A happy Saturday to you, myeloma world.

We have some good news to report today. It also is im­por­tant news related to Darzalex (dara­tu­mu­mab).

Some addi­tional clin­i­cal trial results related to Darzalex were made public earlier this week, but they have not received much attention.

The new results show that adding Darzalex to Velcade (bor­tez­o­mib) and dexa­metha­sone sub­stan­tially – some might even say dramatically – extends pro­gres­sion-free survival in re­lapsed multiple myeloma patients.

The new results expand on news announced at the end of March, which we covered in a pre­vi­ous edition of Myeloma Morning. The March news, how­ever, was only qualitative in nature. All that was reported at that time was that Darzalex extends pro­gres­sion-free survival when added to Velcade and dexa­metha­sone, and that the impact is statistically sig­nif­i­cant. The actual magnitude of the im­prove­ment was not announced in March.

It is this magnitude that is now known. And it is “very impressive”, according to Beacon Medical Advisor Dr. Prashant Kapoor of the Mayo Clinic, who was not involved in the trial.

We have more on the Darzalex news below.

The other news we'd like to discuss in today's report is a study about Treanda (bendamustine) that we first reviewed earlier this week. We have some addi­tional perspective on the study that we thought you would like to know.

We also have our daily list of new multiple myeloma research studies. We have enough to discuss in today's report with the Darzalex news and Treanda study, though, that we will be holding off for now on discussing the other studies. Look for perspectives on some of them, how­ever, in coming days.

New Results From The Darzalex MMY3004 / CASTOR Clinical Trial

Back at the end of March, we reported that Darzalex was showing pos­i­tive results in the MMY3004 / CASTOR clin­i­cal trial. The trial is com­par­ing Darzalex, Velcade, and dexa­metha­sone to Velcade and dexa­metha­sone in multiple myeloma patients who have had at least one prior line of ther­apy.

What we learned at the end of March was mainly qualitative in nature. In particular, we learned that patients in the Darzalex, Velcade, and dexa­metha­sone arm of the CASTOR trial had longer pro­gres­sion-free survival than patients in the Velcade and dexa­metha­sone arm. We also were told that the impact of Darzalex was statistically sig­nif­i­cant. But we did not know exactly how big the impact was.

We now know. And, for results from a multiple myeloma clin­i­cal trial, the dif­fer­ence is big.

In a press release earlier this week, Genmab, the com­pany that initially devel­oped Darzalex, announced that detailed results of the CASTOR trial would be presented at the American Society of Clinical Oncology (ASCO) meeting in early June. In the same press release, the com­pany also reported these key facts:

• The median progression-free survival for the patients treated with Velcade and dexa­metha­sone is 7.2 months
• The median progression-free survival for the patients treated with Darzalex, Velcade, and dexa­metha­sone has not yet been reached
• The hazard rate (HR) for progression-free survival is 0.39.

The hazard rate (HR) result is the particularly im­por­tant result from the above list.

The hazard rate of 0.39 indicates that, at an average point in time during treat­ment, patients on the Darzalex-based treat­ment regi­men were only 39 per­cent as likely to have their disease progress com­pared to patients treated with only Velcade and dexa­metha­sone.

Another way of looking at the hazard rate is that it says that patients who were treated with Darzalex had a 61 per­cent lower risk of their myeloma progressing at any given time than patients who were not treated with Darzalex.

When we asked the Mayo Clinic's Dr. Kapoor for his perspective on the 0.39 hazard rate, he described its magnitude as “unprecedented in myeloma.”

Dr. Kapoor also noted that the result is “not surprising, since Darzalex has dem­onstrated the highest single-agent activity in multiply re­lapsed multiple myeloma.”

How Significant Are The Results?

To put the 0.39 hazard rate in perspective, con­sider the results of the ASPIRE clin­i­cal trial. It tested the impact Kyprolis (car­filz­o­mib) has when added to Revlimid (lena­lido­mide) and dexa­metha­sone to treat re­lapsed multiple myeloma patients.

Kyprolis is generally con­sidered to have per­formed very well in the ASPIRE trial. The hazard rate for its impact on pro­gres­sion-free survival in that trial was 0.69 (full text).

The results were similar for Empliciti (elotuzumab) in the ELOQUENT-2 trial. That study tested the impact of adding Empliciti to Revlimid and dexa­metha­sone in re­lapsed myeloma patients. The hazard rate for Empliciti's impact on pro­gres­sion-free survival was 0.70 (full text).

So, Kyprolis and Empliciti reduced the risk of disease pro­gres­sion by about 30 per­cent, while Darzalex reduced the risk of pro­gres­sion by about 60 per­cent.

That dif­fer­ence on disease pro­gres­sion is why Darzalex is being viewed as having such sig­nif­i­cant activity as a multiple myeloma ther­apy.

Here at The Beacon, we cur­rently esti­mate that the pro­gres­sion-free survival of the Darzalex-treated patients in the CASTOR trial Could be 10 or 11 months longer than the 7.2 month pro­gres­sion-free survival of the patients in the trial who were not treated with Darzalex.

Why Haven't These Results Received More Attention?

The new Darzalex results have been easy to overlook because of the way they were announced.

They were in a press release about an abstract to be presented at the ASCO meeting. Such press releases rarely in­clude in­for­ma­tion that is not already publicly known. Indeed, meeting or­ga­niz­ers usually request that presenters and com­pa­nies sponsoring research not make public any in­for­ma­tion in abstracts until the abstracts have been made public.

It is the Beacon's under­stand­ing, how­ever, that Genmab was compelled by financial reg­u­la­tions in its home country, Denmark, to release the Darzalex CASTOR data once it was informed of it. This is because the CASTOR results could be viewed as being im­por­tant enough to the com­pany's financial health that it would be illegal for the com­pany to withhold the in­for­ma­tion from in­vestors.

More On Treanda During Autologous Stem Cell Transplantation

In this past Tuesday's edition of Myeloma Morning, we reported on a study by Italian researchers investi­gat­ing the use of Treanda during stem cell trans­plan­ta­tion.

Participants in the Italian clin­i­cal trial were newly diag­nosed multiple myeloma patients who underwent tandem au­tol­o­gous stem cell trans­plants as part of their initial treat­ment.

For their first trans­plant, the patients received standard high-dose mel­phalan as the chemo­therapy during the trans­plant process. However, during the second trans­plant, the patients received a com­bi­na­tion of mel­phalan and Treanda as chemo­ther­apy.

The com­bi­na­tion of mel­phalan and Treanda proved effective and also seemed well tolerated. “Based on their findings,” we wrote in our pre­vi­ous report about the study, “the Italian researchers conclude that Treanda plus mel­phalan is feasible as a con­di­tioning regi­men for second trans­plant in multiple myeloma patients. They add that their study may pave the way for Phase 3 studies further investigating this com­bi­na­tion strategy.”

Ever since our initial report about the Treanda study, we've wanted some addi­tional perspective on it – in part because regularly are studies that in­ves­ti­gate whether it is a good idea to “tweak” the high-dose chemo­ther­apy used during stem cell trans­plants.

So we reached out to myeloma and stem cell trans­plant specialist Dr. Mohamad Mohty, the current pres­i­dent of the European Society for Blood and Marrow Transplantation (EBMT). Dr. Mohty is pro­fessor of hematology and head of the hematology and cellular ther­apy department at the Saint-Antoine Hospital and University Pierre & Marie Curie in Paris, France.

In particular, we asked Dr. Mohty for his thoughts on the Treanda study and its implications. Here is what he told us:

“Although the authors of the Treanda-melphalan study found the com­bi­na­tion to be safe, I am a bit skeptical due to the risk of added toxicity from combining two alkylating agents in routine practice outside of a clin­i­cal trial.

“High dose mel­phalan is the standard of care in this setting. Previous studies going back more than 15 year have not found an added benefit to combining mel­phalan with another agent (such as total body irradiation) because of the risk of cumulative toxicities.

“More recently, retro­spec­tive­ data suggest that mel­phalan and busulfan can be an attractive new regi­men. Yet, once again, we are faced with the risk of added toxicity.

“At present, au­tol­o­gous stem cell trans­plan­ta­tion con­di­tioned by high dose mel­phalan is a safe pro­ce­dure that is often per­formed on an outpatient basis. Any other com­bi­na­tion with mel­phalan will mandate hospi­tal­iza­tion of the patient – with all the asso­ci­ated consequences.

“In an era with so many novel myeloma ther­a­pies, most investigators (including myself) would like to stick with the mel­phalan con­di­tioning regi­men and use con­sol­i­da­tion and main­te­nance ther­a­pies after stem cell trans­plan­ta­tion, rather than the con­di­tioning regi­men, for disease control.”

New Myeloma-Related Research Articles

1. Belaidia, N. et al., “Hypercalcemia and elevated concentration of vitamin D: A case report too easy to be true” in Clinica Chimica Acta, April 16, 2016 (abstract)
2. De Veirman, K. et al., “Induction of miR-146a by multiple myeloma cells in mesenchymal stromal cells stimulates their pro-tumoral activity” in Cancer Letters, April 18, 2016 (abstract)
3. Ghasemi, M., et al., “Expression profile of the individual genes corresponding to the genes generated by the cytotoxicity experiments of bortezomib in multiple myeloma” in the Turkish Journal of Hematology, April 18, 2018 (abstract)
4. Harada, T. et al., “Histone deacetylase inhibitors in multiple myeloma: from bench to bedside” in the International Journal of Hematology, April 20, 2016 (abstract)
5. Hossain, N. M. et al., “T-cell receptor-engineered cells for the treatment of hematologic malignancies” in Current Hematologic Malignancy Reports, April 19, 2016 (abstract)
6. Imai, Y. et al., “Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma” in JCI Insights, April 21, 2016 (full text)
7. Jaruvongvanich, V. et al., “An unusual cause of altered mental status in multiple myeloma: an extraosseous manifestation” in the Hawaii Journal of Medicine and Public Health, April 20, 2016 (full-text PDF)
8. Lisenko, K. et al., “Comparison between intermittent and continuous spectra optia leukapheresis systems for autologous peripheral blood stem cell collection” in the Journal of Clinical Apheresis, April 20, 2016 (abstract)
9. Manier, S. et al., “Cell autonomous and microenvironmental regulation of tumor progression in precursor states of multiple myeloma” in Current Opinion in Hematology, April 20, 2016 (abstract)
10. Ray, A. et al., “A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells” in British Journal of Haematology, April 20, 2016 (abstract)
11. Saba R., Saleem N., Peace D., “Long-term survival consequent on the abscopal effect in a patient with multiple myeloma” in the BMJ Case Reports, April 20, 2016 (abstract)
12. Scott, K. et al., “Bortezomib for the treatment of multiple myeloma” in the Cochrane Database of Systematic Reviews, April 20, 2016 (abstract)
13. Stockwin W., Johnson P., Vajpayee N., “Immunohistochemical expression of mTOR in multiple myeloma: retrospective analysis of 31 cases, a clinicopathological study” in the Annals of Clinical and Laboratory Sciences, March/April 2016 (abstract)