Good morning, myeloma world.

We've got a lot of new myeloma-related research to cover today, so we'll get right down to business.

The first two studies we will review are related to autologous (own) stem cell transplantation.

One study looks at whether myeloma cells make their way into the infusion of a patient's own stem cells that a patient gets during the autologous transplant process. The study finds that, in some cases, myeloma cells do make it into the stem cell infusion, and when this happens, it could – again, could – negatively affect transplant outcomes.

The second transplantation-related study looks at the use of cyclophosphamide (Cytoxan, Endoxan) for stem cell mobilization. It finds that, as expected, cyclophosphamide improves the chances of a patient successfully harvesting enough stem cells for a transplant. However, the stem cells harvested after cyclophosphamide-assisted mobilization are not as good at producing white cells as stem cells harvested without the use of cyclophosphamide for mobilization.

Other studies we'll be looking at today include one about the possible use of Folotyn (pralatrexate) to treat multiple myeloma, a potential new target for drugs that could prevent myeloma cells from causing bone lesions, and a study investigating the treatment of elderly multiple myeloma patients with weekly Velcade (bortezomib) administered three weeks out of a four-week cycle.

Myeloma Cells In Stem Cell Reinfusions

French researchers have reported on a study they have carried out. It investigated to what extent myeloma cells (“tumoral plasma cells”) are found in the stem cells and other blood cells harvested from myeloma patients prior to autologous (own) stem cell transplantation. The researchers measured both the total number of plasma cells, and the number of myeloma (tumoral) plasma cells, in the stem cells and other blood cells collected from patients. They carried out these measurements immediately after stem cell collection, and immediately before reinfusion of the cells into the patient during the stem cell transplant process (abstract).

The study included 43 myeloma patients who received an autologous stem cell transplant as part of their initial therapy after diagnosis. All patients received three to four cycles of a three-drug induction regimen. The regimen included dexamethasone and either a proteasome inhibitor or an immuno­modu­la­tory agent, or both. The proteasome inhibitors were either Velcade (bortezomib) or Kyprolis (carfilzomib). The immuno­modu­latory agents were either Revlimid (lenalidomide) or thalidomide (Thalomid).

Stem cell harvesting was performed following mobilization with cyclophosphamide and granulocyte colony stimulating factor (GCSF, for example Neupogen) after Cycle 3.

The researchers found that myeloma cells were detectable in 23 percent of the patient's stem cell samples at the time of collection, and 18 percent of the samples tested at the time of reinfusion. This difference was not statistically significant, and the researchers believe it demonstrates that the stem cell storage and thawing procedure does not affect the composition of the harvested cells.

Progression-free survival was longer for patients who did not have myeloma cells in their stem cell infusions compared to those who did (not yet reached versus a median of 16 months, respectively). The authors of the study note, however, that their data on this point needs to be interpreted cautiously, because patient char­ac­ter­istics and initial treatment varied noticeably across the study participants.

Impact Of Cyclophosphamide Used For Stem Cell Mobilization

Our second study today is from researchers in Finland. They report on a study they carried out to test the impact of cyclophosphamide when it is used for stem cell mobilization (abstract).

In particular, the researchers used two different strategies to mobilize stem cells in myeloma patients plan­ning to have an autologous stem cell transplant. One group of patients received low-dose cyclophosphamide plus granulocyte colony stimulating factor (GCSF, Neupogen). The other group received only GCSF.

Prior to stem cell mobilization, all patients had completed three cycles of induction therapy with Revlimid, Velcade, and dexamethasone.

All patients were able to harvest a sufficient number of cells to have their planned transplant. Patients who received low-dose cyclo­phos­pha­mide plus GCSF had greater stem cell yields, however, and fewer of them required Mozobil (plerixafor) to ensure that they could collect enough stem cells for a transplant.

That having been said, patients who received GCSF alone had higher numbers of T and B lymphocytes as well as natural killer (NK) cells in the blood cells collected at harvest. Also, although the engraftment process and hematologic recovery post transplant was comparable between the two groups of patients, immune recovery was faster for patients receiving GCSF alone.

For example, lymphocyte counts at 15 days post transplant were higher in patients receiving GCSF alone. According to the researchers, this may be due to the cytotoxic effects of cyclophosphamide on lymphoid cells.

Also, at 3 and 6 months post transplant, the total number of natural killer cells also was higher in the GCSF-only patients.

There was no difference, however, in the progression-free survival of the two groups – not even a trend in one direction or another.

Based on their findings, the researchers conclude that GCSF alone might be a preferred mobilization method due to a more rapid and sustained immune recovery after transplantation.

Folotyn Plus Velcade For Relapsed/Refractory Myeloma

A team of U.S. researchers has reported results of a Phase 1 trial investigating Folotyn (pralatrexate) in combination with Velcade as a potential new treatment for multiple myeloma (abstract). Folotyn is already approved by the U.S. Food and Drug Administration as a treatment for patients with relapsed or refractory peripheral T-cell lymphoma. It is being explored as a treatment for various blood cancers and solid tumors.

The Folotyn trial was conducted in a total of 11 relapsed and refractory multiple myeloma patients. Its objective was to determine the recommended Folotyn dose for a potential Phase 2 trial. Thus, various dose levels of the drug were tested during the study. In addition, all patients received Velcade once a week for three weeks in a four-week treatment cycle.

The myeloma patients in the trial had received a median of three prior treatments. The efficacy of Folotyn in combination with Velcade was modest, according to the researchers. One patient achieved a very good partial response, and one had a partial response. In addition, one patient had a minimal response. Two patients experienced dose-limiting side effects (mucositis, an inflammation and ulceration of the mucous membranes lining the digestive tract, which according to the researchers frequently limits use of Folotyn).

The researchers conclude that “when compared to currently approved agents and other novel therapies for refractory multiple myeloma, this treatment regimen did not demonstrate sufficient efficacy to warrant further investigation.”

MMP-13 And Bone Lesions Caused By Multiple Myeloma

An international team of myeloma researchers has published a new study in the respected Journal of Clinical Investigation. The study reports results about an enzyme known as MMP-13. The results could help researchers find new ways to prevent multiple myeloma from causing bone lesions (full text).

MMP-13 is an enzyme known as matrix metalloproteinase 13 (sometimes termed collagenase-3). Previous studies have shown that the enzyme may play an indirect role in the way multiple myeloma causes bone lesions.

The authors of the new study, however, demonstrate that multiple myeloma cells produce MMP-13, and the enzyme plays a direct – rather than indirect – role in the creation of bone lesions.

Thus, therapies that inhibit either the production of MMP-13 by multiple myeloma cells, or the way the enzyme helps create bone lesions, could be a new tool for physicians to prevent bone lesions from occurring in multiple myeloma patients.

Reduced-Dose Velcade For Elderly Myeloma Patients

Researchers from Japan investigated the efficacy and safety of a reduced dosing schedule of Velcade plus dexamethasone in elderly myeloma patients (abstract). The Japanese researchers looked at the modified Velcade dosing schedule in an effort to minimize side effects and to continue the treatment as long as pos­si­ble in this patient population.

The prospective Phase 2 study included 47 relapsed and refractory myeloma patients with a median age of 75 years.  Patients had to be between 60 and 85 years old and have had received at least one prior treat­ment to participate in the study.

Velcade was administered intravenously once a week for three weeks in a four-week treatment cycle for up to eight treatment cycles (subcutaneous Velcade was not available in Japan at the time of the trial). According to the Japanese researchers, this particular dosing schedule has not been investigated in a clinical trial before. None of the patients had previously received Velcade.

More than half of the patients (55 percent) completed the eight treatment cycles. Overall, 49 percent of patients achieved a partial response or better, which the researchers point out is similar to that observed in trials using standard Velcade dosing. Of particular note, all patients with the high-risk chromosomal ab­nor­mality t(4;14) responded to treatment. The progression-free survival time was 9.6 months and the overall survival was 35.1 months.

The researchers point out that retreatment with a Velcade-based regimen was possible and in fact even successful; the median overall survival after retreatment has not been reached yet.

Side effects were similar to those observed in other studies involving Velcade and dexamethasone, and included diarrhea, constipation, and peripheral neuropathy. However, the rate of severe peripheral neuropathy was significantly lower.

Based on their findings, the researchers conclude that the reduced-dose Velcade schedule in combination with dexamethasone is an effective and safe therapeutic strategy in elderly patients with relapsed and/or refractory multiple myeloma.

New Myeloma-Related Research Articles

1. Dicke, C. et al., “Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias” in Annals of Hematology, April 4, 2016 (abstract)
2. Dunn, T. J. et al., “A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma” in the British Journal of Haematology, April 4, 2016 (abstract)
3. Fu, J. et al., “Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease” in The Journal of Clinical Investigation, April 5, 2016 (full text)
4. Mandato, E. et al., “Targeting CK2-driven non-oncogene addiction in B-cell tumors” in Oncogene, April 4, 2016 (abstract)
5. Ozaki, S. et al., “Reduced frequency treatment with bortezomib plus dexamethasone for elderly patients with relapsed and/or refractory multiple myeloma: a phase 2 study of the Japanese Myeloma Study Group (JMSG-0902)” in Annals of Hematology, April 5, 2016 (abstract)
6. Valtola, J. et al., “Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low-dose cyclophosphamide: a randomized comparison” in Transfusion, April 4, 2016 (abstract)
7. Wuillème, S. et al., “Assessment of tumoral plasma cells in apheresis products for autologous stem cell transplantation in multiple myeloma” in Bone Marrow Transplantation, April 4, 2016 (abstract)