Myeloma Morning: Important New Transplantation And Darzalex Trial Results, And More

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
- 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)
- Ali, A. M. et al., “Radioimmunotherapy-based conditioning for hematopoietic stem cell transplantation: Another step forward” in Blood Reviews, May 2, 2016 (abstract)
- Aragona, P. et al., “Corneal structural changes in nonneoplastic and neoplastic monoclonal gammopathies” in Investigative Ophthalmology & Visual Science, May 1, 2016 (full text)
- 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)
- 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)
- Binsfeld, M. et al., “Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma” in Oncotarget, May 10, 2016 (full text)
- 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)
- Faller, E. et al., “Immune thrombocytopenia purpura associated with multiple myeloma” in Annals of Hematology, May 13, 2016 (abstract)
- 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)
- Jian, Y. et al., “Prognostic impact of cytogenetic abnormalities in multiple myeloma: a retrospective analysis of 229 patients” in Medicine, May 2016 (full-text)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
Related Articles:
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Darzalex May Affect Different Uninvolved Immunoglobulins Differently
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Two Darzalex Clinical Trials Halted; Little Impact Expected On Drug’s Use In Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients