Erin Gourley Reid, MD
The last decade has seen unprecedented advances in multiple myeloma therapy with combination chemotherapy regimens resulting in complete remission rates upward of 50 percent and overall survival rates increasing from three to five years in the ’90s to seven to 10 years this decade. However, cure remains elusive for the vast majority of myeloma patients.
Myeloma stem cells have entered the cancer stem cell scene as a glaring stoplight on the road to a cure. Yesterday afternoon’s scientific session, “Therapeutic Targeting of the Myeloma Stem Cell,” chaired by Dr. Raymond Powles, explored the questions surrounding myeloma stem cells and approaches to overcome them. Catch the encore this morning at 9:30 a.m. in Room 230. The following questions will be addressed during this session:
Have we found “the” myeloma stem cell?
There are multiple levels of support for the existence of myeloma stem cells. Clinically, recent combination chemotherapy regimens have resulted in high levels of complete remission but as yet, there is no indication that these result in cure. This implies persistence of a clinically undetectable population of resistant cells. For genomic support of a resistant population, Dr. William Matsui refers us to a study that reports genome-wide changes developing over time in myeloma and selection for bortezomib-resistant clones after bortezomib treatment (abstract #2960 [Magrangeas, F]).
While the majority of malignant plasma cells appear terminally differentiated similar to normal plasma cells, the presenters will present evidence for minority populations of cells that have features reminiscent of stem cells:
• Functional capacity to produce ectopic tumors in vitro and in animal models
• Resistance to multiple agents active in myeloma
• Activated pathways typical of normal stem cells
The precise immunophenotypic features of a myeloma stem cell are not definitively known. However, Dr. Matsui’s research points toward a CD34-/CD138- compartment that contains a CD19+ and CD27+ subset characterized by multi-drug resistance in vitro and activation of the stem cell-associated hedgehog pathway.
Different compartments of malignant cells have now been demonstrated in myeloma representing what Dr. Alberto Orfao refers to as “clonal hierarchy.” His group recently performed extensive typing of the B-cell compartment and did not demonstrate clonotypic-IGH-gene rearrangements outside of the aberrant plasma cell subset, suggesting clonotypic B cells are either present at extremely low frequencies or that they mainly correspond to a B-cell compartment with an aberrant immature plasma cell phenotype.
How can we target myeloma stem cells?
Whether these resistant cell compartments represent a single stem cell population or coexisting resistant compartments, it is difficult to develop strategies targeting such compartments without knowing precise characteristics of the cells involved. However, Dr. Constantine Mitsiades points out that the time is ripe to investigate strategies targeting this minority tumor subset given that we now have therapeutic regimens capable of significantly debulking myeloma providing us an opportunity to observe changes to a small, slowly dividing “stem cell” compartment.
Strategies targeting pathways common to normal stem cells and the resistant myeloma compartments — hedgehog, WNT, NOTCH, and chromatin remodeling — are some of the targets supported by current knowledge.
What are the challenges in identifying agents active against myeloma stem cells?
Current in vitro screening methods have upfront efficiencies for drug development but are limited by inability to explore the critical role of interaction of myeloma cells with the microenvironment. This dynamic interaction has the potential to lead to both tumor stem cell chemo-sensitization and resistance. Proving clinical activity of drugs against the stem cell population is also challenging. Given that population appears to represent a small fraction of tumor bulk, progression-free survival is more likely to reflect activity against tumor stem cells than more rapidly assessable endpoint of response. Correlative studies incorporated into clinical trials may be predictive, particularly by providing a more precise characterization of the target pathway modification within a myeloma stem cell framework.
Dr. Reid receives research funding from Millennium for an investigator-initiated study and is a PI for pharma-sponsored trials from BMS, Millennium, and Novartis.