use is for myeloma patients who have received at least three prior lines of ther­apy, in­clud­ing both an immuno­modu­la­tory agent and a pro­te­a­some inhibitor, and for patients who are “double refractory”, meaning their disease no longer responds to treat­ment with at least one immuno­modu­la­tory agent and at least one pro­te­a­some inhibitor (see the Beacon's article on the FDA approval of Darzalex).

In case you're interested, we also have a quick report below about a study that looks at a lab test-related com­pli­ca­tion of Darzalex.

Long-Term Results of Allogeneic Transplantation

Next, we turn to a new research study about allo­geneic trans­plan­ta­tion in multiple myeloma patients. It is from researchers in the Netherlands. They report on the results of allo­geneic trans­plants carried out in 147 multiple myeloma patients be­tween April 2001 and January 2014. All patients were seen at a single institution – the University Medical Center in Utrecht, Netherlands – and the median follow-up for the study was 89 months.

About 40 per­cent of the Utrecht trans­plants were done as part of the initial ther­apy the patients received after diag­nosis. The rest of the patients had their allo­geneic trans­plants at relapse. During the period covered by the study, it was standard practice at the Utrecht center that all multiple myeloma patients below the age of 66 – and who had a suitable sibling stem cell donor – be given the option of having an allo­geneic stem cell trans­plant as part of their first-line ther­apy.

Outcomes of allo­geneic trans­plan­ta­tion were the best in the patients doing the trans­plants as part of initial ther­apy. Half of these patients were still alive 10 years after diag­nosis, and the median pro­gres­sion-free survival was 30 months. Estimated total non-relapse mortality, a measure of how dangerous a treat­ment can be, was 16 per­cent in these patients.

Patients who had a deeper response (complete response or very good response) prior to their allo­geneic trans­plant tended to have longer pro­gres­sion-free and over­all survival.

Allogeneic trans­plant out­comes in the re­lapsed patients were not so en­cour­ag­ing. Indeed, they were disappointingly discouraging. Median pro­gres­sion-free survival was just 8 months, and median over­all survival was 29 months.

Outcomes among re­lapsed patients were better for younger patients and patients who had a better response to their pre-transplant treat­ment. Also, patients who devel­oped chronic graft versus host disease after their trans­plant also were likely to have longer survival.

Chromosomal ab­nor­mal­ity data for the Utrecht patients was not extensive enough to permit a detailed analysis of whether allo­geneic trans­plant out­comes depended on a patient's risk status using current definitions of high- and standard-risk status.

Finally, a tech­ni­cal detail for those particularly interested in allo­geneic trans­plan­ta­tion: Almost all the donor trans­plants covered in this study were reduced intensity / non-myeloablative trans­plants. T-cell depletion was done in a bit more than half the patients, with anti-thymocyte globulin (ATG) being used for about 60 per­cent of the T-cell depleted trans­plants, and alemtuzumab for the rest.

Hybrid PET-MRI

A new article has been published with a review of an imaging method described as “hybrid PET-MRI”, or just “PET-MRI” (full text). As you might ex­pec­t, PET-MRI is a com­bi­na­tion of PET scanning and MRI scanning, much the way PET-CT is a com­bi­na­tion of PET and CT scanning.

The new research article is not specific to the use of PET-MRI in multiple myeloma patients, but it does have a section related to the disease.

We thought we'd take ad­van­tage of the publication of the article, how­ever, to check with Beacon Medical Advisor Dr. Prashant Kapoor about PET-MRI and how it's being used in multiple myeloma. Dr. Kapoor is a myeloma specialist at the Mayo Clinic in Rochester, Minnesota.

Here is what Dr. Kapoor told us:

“The role of PET-MRI in myeloma is still under intense evaluation. I feel that PET-MRI can be poten­tially useful for response-assessment both at the intramedullary (within the bones) and extramedullary (outside the bones) level in myeloma patients.

“For example, in the im­medi­ate post-autologous stem cell trans­plant setting of low tumor burden, myeloma patients are unlikely to have new destruction of the outer bone layer, which typically is easily detected by CT. Instead, post au­tol­o­gous trans­plant patients may con­tinue to have persistent bone marrow infiltration by myeloma cells with patchy distribution that could be better assessed via MRI. However, false-positive results (evidence of residual disease when it is truly absent) on post-autologous trans­plant whole-body MRI suggest that its com­bi­na­tion with imaging methods that reveal ‘active’ lesions – such as PET – might be of greater value.

“Few reports exist re­gard­ing the prognostic role of PET-CT in multiple myeloma, and none exist for PET-MRI, although both tests have been individually shown to be useful. Further, the incremental value of adding PET-MRI to the current marrow-based minimal residual disease (MRD) diagnostics is unknown. Many investigators, in­clud­ing us at Mayo Clinic, are in the process of studying this.”

Although Dr. Kapoor discusses using PET-MRI in the post-transplant setting, he noted in further discussion with Myeloma Morning that the method also could be used – for similar reasons – after a patient has achieved a deep response to first-line ther­apy without a sub­se­quent trans­plant.

Testing-Related Complication of Darzalex

A com­pli­ca­tion of Darzalex that is not widely known is that, in some multiple myeloma patients, the treat­ment can interfere with the serum immuno­fix­a­tion electrophoresis (IFE) test, which de­ter­mines whether or not a myeloma patient has mono­clonal protein (paraprotein) in their blood.

Normal IFE testing can pick up Darzalex when it is in a patient's blood, and it sometimes will think that Darzalex is the same type of mono­clonal protein as the protein generated by a patient's multiple myeloma. Thus, the test can end up saying that a patient still has myeloma-generated mono­clonal protein in their blood, even though none is actually present.

A new research article summarizes work that has been done by an inter­na­tional team of researchers to come up with a modified IFE test that can be used in myeloma patients being treated with Darzalex (full text). Such a test has been devel­oped, and Dr. Kate Sasser of Janssen Research & Development – one of the authors of the study – told The Beacon that the test will be avail­able at a commercial clin­i­cal laboratory in the United States this fall.

Once the modified IFE test is avail­able this fall, patients being treated with Darzalex can have their blood sent to the laboratory for IFE testing.

Dr. Sasser also said that plans are underway to request regu­la­tory approval in the United States and other countries for this modified IFE test to be sold to any laboratory testing or­ga­ni­za­tion. There is no publicly announced timetable at this point, how­ever, for such regu­la­tory filings.

Quick Mentions

There are two new research articles we want to mention, albeit to say that we'll be discussing them further in future editions of Myeloma Morning. The first is another study of allo­geneic trans­plan­ta­tion in multiple myeloma patients (abstract). The second con­cerns gene ex­pres­sion profiling (GEP) (abstract).

Conversations in the Beacon's Discussion Forum

Things have quieted down a bit in the Beacon's forum after a lot of activity during the past week or so. Lisa has asked for feedback from myeloma patients being treated with IVIG. Also, given the Dutch study about allo­geneic trans­plan­ta­tion that we discuss above, it seems appro­pri­ate to mention that there are more than 60 discussions in the forum related to allo­geneic stem cell transplans.

New myeloma-related research articles

1. Chaudhry, A. A. et al., “Utility of positron emission tomography-magnetic resonance imaging in musculoskeletal imaging” in the World Journal of Radiology, March 28, 2016 (full text)
2. Dhakal, B. et al., “Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival” in Clinical Lymphoma, Myeloma & Leukemia, March 30, 2016 (abstract)
3. Franssen, L. et al., “Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution” in the European Journal of Haematology, March 29, 2016 (abstract)
4. Hermansen, N E. et al., “Gene expression risk signatures maintain prognostic power in multiple myeloma despite microarray probe set translation” in the International Journal of Laboratory Hematology, March 29, 2016 (abstract)
5. Linskog, C. et al., “A systematic characterization of aquaporin-9 expression in human normal and pathological tissues” in the Journal of Histochemistry & Cytochemistry, March 29, 2016 (abstract)
6. McCudden, C. et al., “Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference” in Clinical Chemistry and Laboratory Medicine, March 30, 2016 (full text)