Good morning, myeloma world.

We hope you had a pleasant weekend and that your new week is off to a good start.

The big news today is that Darzalex (daratumumab) has been approved in Europe as a new treatment for multiple myeloma. We will be pub­lish­ing a separate news article on the approval, which was announced a few hours ago. In the mean­time, you can find information about the approval in this press release from Genmab, the company that initially developed Darzalex.

The other news we have for you today focuses primarily on new research related to autologous (own) stem cell transplantation for multiple myeloma.

First, a study by U.S. researchers looks at the impact of kidney impairment on the outcomes of stem cell transplantation in myeloma patients. It finds that, among 149 myeloma patients who underwent stem cell transplants with the standard high dose of melphalan, patients with kidney impairment had equal or better survival outcomes in the intermediate term than patients without kidney impairment.

Second, a German study examines the use of upfront stem cell transplantation in older multiple myeloma patients in Germany. It finds that increased upfront transplantation in older patients may be one of the reasons the survival of German myeloma patients has improved during the past 20 years.

At the end of today’s report, we quickly summarize results of two other studies. One examines long-term overall survival results from a Phase 3 trial comparing Velcade plus Doxil to Velcade alone in relapsed multiple myeloma patients. The other investigates the association between leisure-time physical activity and the risk of developing certain cancers, including multiple myeloma.

Stem Cell Transplantation In Multiple Myeloma Patients With Kidney Impairment

A group of researchers from the University in Illinois has investigated the impact of kidney impairment on the outcomes of autologous stem cell transplantation carried out with standard high-dose melphalan (abstract). All patients in the study had multiple myeloma, and kidney impairment was defined as having a creatinine clearance of less than 60 mL/min prior to stem cell transplantation.

According to the study authors, patients with kidney impairment often receive lower doses of melphalan because there is no clear guidance on what melphalan dose is appropriate for such patients. At the same time, there is no conclusive evidence that kidney function plays a significant role in how the body processes melphalan. It may be entirely appropriate for patients with kidney impairment to receive the same melphalan dose as other patients.

The researchers therefore retrospectively analyzed data from 149 multiple myeloma patients who received an autologous stem cell transplant with high-dose melphalan (200 mg/m²) in the University of Illinois Hospital and Health Sciences System between January 2001 and September 2012.

The study authors did not include in their sample patients who were on dialysis at the time of their transplant, had received an autologous transplant within the previous six months, or had previously received an allogeneic (donor) stem cell transplant.

Of the 149 patients included in the analysis, approximately a third (46 patients) had kidney impairment at the time of their transplant.

Patients with kidney impairment were slightly older (median age of 61 years) than the patients without kidney impairment (median age 58 years). Otherwise, the characteristics were similar between the two patient groups.

Patients in both groups had received a median of two prior therapies. Overall, 59 percent of patients with kidney impairment, and 45 percent of patients without kidney impairment, had previously received treatment with a proteasome inhibitor, such as Velcade (bortezomib) or Kyprolis (carfilzomib). Similarly, 48 of patients with kidney impairment and 34 percent of patients without kidney impairment had previously received treatment with an immunomodulatory agent, such as thalidomide or Revlimid (lenalidomide).

Transplant Outcomes

The researchers found that patients with kidney impairment had longer time to neutrophil engraftment (10 days versus 9 days for patients without kidney impairment) and platelet engraftment (12 days versus 10 days).

In addition, patients with kidney impairment had more short-term toxicities during the transplant process than patients without kidney impairment. In particular, diarrhea and infections occurred more often in patients with kidney impairment, and those patients also received more infused nutritional assistance than the other patients.

However, the researchers did not observe any negative impact of high-dose melphalan on kidney function in the patients with kidney impairment.

In addition, with a median follow-up of 35 months for patients with kidney impairment and 47 months in patients without kidney impairment, overall survival was comparable between the two patient groups.

Moreover, median treatment-free survival was longer in patients with kidney impairment compared to patients without kidney impairment (37 months versus 17 months).

Given the difference in treatment-free survival, the researchers analyzed the use of maintenance therapy after the transplant. To their surprise, they found that significantly more patients without kidney impairment received maintenance therapy (40 percent versus 10 percent of patients with kidney impairment).

The researchers then analyzed to what extent treatment-free survival was affected by a range of different factors, including, among others, age, race, and pretransplant treatment response. They found that only impaired kidney function and prior treatment with a proteasome inhibitor therapy had a statistically significant impact on treatment-free survival.

The researchers conclude that, based on their findings, “kidney impairment should not be a barrier to consideration for autologous transplant.”

Perspective On The Study Results

In a commentary accompanying the article by the University of Illinois researchers, Dr. Jeffrey Szer from the Royal Melbourne Hospital in Australia wrote that the sample size, selection bias, and the retrospective nature of the study could be reasons for the improved treatment-free survival observed in the patients with kidney impairment.

Dr. Szer also speculated that “the amount of kidney impairment in the patient population resulted in just enough additional exposure to melphalan, without overwhelming toxicity, resulting in a balance in favor of disease control in these patients.” This result, he added, could support more research into personalizing the dosing of melphalan during transplantation, as is commonly done when busulfan is part of the transplant process.

Potential Benefit Of Upfront Stem Cell Transplantation In Older Multiple Myeloma Patients

A group of researchers from Germany has investigated the impact of upfront autologous stem cell transplantation in older multiple myeloma patients (abstract). The researchers found that older patients who underwent an upfront transplant had five-year survival rates that were higher than the five year survival rates of all similarly aged multiple myeloma patients – that is, similarly aged myeloma patients who did, and who did not, undergo upfront transplants.

In the case of this study, “older” patients includes those who are aged 60 to 79 years. (In their study, the authors use the term “elderly” instead of “older” for this group of patients. The Beacon, however, believes the term “older” may better reflect the age of these patients.)

The researchers undertook their study, in part, to better understand reasons for the improved survival of all German multiple myeloma patients in the last 20 years. They wondered to what extent the improved survival may be due to changes in stem cell transplantation among older German myeloma patients.

The analysis was based on data from the German Registry for Stem Cell Transplantation. In particular, the researchers analyzed data for 3,591 newly diagnosed multiple myeloma patients in Germany who had received an autologous stem cell transplant between 1998 and 2011 within 12 months of their diagnosis.

The researchers found that the use of upfront stem cell transplantation increased for all older patients over the analyzed time period, albeit at different rates. For patients aged 60 to 64 years at diagnosis, the share of patients undergoing an upfront transplant increased from 17 percent in 2000 to 2002 to 43 percent in 2009 to 2011. In patients aged 65 to 69 years, the share increased from 7 percent to 24 percent, and in patients aged 70 to 79 the share went from 0.4 percent to 4 percent.

Five-year overall survival for the older myeloma patients who received an upfront transplant improved continuously over the last decades from 44 percent in 1998 to 2000 to 56 percent in 2007 to 2009. Factors associated with longer survival in these patients included the achievement of a complete response after transplantation and the use of tandem transplants.

When the researchers compared relative survival rates from the older patients who received an upfront transplant to those of older patients from the general German myeloma population, they found the five-year relative survival of patients who received an upfront transplant of patients was higher across all age groups.

For 2009 to 2011, for example, the researchers estimate that five-year relative survival will be 66 percent (in upfront transplant recipients) and 59 percent (in all patients) in the 60 to 64 age group; 62 percent versus 57 percent, respectively, in the 65 to 69 age group; and 57 percent versus 51 percent, respectively, in the 70 to 79 age group.

Note that, to ensure a fair comparison of survival rates, the “all patients” survival rates listed in the previous paragraph are for all myeloma patients who survived at least one year after diagnosis.

Based on their results, the authors conclude that “autologous stem cell transplantation might be a contributor to the improved outcome of [older] multiple myeloma patients” in Germany. They also conclude that transplantation “is an effective therapeutic option proven to be feasible and safe” for older patients.

The researchers acknowledge, however, that their analysis has some limitations that need to be considered when interpreting their results. Chief among these is the potential for selection bias, particularly the possibility that stem cell transplant patients may be generally healthier patients.

The researchers did not have information on other diseases patients may have had, or which treatments patients received before and after transplantation.

(For more details on what relative and absolute survival rates are, please see the background information at the end of this previous edition of Myeloma Morning.)

Quickly Noted

An international team of myeloma researchers last week published long-term overall survival results from a Phase 3 study comparing Velcade plus Doxil (doxorubicin liposomal, Caelyx) to Velcade alone in relapsed and refractory multiple myeloma patients (abstract). The study included 646 patients who had a received at least one prior line of therapy. Previously published results showed that the addition of Doxil to Velcade extended progression-free survival (9.3 months compared to 6.5 months for Velcade alone). However, the new results show that the addition of Doxil to Velcade did not significantly extend overall survival. After a median follow-up of 8.6 years, the median overall survival for patients who received the Velcade-Doxil combination was 33.0 months from the time treatment with the two-drug combination started, compared to 30.8 months for patients who received Velcade alone.

Another international group of researchers has investigated the impact leisure-time physical activity on the risk of developing certain cancers, including multiple myeloma (abstract). Leisure-time physical activities were defined as activities done at an individual’s discretion that improve or maintain fitness or health. The study is based on data from 1.44 million people who took part in 12 different long-term health studies. Levels of physical activity were self reported by the study participants. During a median 11 years of follow-up, 186,932 cases of cancers were identified. The researchers found that a higher level of leisure-time physical activity was associated with a lower risk of 13 of 26 types of cancer investigated during the study. Multiple myeloma was one of the 13 cancers associated with a lower risk. The researchers write that their findings “support promoting physical activity as a key component of population-wide cancer prevention and control efforts.”

New Myeloma-Related Research Articles

1. Agarwal, P. et al., “Leukaemic transformation of multiple myeloma in post chemotherapy remission phase” in the Journal of Clinical and Diagnostic Research, April 1, 2016 (abstract)
2. Bejhed, R. S., Kharazmi, M., Hallberg P., “Identification of risk factors for bisphosphonate-associated atypical femoral fractures and osteonecrosis of the jaw in a pharmacovigilance database” in Annals of Pharmacotherapy, May 13, 2016 (abstract)
3. DeFilipp, Z. et al., “Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT” in Biology of Blood and Marrow Transplantation, May 13, 2016 (abstract)
4. Dupéré-Richer, D. et al., “Increased protein processing gene signature in HDACi-resistant cells predicts response to proteasome inhibitors” in Leukemia & Lymphoma, May 17, 2016 (abstract)
5. Galassi, G. et al., “Long-term disability and prognostic factors in polyneuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies” in the International Journal of Neuroscience, May 17, 2016 (abstract)
6. Gupta, N. et al., “A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis” in British Journal of Hematology, May 16, 2016 (full text)
7. Lin, J. et al., “A clinically relevant in vivo zebrafish model of human multiple myeloma (MM) to study preclinical therapeutic efficacy” in Blood, May 18, 2016 (abstract)
8. Liu, H. et al., “RBQ3 participates in multiple myeloma cell proliferation, adhesion and chemoresistance” in the International Journal of Biological Macromolecules, May 14, 2016 (abstract)
9. Merz, M. et al., “Survival of elderly patients with multiple myeloma - Effect of upfront autologous stem cell transplantation” in the European Journal of Cancer, May 10, 2016 (abstract)
10. Moore, S. C. et al., “Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults” in JAMA Internal Medicine, May 16, 2016 (abstract)
11. Orlowski, R. Z. et al., “Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma” in Cancer, May 18, 2016 (abstract)
12. Suen, H. et al., “Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade” in Leukemia, May 17, 2016 (abstract)
13. Sweiss, K. et al., “Melphalan 200 mg/m² in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival” in Bone Marrow Transplantation, May 16, 2016 (abstract)
14. Szer, J. , “Could renal impairment be a positive predictor of outcome in autografts for myeloma?” in Bone Marrow Transplantation, May 16, 2016 (abstract)