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In Search Of The Myeloma Stem Cell: A Special Report
By The Unknown Patient
12.21.03

At this year’s ASH meeting, the Unknown Patient was privileged to meet a team of young investigators pursuing an ambitious and innovative objective-- finding the myeloma stem cell. Drs. William Matsui and Carol Ann Huff are part of a team headed by Dr. Richard Jones at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.


William H. Matsui, MD


Carol Ann Huff, MD

The Unknown Patient has attended the annual meeting of ASH each year for almost ten years now. It is always an overwhelming experience. For lay people, it’s a dive into the deep end of the scientific pool. Wave after wave of jargon and complex charts wash over you, at once overwhelming and confusing but telling a consistent story of promising developments that bring us closer to the cure.

In the pecking order at scientific meetings, you can generally tell how important the community thinks a paper is by where it is presented. The most coveted presentation slots are at the plenary sessions, where the most important findings are presented to the full group. Next are the simultaneous sessions, where smaller groups gather to hear presentations of interest to specialists in a particular area. To accommodate the many scientists with interesting findings to share, there are also poster sessions, where hundreds of papers are displayed in a large hall and the authors stand by them to discuss their work and answer questions.

Often, some of the most innovative and promising ideas don’t capture the imagination of the reviewers who dole out the presentation slots. Or, the work is at a stage too early to warrant broad exposure.

Such was the case when the Unknown Patient happened upon ASH 2003 abstract #3467, “Multiple Myeloma Cells Arise From Post–Germinal Center B Cells And Are Inhibited By Rituximab.” This finding, also accepted by the prestigious hematology journal Blood, was authored by Drs. William Matsui, Carol Ann Huff, and colleagues Quiju Wang, James Barber, B. Douglas Smith and Richard Jones.

The investigators present findings suggesting that they have identified the myeloma stem cell, which has been the focus of much speculation and investigation, and thus far eluded detection.

What is the myeloma stem cell and why is it important?

Myeloma is a cancer of the plasma cells. Malignant plasma cells proliferate in the bone marrow. For all their destructive power, the mature myeloma plasma (bone marrow) cells that are commonly observed in patients’ bone marrow biopsies lack a critical capability—they typically cannot reproduce beyond 3-5 cell cycles.

Where do the seemingly endless hordes of myeloma cells come from when the disease is active? And, how do they reappear out of nowhere when the disease relapses? The answer is stem cells. Stem cells are one of the wonders of the human body. They are the body’s “seed corn.” They are held in reserve to be grown into mature, “differentiated” cells when they are needed. There are different types of stem cells, each capable of a unique repertoire of differentiation. For example, hematopoietic stem cells are capable of reconstituting the bone marrow. That is why they are “harvested” and used to “rescue” patients who, as part of a stem cell transplant procedure, are given high-dose therapy that destroys their bone marrow. Figure 1 shows the birth of a plasma cell through differentiation of a hematopoietic stem cell.


Figure 1. The birth of a mature plasma cell

Even if a treatment were to kill all of the myeloma cells in the bone marrow, it is felt that there are “clonogenic” stem cells, precursors of the mature myeloma cells, waiting in the wings to replace their fallen comrades. These cells are called “clonogenic” because they have the ability to recreate the monoclonal (malignant, genetically identical) population of myeloma cells. Figure 2 shows stem cells reproducing and then differentiating into myeloma cells.


Figure 2. Proliferation of myeloma cells via stem cell differentiation and differentiation

When myeloma treatments have a “durable response" (i.e., the effect lasts long after the treatment is stopped), it is felt that they have not only killed the visible, mature monoclonal plasma cells, but also some of their more elusive precursor stem cells. This is consistent with what we know about treatments like melphalan. Melphalan is known to damage hematopoietic stem cells and is therefore not recommended for people who want to be able to harvest stem cells for a transplant. Melphalan also is known to have a durable response. This is consistent with the hypothesis that those precursor cells will ultimately be responsible for the reappearance of mature myeloma cells in the bone marrow.

Steroids like dexamethasone and prednisone are powerful anti-myeloma drugs but do not damage stem cells. They can dramatically reduce the myeloma tumor burden. However, once the treatment is stopped, the disease will often bounce right back. Again, this is consistent with the stem cell hypothesis because steroids kill the mature cells but spare the stem cells, leaving them ready to quickly regenerate the tumor cell population.

How could finding the myeloma stem cell translate into new treatment approaches?

It is hypothesized that stem cells regenerate the tumor cell population by first replicating themselves and then “differentiating” into mature monoclonal plasma cells (myeloma cells.). If the myeloma stem cell was known and detectable, treatments could target the “seed corn” as well as the current crop of tumor cells, offering the potential of longer remissions and cure. To do this, five things need to be accomplished:

  1. Identify the myeloma stem cell population
  2. Design a reliable assay (test) to detect them in patients
  3. Develop treatments that either kill the myeloma stem cells or prevent them from reproducing
  4. Force any remaining myeloma stem cells to differentiate into mature myeloma cells
  5. Kill the mature myeloma cells
THE FINDINGS OF MATSUI, HUFF, ET AL.

Matsui and Huff are junior members of an accomplished team of researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The group, led by Dr. Richard Jones, is known for its groundbreaking work in leukemias. Matsui and Huff both joined the group just over four years ago. They decided to focus their attention on myeloma, hoping to discover applications in myeloma for the substantial experience the group has in related blood cancers, primarily leukemia. The group had previously published work identifying stem cells in chronic myeloid leukemia, using innovative techniques to culture (grow) and sort cells. Hence, looking for the myeloma stem cell was a logical avenue of scientific exploration for this new team of myeloma investigators.

The work was done using specimens from myeloma cell lines RPMI 8226 and NCI-H929 (self-renewing stores of myeloma cells maintained in the lab for use in research.) Mature plasma cells were removed using a magnetic sorting column and other techniques that separate out cells based on whether or not their surfaces express the antigen CD138. Mature plasma cells are known to express this antigen while other B cells do not. The cells that pass through the column are CD138 negative (CD138neg) B cells, which should not include any mature myeloma cells, because all mature plasma cells (including myeloma cells) are CD138 positive (CD138pos).

Having eliminated the mature normal and malignant (myeloma) B cells by selecting out the CD138pos cells, the investigators cultured the remaining cells. Within the cultures, colonies of plasma cells were identified. The cells in those colonies are predominantly CD138pos. Within those colonies, the researchers found a small population of cells that were CD138neg. It is hypothesized that these cells are the myeloma stem cells, and that the CD138pos cells in the colony are the result of differentiation of those clonogenic cells into mature plasma cells.

The cell culturing approach followed by Matsui, Huff, et al. uses a custom-formulated growth medium and a diverse population of CD138neg cells. Matsui, Huff, et al. hypothesize that part of the reason these myeloma cell colonies are able to grow could be the result of the presence of other cells upon which their growth cycle is dependent. As a result, avenues for further investigation include examining inter-cell signaling occurring within the cultures. The growth medium used was originally developed by Dr. Anne Hamburger, who worked with Drs. Durie and Salmon at the University of Arizona. Dr. Hamburger subsequently moved to the University of Maryland, where she assisted Dr. Jones with his initial leukemia studies.1,2,3

Tumor cells that are phenotypically distinct and display different surface proteins different from their progenitor (stem) cells, have been observed in a number of other cancers, including acute myelogenous leukemia (AML)4, acute lymphocytic leukemia(ALL)5, myelodysplastic syndrome (MDS)6 and breast cancer. 7 Thus, the finding of a myeloma progenitor cell that, unlike the fully differentiated tumor cell is CD138neg, is consistent with these findings.

Figure 3 illustrates a potential approach to treatment based on these findings.


Figure 3. Potential treatment approach focusing on the tumor cell as well as its precursor

Matsui, Huff, et. al. found that rituximab inhibits in vitro (in the laboratory) clonogenic myeloma cell growth. This contradicts a recent report showing to 4-8 weeks of rituximab therapy was not effective when measured at 3-6 months in the majority of patients with myeloma.8 Since both normal and myeloma plasma cells, although terminally differentiated, are long-lived,9,10 therapies that target myeloma stem cells may not show a response using standard criteria (M protein or percentage of plasma cells in the bone marrow) until the remaining population of mature plasma cells gradually undergoes spontaneous cell death. Therefore, potentially useful therapies with activity primarily against myeloma stem cells could be prematurely abandoned before they can show efficacy.11 Conversely, therapies that target malignant plasma cells (myeloma cells) may lead to rapid response but are unlikely to be durable or curative unless myeloma stem cells are also eliminated.

WHAT HAPPENS NEXT?

There is much work to be done to validate and extend the findings of Matsui, Huff, et. al. and then to develop new treatment strategies based on their work. It has great potential if it can be confirmed. It heralds the entry of two dedicated and talented young investigators into myeloma research. And, these investigators are part of a group at Johns Hopkins with an impressive record of accomplishment in other hematological malignancies (i.e., leukemias and lymphomas). Drugs like rituximab are available to target these myeloma stem cells, although much work will be required to understand related cell signaling and which other agents with which rituximab should best be combined and what the appropriate timeframes for response should be to show clinical effect on both the stem cell and mature plasma cell populations.

The Unknown Patient congratulates these young investigators and their mentors and thanks them for their work on behalf of all myeloma patients. Other investigators from the myeloma community, while retaining a healthy skepticism, seem receptive to these new ideas. The Unknown Patient spoke with a number of them between sessions at ASH and also observed the discussions at the poster session for this abstract. A number of credible scientists in the myeloma community seem quite interested in the work and in collaborating with these folks. The Unknown Patient hopes to hear exciting things about this work as these scientists take the next steps.

References:

  1. Hamburger AW, Salmon SE. Primary bioassay of human myeloma stem cells. J. Clin. Invest 60: 846-854, 1977.
  2. Salmon SE, Hamburger et al. Quantitation of differential sensitivity of human tumor stem cells to anti cancer drugs. N. Engl J. Med 298: 1321-1327, 1978.
  3. Durie BGM, Young YA et al. Human Myeloma in intro colony growth interrelationships between drug sensitivity cell kinetics and patient survival duration. Blood 61: 929-934, 1983.
  4. Lapidot T, Sirard C, Vormoor J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645-648.
  5. George AA, Franklin J, Kerkof K et al. Detection of leukemic cells in the CD34+CD38-{} bone marrow progenitor population in children with acute lymphoblastic leukemia. Blood. 2001;97:3925.
  6. Nilsson L, Astrand-Grundstrom I, Arvidsson I et al. Isolation and characterization of progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the stem cell level. Blood. 2000;96:2012.
  7. Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988.
  8. Treon SP, Pilarski LM, Belch AR et al. CD20-directed serotherapy in patients with multiple myeloma: biologic considerations and therapeutic applications. J Immunother. 2002;25:72-81.
  9. Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow SI. The growth fraction of human myeloma cells. Blood. 1981;57:333-338.
  10. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to longlived plasma cells. Immunity. 1998;8:363-372.
  11. Chilosi M, Adami F, Lestani M et al. CD138/syndecan-1: a useful immunohistochemical marker of normal and neoplastic plasma cells on routine trephine bone marrow biopsies. Mod Pathol. 1999;12:1101-1106.

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William Matsui, MD, The Myeloma Stem Cell
ASH 2010 Presentations About The Myeloma Stem Cell


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