Good morning, myeloma world.

Since the last edition of Myeloma Morning, abstracts for two im­por­tant upcoming medical meetings have been made public: the American Society of Clinical Oncology (ASCO) annual meeting, which will take place June 3 through June 7 in Chicago, and the European Hematology Association (EHA) annual congress, which is scheduled for June 9 through June 12 in Copenhagen, Denmark.

The publication of the abstracts and the meetings themselves mean that there is going to be a lot of multiple myeloma-related news in the coming weeks. We will do our best to pace our coverage. However, it still will be the case that our reports are likely to be longer, and more frequent, during the next month.

Today's edition of Myeloma Morning is a perfect example. It's very long. Very, very, long. Most readers will want to digest it in two or three sittings.

Do take the time, how­ever, to review at least the first two sections of the report, as they report on some very im­por­tant research.

In particular, the first section of the report discusses initial results of an im­por­tant European trial that will be presented at the upcoming ASCO meeting. The trial in­ves­ti­gates the use of stem cell trans­plan­ta­tion in newly diag­nosed multiple myeloma patients. Given the poten­tial sig­nif­i­cance of the results, we in­clude in our summary some perspective on them from Dr. Paul Richardson of the Dana-Farber Cancer Institute.

In the second section, we look at new Darzalex trial results that will be presented at the EHA meeting. These im­por­tant results are from a Phase 3 trial testing how much Darzalex (dara­tu­mu­mab) im­proves treat­ment out­comes when it is added to Revlimid (lena­lido­mide) and dexa­metha­sone treat­ment for re­lapsed multiple myeloma patients.

We then have three sections for three separate studies from recently published journal articles.

One study looks at the rela­tion­ship be­tween treat­ment response and over­all survival in heavily pre­treated myeloma patients who received Pomalyst (poma­lido­mide) and dexa­metha­sone ther­apy.

A second study explores the possibility of treating myeloma with a four-drug com­bi­na­tion based on Velcade (bor­tez­o­mib), cyclophosphamide (Cytoxan), dexa­metha­sone, and Doxil (doxorubicin lipo­somal).

Finally, the third and last study in­ves­ti­gates whether the serum free light chain ratio – or “kappa-lambda ratio” – is a reliable indicator of treat­ment response in myeloma patients who have achieved a deep response after a stem cell trans­plant.

Multiple Myeloma-Related Abstracts From The 2016 ASCO And EHA Meetings

As we mentioned, abstracts have been published for the presentations that will be made at the upcoming ASCO and EHA annual meetings.

Titles of the ASCO presentations – but not the abstracts – were made public several weeks ago. You may recall that we discussed the presentations in two pre­vi­ous editions of Myeloma Morning: one focused on the oral presentations, and one on the poster presentations.

We also have created two pages here at The Beacon that give you overviews of all the multiple myeloma-related oral presentations and poster presentations at the upcoming ASCO 2016 meeting. Each page lists presentation titles and author names, and for each presentation there is a link that will take you to the com­plete text of the presentation's abstract.

We will be devel­op­ing a few addi­tional pages related to the ASCO 2016 meeting and similar pages for the EHA meeting.

For at least the next several months, you will find an area in the Beacon's sidebar – on the right of each Beacon page – which will display links to the pages with lists of the myeloma-related ASCO and EHA abstracts. Currently, on pages such as this one, the links are displayed im­medi­ately below the area where logos of Beacon sponsors are displayed.

If you would like to search the ASCO and EHA abstracts on your own, you can do so by going to this link for the ASCO meeting, and this link for the EHA meeting. Keep in mind that, when search­ing for abstracts about a particular drug treat­ment, you should use the drug's generic name rather than its brand name (e.g., lena­lido­mide instead of Revlimid, or bor­tez­o­mib instead of Velcade).

Initial Results Of EMN02/HO95 MM Transplantation vs. Novel Therapy Trial

One of the presentations planned for the ASCO meeting will report initial results of an im­por­tant European trial involving newly diag­nosed multiple myeloma patients. The trial, known as the EMN02/HO95 MM (“EMN”) study, compares two dif­fer­en­t ap­proaches to treating these patients. One ap­proach in­cludes au­tol­o­gous stem cell trans­planta­tion, while the other does not.

The initial results of the EMN trial indicate that patients who received trans­plants had longer pro­gres­sion-free survival than the patients who did not. There is no dif­fer­ence at this time, how­ever, in over­all survival be­tween the two groups of patients (abstract).

Design Of The Trial

A total of 1503 newly diag­nosed multiple myeloma patients were recruited be­tween February 2011 and April 2014 to take part in the EMN trial. All patients initially received treat­ment with Velcade, cyclophosphamide, and dexa­metha­sone for four cycles. Patients then were ran­domly assigned to have either one or two au­tol­o­gous stem cell trans­plants (754 patients) or four cycles of Velcade, mel­phalan, and pred­ni­sone (VMP) treat­ment (512 patients).

Following their trans­plants or VMP treat­ment, patients were once again ran­domly assigned to receive either two cycles of con­soli­da­tion treat­ment with Revlimid, Velcade, and dexa­metha­sone (RVD), or no con­solida­tion ther­apy.

As the final stage in their treat­ment, all patients received Revlimid main­te­nance ther­apy, which con­tinued until the patient's disease progressed.

(Full details of the trial's design can be found in this PDF document.)

Key Trial Results

In their ASCO abstract, the EMN trial investigators report that, after a median follow-up of 2 years from the time patients were ran­dom­ized to either trans­planta­tion or VMP treat­ment, the patients who had trans­plants ex­peri­enced longer pro­gres­sion-free survival.

The investigators do not report specific pro­gres­sion-free survival times or per­cent­ages. They do report, how­ever, that a trans­plant patient's risk of disease pro­gres­sion or death was on average 24 per­cent lower than that of patients who did not receive a trans­plant (that is, the hazard ratio for pro­gres­sion-free survival was 0.74).

Transplantation's impact on pro­gres­sion-free survival was seen not just across all patients, but also in key patient subgroups, such as patients with more ad­vanced disease at diag­nosis, and patients with high-risk chromosomal ab­nor­mal­i­ties. The impact also was as strong, if not stronger, when the investigator's statistically controlled for patient char­ac­ter­istics such as age, disease stage at diag­nosis, and risk status.

That said, the investigators also note in their abstract that “Overall survival was not yet mature and no dif­fer­ence be­tween the treat­ment groups was evident.”

Implications of the Study Findings

The design and objectives of the EMN02/HO95 study are similar to those of another im­por­tant trans­­planta­tion-related trial: the IFM2009/DFCI trial (“IFM”), which has been carried out in Europe and the United States. Initial results of the European side of that trial were reported at the 2015 American Society of Hematology annual meeting (abstract).

The EMN and IFM studies are also similar in terms of their results. In both trials, patients who received stem cell trans­plants ex­peri­enced longer pro­gres­sion-free survival, but no dif­fer­ence in over­all survival.

Given the similarities shared by the two trials, one would ex­pec­t reac­tion to the EMN results to be much the same as the reac­tion to the IFM results: ap­pre­ci­a­tion of the pro­gres­sion-free survival results, but recognition that the over­all survival results make it unclear whether trans­plan­ta­tion should be done early, or later, in a patient's treat­ment.

Thus far, how­ever, reports about the EMN results have suggested they unequivocally favor early trans­plan­ta­tion. Headlines such such as “Upfront Transplant Best for Younger Multiple Myeloma Patients” and even “Transplant Remains King for New Myeloma" have been common.

We there­fore turned for some perspective on the EMN results to Dr. Paul Richardson, a leading myeloma specialist based at the Dana-Farber Cancer Institute in Boston. He agreed that there was nothing in the EMN results that should suggest conclusions dif­fer­en­t than what might have been drawn based on the results of the IFM trial. Dr. Richardson told The Beacon,

“The pro­gres­sion-free survival ad­van­tage seen in the EMN02/HO95 MM trial results was ex­pec­ted, but the absence of an over­all survival dif­fer­ence is noted – again suggesting that patients have a choice be­tween early versus late tran­splan­tation. VMP is chal­leng­ing to interpret as a control, particularly as RVD and regi­mens like it appear to be so much more efficacious. The inclusion in the trial of Revlimid main­te­nance until disease pro­gres­sion is a strength, ‎but interpretation of these results over­all, and what they mean for U.S. practice, requires caution in my view.

“Participation in current studies should be a priority and the advent of newer, highly active induction regi­mens incorporating mono­clonal anti­bodies is going to change the paradigm yet further. This will make the question more complex, but in a good way, and again emphasizes the importance of patients and their providers being able to choose and poten­tially tailor ther­apy accordingly. Finally, I do think we need further follow up from these trials and, critically, results from our ongoing U.S. studies before drawing definitive conclusions.”

Darzalex, Revlimid, and dexa­metha­sone in Relapsed Myeloma Patients

Regular Beacon readers will recall that we recently reported on im­por­tant new results for Darzalex in the treat­ment of re­lapsed multiple myeloma patients.

Initial results of the “CASTOR” clin­i­cal trial were made public in mid April. Those results indicate that adding Darzalex to Velcade and dexa­metha­sone leads to a very sig­nif­i­cant in­crease in pro­gres­sion-free survival com­pared to Velcade and dexa­metha­sone alone.

As we explained in our earlier article, adding Darzalex to Velcade and dexa­metha­sone reduced a patient's risk of disease pro­gres­sion, or death prior to pro­gres­sion, by 61 per­cent. This is much greater than the typically 30 per­cent reduction seen in recent trials for other drugs added to two-drug com­bi­na­tions to treat re­lapsed myeloma patients.

New results to be presented at the EHA meeting suggest that the Darzalex's results in the CASTOR trial are not a fluke. The new results show that Darzalex has just as sig­nif­i­cant an effect on pro­gres­sion-free survival when it is added to Revlimid and dexa­metha­sone as it does when it is added to Velcade and dexa­metha­sone.

The new results are from the POLLUX (MMY3003) clin­i­cal trial. Genmab, the Danish com­pany that initially devel­oped Darzalex, has issued a press release with key initial results from the trial. More com­plete results will be in the EHA presentation and its asso­ci­ated abstract (which cur­rently is subject to media embargo).

The POLLUX trial is com­par­ing treat­ment with Darzalex, Revlimid and dexa­metha­sone to Revlimid and dexa­metha­sone alone in myeloma patients who have had at least one prior line of treat­ment. The 569 par­tic­i­pants in the trial were ran­domly assigned to be treated with either the three-drug regi­men that in­cludes Darzalex, or the two-drug regi­men without Darzalex.

Genmab reported in its press release that adding Darzalex to Revlimid and dexa­metha­sone reduced the rate of pro­gres­sion, or death prior to pro­gres­sion, by 63 per­cent com­pared to treat­ment with Revlimid and dexa­metha­sone alone.

In other words, the hazard rate for pro­gres­sion-free survival was 0.37, or slightly better than the 0.39 hazard rate seen in the initial CASTOR trial results for Darzalex, Velcade, and dexa­metha­sone.

Readers may recall from the Beacon's previous reporting that myeloma specialist Dr. Prashant Kapoor of the Mayo Clinic described the 0.39 hazard rate seen for Darzalex in the CASTOR trial as “unprecedented in myeloma.” He also added that the result was “not surprising” given the sig­nif­i­cant anti-myeloma activity Darzalex has dem­onstrated in the past.

Median pro­gres­sion-free survival has not yet been reached among the patients in the POLLUX trial who were treated with Darzalex, Revlimid, and dexa­metha­sone, versus 18.4 months for the patients treated with just Revlimid and dexa­metha­sone.

Genmab also reported in its press release about the POLLUX trial results that the safety profile for Darzalex, Revlimid, and dexa­metha­sone was similar to what was seen in an earlier Phase 2 trial, known as GEN503, that also tested the same three-drug regi­men. Results of that trial were presented at the ASH 2015 meeting in December (abstract, related slide presentation).

Treatment Response And Survival In Heavily Pretreated Patients

We next turn to research that has been published recently in journal articles, rather than meeting abstracts.

The first such study we look at is a new analysis of data from the MM-003 / NIMBUS Phase 3 trial, which com­pared Pomalyst plus low-dose dexa­metha­sone to high-dose dexa­metha­sone alone in heavily pre­treated patients. In the new analysis, researchers in­ves­ti­gate the rela­tion­ship be­tween treat­ment response and over­all survival in the patients who received the Pomalyst-dexa­metha­sone com­bi­na­tion (abstract).

The results of this study are useful because they help explain why, in some clin­i­cal trials, researchers focus on a broader measure of treat­ment response than the “overall response rate” that is typically the focus when reviewing myeloma trial results.

More specifically, in trials involving myeloma patients who have had many pre­vi­ous treat­ments, researchers often report a “clinical benefit ratio.” Unlike the over­all response rate, which is the share of all patients who had at least a partial response to treat­ment, the clin­i­cal benefit ratio is the share of patients who achieved at least stable disease in response to treat­ment.

This raises an im­por­tant question: What evi­dence is there that there is value in knowing not just what share of patients achieve at least a partial response, but also what share achieve at least stable disease?

The analysis of the NIMBUS data helps answer that exact question. It dem­onstrates that there is value to the clin­i­cal benefit ratio when patients in a study have been heavily pre­treated.

The NIMBUS trial in­cluded 455 re­lapsed and refractory myeloma patients with a median age of 64 years. The patients were heavily pre­treated; they had received a median of five prior ther­a­pies.

Two-thirds of the study par­tic­i­pants were treated with 4 mg of Pomalyst on days 1 to 21 and 40 mg of dexa­metha­sone once per week of a 28-day treat­ment cycle. The remaining third were treated with high-dose dexa­metha­sone, 40 mg per day on days 1 to 4, 9 to 12, and 17 to 20 of a 28-day cycle.

The authors of the new study com­pared survival of patients with stable disease, patients with progressive disease, and patients with at least a partial response. They limited their analysis to patients who were treated with Pomalyst plus low-dose dexa­metha­sone.

Among the 302 patients receiving Pomalyst plus low-dose dexa­metha­sone, 19 per­cent had achieved at a least a partial response, 38 per­cent were in stable disease, and 15 per­cent showed progressive disease at the start of cycle 3. Some patients with stable disease at the start of treat­ment cycles 3 (17 per­cent) and 5 (13 per­cent) ex­peri­enced im­proved responses at later cycles.

The researchers found that patients who were in stable disease at the start of treat­ment cycles 3, 5, and 7 had slightly lower – but statistically similar – over­all survival as patients who achieved a partial response at the same time points.

Specifically, median over­all survival based on response at cycle 3 was 22.4 months for patients who had achieved at least a partial response, and 16.2 months for patients in stable disease. These survival out­comes were not only similar, but also much greater, than the median over­all survival of 6.3 months for patients seen in patients whose disease had progressed by cycle 3.

The researchers observed similar patterns based on responses to treat­ment measured at the start of treat­ment cycles 5 and 7.

The researchers’ findings con­firm pre­vi­ous findings that the response status of patients at early assess­ments was predictive of over­all survival. Some re­lapsed and refractory myeloma patients may derive benefit from any response to treat­ment, in­clud­ing disease stabilization, and in some cases achieve prolonged survival.

CyBorD Plus Doxil

Next, we report on a small trial carried out by researchers from various hos­pi­tals in Washington state. The trial in­ves­ti­gated the efficacy and safety of cyclophosphamide, Velcade, and dexa­metha­sone plus Doxil (pegylated lipo­somal doxorubicin) (full text).

The three-drug com­bi­na­tion of cyclophosphamide, Velcade, and dexa­metha­sone, commonly abbre­vi­ated as CyBorD or VCD, is often used as initial treat­ment for newly diag­nosed multiple myeloma patients.

By adding Doxil to the CyBorD, the researchers sought to im­prove the depth of response and over­all response rate com­pared to three-drug regi­mens. In addi­tion, Velcade was admin­istered once a week (that is, days 1, 4, 8 and 11) rather than twice weekly (the standard dosing at study inception) in an effort to im­prove the ease of admin­istra­tion.

The study consisted of two parts: a pilot phase to test the safety of the four-drug com­bi­na­tion in re­lapsed patients, and a main part that tested the com­bi­na­tion in newly diag­nosed multiple myeloma patients eli­gible for au­tol­o­gous stem cell trans­plan­ta­tion.

Patients received 1.6 mg/m² of Velcade, 300 mg/m² of cyclophosphamide IV, and 40 mg of dexa­metha­sone on days 1, 8 and 15, and 30 mg/m² of Doxil on day 8 of a 28-day treat­ment cycle.

The newly diag­nosed patients were supposed to receive four cycles before proceeding to au­tol­o­gous stem cell trans­plan­ta­tion.

Overall, 31 patients were enrolled in the study (six re­lapsed and refractory patients and 25 newly diag­nosed patients).

Of the six re­lapsed patients who received two to four cycles of treat­ment, one achieved a very good partial response, one a partial response, two a minimal response and two stable disease.

Of the 20 patients with newly diag­nosed multiple myeloma who com­pleted the planned four cycles of treat­ment, 90 per­cent responded, with 10 per­cent achieving a com­plete responses, 30 per­cent a very good partial response, and 50 per­cent a partial response.

According to the researchers, the over­all response rate they observed with CyBorD plus Doxil is in line with what has been observed for other four-drug com­bi­na­tions, such as Revlimid, Velcade, Doxil, and dexa­metha­sone or Velcade, Revlimid, cyclophosphamide, and dexa­metha­sone.

Median follow-up of the 20 newly diag­nosed patients was 49 months. The three-year over­all survival rate among those patients was 80 per­cent. The median over­all survival has not been reached yet.

According to the researchers, the four-drug regi­men was well tolerated. The most common severe side effects in­cluded hand/foot syn­drome (2), in­fec­tion (2), and gastro­in­tes­ti­nal hemorrhage (1), diarrhea (1), weight loss (1), anemia (1), mucositis (1) and chronic obstructive pul­mo­nary disease exacerbation (1).

Based on their findings, the researchers rec­om­mend a direct comparison be­tween the in­ves­ti­gated four-drug com­bi­na­tion and other commonly used drug regi­mens.

Reliability Of The Serum Free Light Chain Ratio In Assessing Treatment Response

We conclude our report today with a quick summary of a paper by researchers at the University of Iowa. They report on an in­ves­ti­ga­tion they carried out into the reliability of the serum free light chain ratio, or “kappa-lambda ratio,” as a measure of treat­ment response.

The Iowa authors report that, in patients who have had a trans­plant and other­wise appear to have achieved a com­plete response, the serum free light chain ratio may not be as reliable an indicator treat­ment response as commonly assumed (abstract).

The researchers devel­oped a database of 142 multiple myeloma patients who received a single or tandem au­tol­o­gous trans­plant at their treat­ment center be­tween January 2012 and June 2015.

Among those 142 patients, they found 17 who, on one or more serum free light chain (sFLC) tests, had an ab­nor­mal kappa-lambda ratio, but had absolutely no other sign of residual disease based on their M-spike, serum immuno­fix­a­tion, minimal residual disease testing, and very sensitive FISH testing.

Interestingly, in all 17 cases an elevated kappa free light chain was the cause of the ab­nor­mal free light chain ratio.

In a number of cases, the ab­nor­mal free light chain ratio persisted for many months.

The authors conclude that, based on their findings, the definition of stringent com­plete response – which requires a nor­mal free light chain ratio – “should be adjusted.”

New Myeloma-Related Research Articles

1. Abbi, K. K. S. et al., “Potential pitfalls of serum free light chain analysis to assess treatment response for multiple myeloma” in the British Journal of Haematology, May 12, 2016 (abstract)
2. Ali, A. M. et al., “Radioimmunotherapy-based conditioning for hematopoietic stem cell transplantation: Another step forward” in Blood Reviews, May 2, 2016 (abstract)
3. Aragona, P. et al., “Corneal structural changes in nonneoplastic and neoplastic monoclonal gammopathies” in Investigative Ophthalmology & Visual Science, May 1, 2016 (full text)
4. Becker, P. S. et al., “A phase 2 study of bortezomib, cyclophosphamide, pegylated liposomal doxorubicin and dexamethasone for newly diagnosed multiple myeloma” in Blood Cancer Journal, May 13, 2016 (full text)
5. Brown, S. et al., “The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma” in BMC Hematology, May 17, 2016 (full text)
6. Binsfeld, M. et al., “Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma” in Oncotarget, May 10, 2016 (full text)
7. El-Ghammaz, A. M. S., Abdelwahed, E. “Bortezomib-based induction improves progression-free survival of myeloma patients harboring 17p deletion and/or t(4;14) and overcomes their adverse prognosis” in Annals of Hematology, May 16, 2016 (abstract)
8. Faller, E. et al., “Immune thrombocytopenia purpura associated with multiple myeloma” in Annals of Hematology, May 13, 2016 (abstract)
9. Hatsuse, M. et al., “Transition to aggressive phase in a multiple myeloma patient with IgH/CCND1 translocation and diffuse osteosclerotic lesions” in Rinsho Ketsueki, April 2016 (abstract)
10. Jian, Y. et al., “Prognostic impact of cytogenetic abnormalities in multiple myeloma: a retrospective analysis of 229 patients” in Medicine, May 2016 (full-text)
11. Krishnan, S. R. et al., “Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review)” in the International Journal of Oncology, May 11, 2016 (abstract)
12. Moreau, P. et al., “Relationship of response and survival in patients with relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone in the MM-003 trial randomized phase III trial (NIMBUS)” in Leukemia & Lymphoma, May 13, 2016 (abstract)
13. Polanco, T. O. et al., “A rare case of listeriosis, acute cholecystitis and multiple myeloma” in the Journal of Surgical Case Reports, May 12, 2016 (full text)
14. Ri, M., “Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma” in the International Journal of Hematology, May 12, 2016 (abstract)
15. Van Merode, T. et al., “Describing patients' needs in the context of research priorities in patients with multiple myeloma or Waldenstrom's disease: A truly patient-driven study” in Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen, May 9, 2016 (abstract)
16. Westin, G. F., Dias, A. L., Go, R. S., “Exploring big data in hematological malignancies: challenges and opportunities” in Current Hematologic Malignancy Reports, May 13, 2016 (abstract)
17. Xu, X. et al., “Cell adhesion induces overexpression of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) and contributes to cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells” in Leukemia Research, May 12, 2016 (abstract)