NEWLY DIAGNOSED PATIENTS:

WHAT IS MULTIPLE MYELOMA

Myeloma Bone Disease

The most visible aspect of myeloma disease is its effect on bones throughout the body. In the majority of patients with multiple myeloma, soft spots develop where the bone structure has been damaged. These can extend from the inner bone marrow to the outside surface of the bone. Soft spots appear as "holes" on a standard bone x-ray and are referred to as osteolytic lesions (see figure). These lesions weaken the bone, causing pain and increasing the risk of fractures.

Although it affects the bone, myeloma is considered a hematologic cancer (or blood cancer), because it develops in the blood's B cells. Treatment of myeloma differs from that of bone cancers (known as sarcomas of the bone).

Causes of Bone Destruction in Myeloma

Bone destruction by osteolytic lesions is caused by two separate events. Rapid growth of myeloma cells inhibits normal bone-forming cells, damaging bone. In addition, production of substances that activate the cells that resorb bone called osteoclasts is increased. Osteoclasts normally break down old or worn out bone and work with bone-forming cells to repair bone. Increased activity of osteoclasts, however, causes bone loss with concomitant loss of bone repair and growth from the suppression of bone formation.

Normal Bone Cell Activity

Normally, osteoclasts function with bone-forming cells called osteoblasts to rebuild areas of bone that are wearing out (fatigued). This process is called bone remodeling and healthy bone is continually being remodeled.

During the normal process of bone remodeling, the following steps occur:

1. Osteoclasts are attracted to the area of fatigued bone.
2. Osteoclasts remove the fatigued bone by breaking it down, creating a cavity in the bone.
3. Osteoblasts are attracted to the cavity in the bone.
4. Osteoblasts fill in the cavity with a matrix or framework.
5. Eventually, new bone forms.

The process of bone remodeling, courtesy of Dr. Susan Ott:

Bone Cell Activity in Myeloma

Normally, the activity of the osteoclasts and osteoblasts is well balanced - the osteoclasts clear out the fatigued bone and the osteoblasts begin the rebuilding of new bone. In patients with multiple myeloma, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increasing amounts in the patient's serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.

In myeloma there is an increase in osteoclast activity that is caused by factors called osteoclastic activating factors or OAFs. These osteoclastic activating factors are known to be released by tumor cells and include a variety of soluble factors known as cytokines. Some of these cytokines are shown in the figure below and described in the next section.

The Bone Marrow Microenvironment and it's Role in Bone Resorption

The bone marrow microenvironment is the area within the bone (the marrow) where stem cells develop into blood cells and the cells of the immune system. In multiple myeloma, the bone marrow microenvironment is the area where the malignant plasma cells develop and grow. An important and promising area of myeloma research is the investigation of ways to make the bone marrow microenvironment less hospitable to myeloma cells.

The bone marrow microenvironment plays an important role in the increased bone resorption that occurs in myeloma. The following steps outline what happens:

1. Within the bone marrow microenvironment, tumor cells adhere to the bone marrow stromal cells (BMSCs), which are the structural cells of the bone marrow.
   
2. Adherence of the multiple myeloma cells to stromal cells increases the stromal cell production of the growth factor interleukin 6 (IL-6), which appears to be necessary for the continued growth and survival of the myeloma cells.
   
3. Adherence of the myeloma cells to stromal cells also allows the myeloma tumor cells to produce other osteoclast-activating factors including interleukin 1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-a).
   
4. These osteoclast-stimulating factors prompt the bone marrow stromal cells and the osteoblasts to produce yet another growth factor called RANKL.
   
5. TNF induces the development and growth of osteoclast cells and thus increases osteoclast activity that results in the bone disease of myeloma.
   
6. This increase in osteoclastic activity also results in the release of certain cytokines such as IL-6, which contribute to tumor cell growth and survival.