Saturday, 1 September 2012

Myeloma WTF?!

You're not easy to love, no. Why is everything with you so complicated?
Complicated - Rihanna

It doesn't help, when you're told what's wrong, if you haven't even heard of it. I did a bit of research. Here's what I found.

The immune system

Antibodies enable the body to fight infection. They are produced by blood cells called B-cells, which are found in blood plasma, inside your bone marrow. Each antibody is in 2 halves, and each half consists of a heavy-chain and a light-chain connected together. The two halves sit side by side and the whole thing makes a “Y” shape.
There are 5 types of heavy-chain immunoglobulins: IgG, IgA, IgM, IgD, IgE
There are 2 types of light-chain: kappa (κ) and lamda (λ).
Each antibody contains just one type of heavy chain and one type of light chain, but your total immune system contains many different antibodies - with different specialised ends to the molecules so that each can detect a different kind of infection.

If you want to know anything else about how antibodies work and what they are supposed to do, you’ll have to read it elsewhere, because that's not the point of this post (and I'm no biologist).

What is myeloma?

We all produce defective cells all the time. Most of them don't reproduce, so they die out pretty quickly. A few are self replicating - cancerous. Most of these will fail to establish, or be detected and destroyed by the immune system. But if it is a particularly virulent cancer, and/or your immune system is low and/or you are just plain unlucky, a colony of cancer cells can become established.

Myeloma is just a story of what happens when things go wrong, where one rogue antibody-producing B-cell has become cancerous and multiplies uncontrollably. It starts to fill up the bone marrow, leaving less and less room for all the other cells that should be producing blood cells - red cells, white cells, antibodies and platelets.

In most cases (c.80%, but not mine) the myeloma cells produce antibodies. So myeloma can usually be detected by looking for immunoglobulins, where it will show up as a “spike” on the graph – indicating a huge number of monoclonal (i.e. identical) paraproteins (i.e. proteins that aren’t really supposed to be there). The cancer will produce a single type of immunoglobulin. IgG-myeloma is most common. IgA- is also relatively common, while IgM- is much less common, and IgD- and IgE- are very rare.

Myeloma can usually also be detected in light-chains, and in around 20% of cases (that’s me) the cancer cells only produce light-chains. The normal ratio for κ:λ light-chains in the blood is around 2:1 and any major deviation is a strong sign of some kind of neoplasm (i.e. some kind of abnormal proliferation). Myeloma is more common in the kappa chains (which includes me).

In a small percentage of cases the myeloma doesn’t secrete even light-chains beyond the bone marrow. This is called non-secretary myeloma and obviously makes detection and monitoring even more difficult.

How is myeloma detected?

Myeloma is diagnosed through a combination of
(a) symptoms (of which more below)
(b) immunoglobulin and light-chain detection in blood or urine, and
(c) bone marrow biopsy.

The actual level of paraprotein produced, in relation to the damage the myeloma is doing in the bones, varies from person to person. For me a light chain score of 1,500 was debilitating and life threatening. Some people present with scores of 15,000... or even more. Every case of myeloma is unique.

Its worth noting, as an example of how the science of myeloma is changing, that light-chain detection used to have to be done in urine, which is less than ideal because this is after they’ve passed through the kidneys, which will have removed a lot of them. This would mean later detection, and more risk of kidney damage. It is now possible to detect light-chains from blood (which is the test that effectively proved my myeloma diagnosis).

It’s also worth noting that the less said about bone marrow biopsy, the better.

What are the symptoms?

Because the body is producing large quantities of myeloma cells the ability to carry out other key functions in the bone marrow is crowded out. So in active myeloma there are reductions to red and white blood cell counts. So it causes anaemia, and a weak immune system.

Myeloma cells also disrupt the process of bone regeneration. Bones are living parts of the body and constantly being regenerated - old bone is broken down by cells called osteoclasts and replaced by new bone, formed by cells called osteoblasts.  Myeloma disrupts the osteoblasts, leading to bone failure. This typically takes the form of “holes”, though exactly what form depends on how bad the damage has become. My skeleton shows “latencies” from skull to pelvis under an MRI/PET scan, but these areas of lower bone density are not as severe as the lytic lesions located in my spine and ribs, which show up clearly on a bone scan. In particular, my spine lesions are bad enough that a number of my vertebrae fractured (when I stumbled off a kerb). Fractures are not uncommon – indeed it’s a very typical symptom leading to the process ending in myeloma diagnosis. As it happens, I have suffered previous rib fractures over several years, which remained undiagnosed until later. Sadly, in my experience of talking to others, that’s not unusual either. Unfortunately there is a massive job to be done in educating GPs about myeloma.

Bone breakdown can result in hypercalcemia, where there is excess calcium in the blood. Hypercalcemia is associated with “Stones, Bones, Groans, Thrones and Psychiatric Overtones”: just to add to the long list of things to think about if you have myeloma (kidney stones/ bone pain/ abdominal pain and nausea/ excessive urination/ and unsurprisingly, all else being considered, depression and anxiety).

As well as this, the increased pressure within the bones, along with the damage to bone surfaces, (usually in the spine, pelvis, skull and ribs, because this is where most of an adult’s blood plasma is contained, though there’s also some in the long bones of upper arms and legs) can be extremely painful. At first I didn’t know what “bone pain” meant. I’m quite sure now.

The excess protein chains in the blood put strain on the kidneys – this is especially true of the light-chains which are small enough to pass through the initial part of the kidney’s filtration system and clog things up elsewhere. So myeloma can cause kidney damage, and ultimately kidney failure. Again, this can be the symptom which triggers the process of diagnosis. Fortunately for me, at diagnosis my kidneys were still fine.

What's the prognosis?

The majority of myeloma diagnoses are in older people (median age at diagnosis is 70). It’s a rare condition anyway (<4/100,000 people per year, 1% of total cancer, 10% of blood cancers, much less common than leukemia or lymphoma), but even rarer among the “young”. Only 2% of myeloma diagnoses are under 40.

So it’s very difficult to describe the prognosis of a young myeloma patient. Typically around ¼ of myeloma diagnoses proceed downhill fast and die within a year, and another ¼ will die within 3-5 years. For the rest (let’s hope that’s me!) who are young... well, quite simply no-one knows. There are a number of even rarer conditions associated with myeloma –and there’s always the risk that myeloma will lead to something else – such as light-chain amyloidosis (which will probably kill you), or plasma cell leukemia (which will surely kill you). But myeloma is a systemic condition in its own right: it doesn’t move (metastesize) from one organ to another like an organ cancer might “spread”.

It usually relapses from remission. Subsequent periods of remission become shorter each time. Over time it becomes resistant to the currently available treatments.

How is it treated?

Myeloma can be treated through drugs and through stem cell transplants. Most people with myeloma also need treatment for bone damage.

Drugs:

  • Chemotherapy drugs, such as cyclophosphamide, doxorubicin and melphalan slow/stop cell growth. Because cancer cells are growing and multiplying disproportionately fast, they get hit hard by chemotherapy. Other fast changing/dividing cells (such as hair follicles and the surface inside your mouth) also get affected. Chemotherapy drugs make you feel pretty grim.
  • Other “novel agent” drugs target more specifically some of the cell functions particularly associated with myeloma. Thalidomide – despite its infamy – is a key myeloma drug. More recent discoveries include bortezomib, which is a part of a new family of drugs called protoeasome inhibitors. There are other drugs in trial, including monoclonal antibodies, that may re-activate the immune system to fight the myeloma. All these drugs have potential side effects. Peripheral neuropathy is a particular issue.
  • Steroids, such as dexamethasone and prednisone help multiply the effect of chemotherapy and other novel agent drugs, so they are quite often given at the same time. Steroids are also known to have positive effects in myeloma on their own. Steroids tend to create ups (high energy, sleeplessness) and downs (low energy, low mood) as you come on and off them. I do a lot of writing when I’m on steroids (I’m on them now!) They can also cause water retention.
Most initial treatment will involve all three drug types. Mine is “PAD” – which means bortezomib (PS-341), doxorubicin (Adriamycin), Dexamethasone. If successful, the drugs will put myeloma into remission – the levels of paraprotein will drop away and the body will appear to be relatively “normal” apart from the longer lasting consequences of bone and kidney damage. However, myeloma almost certainly relapses in time. It may be successfully treated by the same drugs, or it may become resistant to one drug regime, and have to be treated with another one. Eventually, it may become resistant to all drug regimes (refractory).


  • This is where the body is treated to kill off as much of the blood plasma as possible. Depending on how intensively the blood plasma is attacked – either through chemotherapy (usually using high does of a drug called melphalan) or through body irradiation – it may or may not be possible to completely remove the myeloma from the body.  But in most cases, the answer is not.
  • The body must then be re-infused with blood plasma. This can come from one of two sources: your own (autograft SCT), which would have been harvested in advance, or a donor (allograft SCT). The benefit of using donor cells is that they will potentially attack any residual myeloma cells ("graft versus tumour effect") leading to a complete cure. The benefit of using your own cells is that it is much, much less dangerous. Stem cell donation causes the reverse of the problem encountered in organ donation. Normally the “body” (i.e. the immune system) needs to accept the donated organ, but in a stem cell transplant, the new stem cells – which contain the immune system – need to accept the “body” (i.e. all the organs). If they don't then you get "graft versus host" disease.
  • Even a relatively “gentle” autograft SCT is a major procedure, meaning weeks in hospital and months in recovery. Older people may not be strong enough to withstand any SCT. Younger people may be able to have more than one in their lifetime.
But, aside from the prospect of allograft SCT, and the potential for a cure in the future (there’s a vaccine in trial in Israel, for example but it will be years before it is clear whether or not it might work), myeloma is not currently curable.

There are two ends of the spectrum when it comes to treating myeloma
a) The "throw everything at it at once and hope to cure it" approach. This can involve quite incredible cocktails of drugs, taken over several years, interspersed with multiple SCTs
b) The "use the available treatments one at a time and hope to string it out indefinitely" approach. For better or worse, this is where I'm heading.

Managing bone disease

Because myeloma leads to skeletal issues treatment involves things to directly address the bones too. In most cases – as is common for other conditions like osteoporosis – people with myeloma have monthly doses of bisphosphonates, which help coat the bone surface and reduce bone breakdown. This is normally continued for 2 years. This too can have side effects, such as osteonecrosis of the jaw.

Where there have been fractures, these can be treated too. In some instances this might mean pins in hips, for example. In mine it will mean vertrbroplasty, which is where acrylic cement is  either injected directly into compressed vertebrae to strengthen them, or injected between them after balloons have been used to recreate some of the space that has been lost due to bone compression. Unfortunately, although bones regenerate, they do so slowly – over the same timeframe as myeloma is likely to relapse. So while bone condition can be improved, it can’t be completely restored. And any areas that have suffered fractures are inevitably irreversibly weaker, anyway.

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