About Multiple Myeloma

Disease and Treatment

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Background

Definition and Introduction

Multiple Myeloma (also known as Myeloma or Plasma Cell Myeloma) is a malignancy of plasma cells, which are the white blood cells responsible for the production of antibodies (proteins). Antibodies protect humans from infections.  It is a cancer with a vast spectrum of presentations, ranging from an indolent (slowly developing) form to a virulent form; from a disorder with a minimal protein abnormality and only a small number of malignant plasma cells, to a cancer that can result in rapid progression and death.  The disease has numerous consequences, including anemia causing fatigue, bone loss resulting in weakening of the bones, bone fractures, and pain, kidney damage sometimes resulting in the need for dialysis, high calcium levels, altered immunity resulting in infections, and nerve damage which can cause numbness, tingling, or even pain and loss of strength.

Classifying Myeloma

Normal plasma cells help to defend the body against infection by producing antibodies. Antibodies typically consist of 2 heavy chains and 2 light chains.  There are 5 kinds of heavy chains termed IgG, IgA, IgM, IgD, and IgE; and 2 distinct types of light chain, termed kappa and lambda. In myeloma, all the abnormal plasma cells make the same antibody.  Therefore the myeloma can be classified by the type of light and heavy chains produced, such as IgG kappa, IgG lambda, IgA kappa, or IgA lambda, etc.  The most common type of heavy chain produced in myeloma is IgG, followed by IgA and then IgD.  IgM myelomas are rare, but when IgM is elevated in the blood, the patient more likely has a related disorder, known as Waldenstrom’s Macroglobulinemia.   (http://www.iwmf.com/WhatIsWM.htm)

Occasionally, the malignant plasma cells make only the light chain component of the antibody. These patients are said to have “light chain myeloma.” In such cases, the light chains are often excreted into the urine and can be identified with a variety of assays, including the Urine Protein Electrophoresis (UPEP), urinary immunofixation electrophoresis (UIFE), and an assay for “Bence-Jones Protein.”  A 24-hour urine collection can be performed to help quantify exactly how much protein is excreted in the urine. In recent years, these urine tests have been largely replaced by the “Free Light Assay,” which is an improved assay designed to identify and quantify these light chain proteins in the blood. Only a small percentage of the light chain is actually in the blood as these proteins are so small that they pass through the kidney into the urine.

Until a few years ago, some patients were thought to have so-called “non-secretory” myeloma.  In these patients, no proteins could be found in the blood or urine, despite a picture of myeloma including marrow involvement with plasma cells, anemia, and/or bone loss. The advent of the Free Light Chain assay has helped demonstrate that almost all of these historically “non-secretory” myelomas were actually “light chain myeloma.” The patients secrete a small amount of protein that previously could not be detected. However, there are some cases of truly non-secretory myeloma where all myeloma protein tests are essentially normal.

What to Expect with Myeloma

Historically, myeloma has been considered an incurable disease and still today few, if any, patients are cured. Rarely, after Stem Cell Transplantation, or following standard therapy, patients have been known to live without disease recurrence for decades, suggesting a possible cure in a small subset of patients. However, there is no easy test to predict how an individual with myeloma will fair.  The typical disease course for an individual patient includes periods of symptomatic myeloma requiring treatment followed by periods of remission or disease inactivity for which no therapy is necessary. Over time, the periods of disease inactivity shorten following subsequent therapies and eventually the disease becomes refractory (nonresponsive) to therapy and an individual succumbs to progressive disease.  Importantly, there have been great advances in therapy for myeloma over the past 15 years. These advances have led to improved response rates to therapy and prolongation of life. More advances are expected and the common goal is to discover better and potentially curative therapies for myeloma. (Hayden et al. 2007, 609-615)

Choosing a Therapy

Currently, when therapy is indicated, it is generally geared toward improving symptoms (i.e., quality of life) and prolonging survival (i.e., quantity of life). Treatment for myeloma usually consists of a multi-modality approach encompassing chemotherapy, targeted small molecule therapy, radiation, high-dose chemotherapy with stem cell transplantation (“autologous” using one’s own cells or “allogeneic” if someone else’s cells are used), orthopedic procedures to stabilize the spine (kyphoplasty or vertebroplasty) or long bones (pins or rods), and medications to prevent bone loss and destruction. (www.Kyphon.com).

Survival measurements depend on how aggressive the disease is, such that those with an indolent process can live for decades, while those with more aggressive disease may only live for months or a few years.  Throughout the 1990’s, 3 years was considered average for those requiring therapy, but with the advent of multiple new agents in the last 15 years, the median survival is certainly more than 5 years.  Today’s medications may have extended survival in patients with myeloma upward of 10 years although an accurate measurement is unavailable due to such rapid progress. 

Etiology, Epidemiology and Pathophysiology

Etiology

The cause or causes of myeloma are unknown, but there is some evidence to support a number of theories of its origin, including viral, genetic, and exposure to toxic chemicals, the most notable being Agent Orange.

Epidemiology

It is estimated that in 2013, approximately 22,350 new cases or multiple myeloma will be identified in the U.S., representing 1% of all malignancies and 10% of all hematological malignancies.  Additionally, there are expected to be 10,710 deaths, which represent 2% of the deaths from cancer, but 20% of deaths from hematological malignancies.  It is estimated that over 50,000 people in the U.S are living with the diagnosis of myeloma. 

Men (6.5:100,000 population) are slightly more likely to have the diagnosis than women (4.2:100,000 population) and African-Americans (11.3:100,000 population) are more than twice as likely to have myeloma as Caucasians (5.1:100,000 population).  Asian-Americans (3.3:100,000 population) have a lower incidence than Caucasians

(Multiple Myeloma incidence and rates by ethnicity and gender)

The average age at diagnosis is 66 years, although 10% of patients with myeloma are under 50 years old and 2% are under age 40.  Moreover, there appears to be a slight shift over time in the diagnosis of younger people.

Pathophysiology 

The malignant plasma cell develops from a post-germinal center B lymphocyte.  Chromosomal translocations have been identified in approximately 50% of patients involving the 14th chromosome (locus 14q32) and a number of other chromosomes, including 11, 4, 6, 16, and 20.  In addition, deletion of parts or all of chromosome 13 have been seen in 50% of cases and significant overlap has been seen between both of these chromosomal abnormalities. (Hideshima et al. 2007, 585-598)

A specific single clone (monoclonal plasma cell) proliferates and causes damage in a multitude of ways.  This clonal overproliferation of plasma cells in the bone marrow causes anemia early in the process and low platelets (thrombocytopenia) as the disease advances. 

The clonal plasma cells cause an overproduction of Interleukin 6 (IL-6) (also known as osteoclast activating factor or OAF) resulting in osteoclast activation and subsequent bone destruction.  These areas of bone destruction, known as lytic lesions, can lead to fractures of long bones such as arms and legs, or even more commonly, to fractures of the vertebral bodies which constitute the spine.  The same process which causes bone loss, causes calcium to be removed from bone, and can cause hypercalcemia (too much calcium in the blood).  (Esteve and Roodman 2007, 613-624)

The proteins manufactured and secreted by the malignant plasma cells can cause kidney damage, especially when light chains become deposited in the kidneys, causing Light Chain Deposition Disease (LCDD).  This can sometimes result in total renal failure and a need for dialysis. 

Light chains can also be deposited in nerve sheaths leading to numbness, tingling, weakness, pain, and sometimes loss of neurological function (neuropathy). 

Overproduction of a single clone of malignant cells often leads to an underproduction of the usual spectrum of plasma cells and a concomitant decrease in their antibody proteins, thus leading to immunological deficiencies and an increase in infections.  Common infections are pneumococcal pneumonia, blood stream infections, and meningitis.

An acronym has been created to remember 4 of these problems.  CRAB represents calcium problems, renal problems, anemia, and bone problems.  Unfortunately, immunological deficiency and neurological problems are not represented by this helpful mnemonic. 

Interestingly and very importantly, as the single clone of cells expands exponentially, it usually produces a single (monoclonal) protein antibody (M-protein), which can be easily measured in the blood or, less commonly, in urine.  This is very helpful, as the M-protein can be used to measure disease progression, or hopefully, response to therapy.

Evaluation and Diagnosis

Blood tests

CBC (Complete Blood Count)
This common blood test can identify anemia (low red blood cell count) and low platelets (thrombocytopenia).

Chemistry Panel
Another common blood test which, along with other tests, measures creatinine (an indicator of kidney function), calcium, albumin (a test which, along with beta 2 microglobulin {see below}, can help predict prognosis), immunoglobulins, and total protein (the latter two of which might be elevated in myeloma).

Quantitative Immunoglobulins
Each of the heavy chains (IgG, IgA, IgM, IgD and IgE) can be quantified, and followed serially to assess one’s response to treatment.  One caveat is that these measurements include both the normal (made by normal plasma cells) and abnormal amount of heavy chain (i.e., IgG, IgA made by myeloma cells).   The SPEP can better differentiate and quantify abnormal from normal proteins and some physicians follow SPEP levels preferentially over Ig heavy chain levels.

Serum Protein Electrophoresis (SPEP)
The SPEP is a blood test which can measure all of the proteins in plasma but can also identify an abnormal elevation (spike) in patients with myeloma (spike is usually in the “beta” or “gamma” region).  The SPEP can identify this malignant or monoclonal spike (M-spike) and can precisely quantify the amount of abnormal protein. This test is more sensitive then the immunoglobulin tests (IgG or IgA).  The SPEP is quite helpful in following the progress of the disease, with therapy. One goal of therapy is to drop the M-spike to a normal value of zero.

Immunoelectrophoresis or Immunofixation (IEP, IF, IFE)
This blood test is helpful with identifying the specific type of malignant heavy chain and light chain (e.g., IgG kappa or IgA lambda) present.  It is not helpful in following response to treatment and is only helpful again when it can be established that the protein is no longer identifiable by SPEP. When the SPEP is normal and the IFE is normal the patient is considered to be in “complete remission,” the ultimate goal of myeloma therapy.

Free Light Chain (FLC) Analysis
FLC is a recently developed assay (www.freelite.co.uk) (The Binding Site) that has become very useful in identifying so-called “non-secretory” myeloma.  This assay has made it generally unnecessary to continue to measure urine SPEP or 24-hour urine collections for protein, since most patients who show protein in the urine also have abnormal serum (blood) free light chains. Some exceptions to this rule exist and some physicians still feel inclined to follow 24-hour urine measurements.

After the SPEP becomes negative, the FLC assay may remain positive. In such cases the FLC assay may be more sensitive for following response to therapy. For patients with a positive FLC assay, the goals of therapy are to decrease the FLC proteins to the normal range.

Some data suggest that the free light chain assay results may prove useful in predicting prognosis, especially in monoclonal gammopathy of undetermined significance (MGUS) which is described in more detail below (Rajkumar et al. 2004, 308-310). The FLC assay is an excellent test for what we now call stringent complete response.

Beta 2 Microglobulin
This blood test is very helpful at the time of diagnosis (along with albumin) for predicting outcome.  It is not very helpful for following the response or progression of disease, because the change in this lab test is too slow.  It is also not helpful in the presence of renal problems (i.e., if the creatinine is >2 mg/dL), as then the test is falsely elevated.

Bone Imaging Tests

Plain X-rays and Bone Surveys
Traditionally, regular x-rays of bone have been used to identify lytic lesions and fractures.  A bone survey of all bones, while tedious, might discover asymptomatic areas of involvement and help establish a diagnosis of myeloma.  While still helpful for some diagnostics, plain x-rays are quite insensitive and have been surpassed by other tests in the evaluation of myeloma.

Magnetic Resonance Imaging (MRI) is a very sensitive imaging technique using magnets, which can identify areas of myeloma and impending fractures.   For myeloma, we now have on a limited basis, the ability to do whole body MRI.

Positron Emission Tomography (PET)
PET scanning is a nuclear medical technique using minute amounts of radioactively-labeled sugar, which can identify plasma cell tumors in any of the bones of the body.  It is quite sensitive and can very quickly identify responses and relapses.  It also has the advantage of providing a view of the entire body at once.


Bone Marrow Aspiration and Biopsy

Bone marrow aspirations and biopsies are almost always obtained from the posterior pelvis (not the spine) and very rarely the breastbone (sternum). 

After local, and sometimes mild systemic anesthesia, a needle is inserted into the bone and fluid is removed (aspirated).  This fluid is predominantly blood, but mixed in are bone marrow particles (spicules) which are then spread onto glass slides, stained, and examined by hematologists and pathologists to look for the presence of plasma cells.  The presence of these cells is represented as a percentage of the total white cells.  Additional special stains are performed (e.g., CD 138, which stains only plasma cells) to help identify and enumerate the plasma cell percentage.  Flow cytometry may also be performed with a small portion of the aspirated material to help confirm the percentage of plasma cells or to identify other abnormalities.

A second needle stick will then be performed, this time to obtain a core of bone/bone marrow.  This core will be processed in the laboratory, calcium will be removed and the specimen will be sliced and reviewed on a slide by the pathologist. This process takes over 24 hours to complete.  Again, plasma cell percentages and other abnormalities will be identified.

Additional marrow aspirate should always be sent at the time of diagnosis for chromosome analysis by traditional cytogenetic techniques, and more recently evidence would also support performing FISH (Fluorescence In-situ Hybridization) analysis, to help with prognosis.

Symptoms, Diagnosis and Staging

Symptoms

Patients with myeloma present to their physicians in a number of ways.  Commonly, they have back pain, either acutely or more chronically.  This pain generally represents myeloma in the spine which causes weakening of the vertebrae, small fractures, or even vertebral body collapse.

Patients may see their physician for fatigue, which represents anemia, increased urination, confusion, or abdominal cramping representing hypercalcemia, or repeated infections because of the weak immune system and abnormal immunoglobulins.

Often, myeloma is discovered incidentally on a routine blood or urine examination, when the physician notes asymptomatic anemia or elevated proteins in the blood or urine.

Diagnostic Criteria

Myeloma is part of a spectrum of disorders called plasma cell dyscrasias.  Criteria have been developed to help distinguish these abnormal conditions so as to be able to make predictions on prognosis and to determine whether to, and how to treat. 

In 2003, the International Myeloma Working Group agreed on diagnostic criteria for three conditions: 1) symptomatic myeloma, 2) asymptomatic myeloma, and 3) MGUS (monoclonal gammopathy of undetermined significance) (International Myeloma Working Group 2003, 749-757):


Condition

Diagnostic Criteria

Symptomatic myeloma

  1. Clonal (all of one type) plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
  2. A monoclonal protein (paraprotein) in either serum or urine
  3. Evidence of end-organ damage (related organ or tissue impairment {ROTI}):
  • Hypercalcemia
  • Renal insufficiency attributable to myeloma
  • Anemia (hemoglobin <10 g/dL)
  • Bone lesions (lytic lesions or osteoporosis with compression fractures)
  • Frequent severe infections (>2/year)
  • Amyloidosis of other organs
  • Hyperviscosity syndrome

Asymptomatic myeloma (smoldering myeloma)

  1. Serum paraprotein >3.0 g/dL AND/OR
  2. Clonal plasma cells >10% on bone marrow biopsy AND
  3. NO myeloma-related organ or tissue impairment

Monoclonal gammopathy of undetermined significance (MGUS)

  1. Serum paraprotein <3.0 g/dL AND
  2. Clonal plasma cells <10% on bone marrow biopsy AND
  3. NO myeloma-related organ or tissue impairment

Related conditions that need to be differentiated from myeloma include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (in this diagnosis only the antibodies produce symptoms, e.g., AL amyloidosis), POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes), and Waldenstrom’s macroglobulinemia.  (http://www.iwmf.com/WhatIsWM.htm)


Staging

International Staging System (ISS)
The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005 (Greipp et al. 2005, 3412-3420).  After significant validation, it proved to be the simplest, most powerful and most reproducible system for staging.

  • Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >/= 3.5 g/dL
  • Stage II: β2M < 3.5 mg/L and albumin < 3.5 g/dL; or β2M >/= 3.5 mg/L and albumin < 5.5 g/dL
  • Stage III: β2M >/= 5.5 mg/L

Overall median survivals for the 3 stages in 2005 were shown to be: Stage I: 62 months, Stage II: 45 months, Stage III: 29 months. Of note, these survival figures represent patients treated over the past 10-20 years and may not correspond to currently projected survival estimates. 

Durie-Salmon Staging System
The Durie-Salmon staging system (Durie , Salmon 1975 Cancer 36 (3): 842–54), first published in 1975, is still in use, but has largely been replaced by the simpler ISS shown above. The Durie-Salmon staging sytem also consists of 3 stages, as follows:

  • Stage 1
    • All of:
      • Hb > 10g/dL
      • Normal serum calcium
      • Skeletal survey: normal or single plasmacytoma 
      • Serum paraprotein level
        • IgG < 5 g/dL
        • IgA < 3 g/dL 
      • Urinary light chain excretion < 4 g/24h
  • Stage 2
  • Fulfilling the criteria of neither 1 nor 3
  • One or more of:
    • Hb < 8.5g/dL
    • High serum calcium > 12mg/dL (adjusted to albumin)
    • Skeletal survey: 3 or more lytic bone lesions
    • Serum paraprotein IgG >7g/dL, IgA > 5 g/dL 
  • Urinary light chain excretion > 12g/24h urine collection
  • Stage 3

Stages 1, 2, and 3 of the Durie-Salmon staging system can be further divided into A or B depending on serum creatinine:

  • A: serum creatinine < 2mg/dL 
  • B: serum creatinine > 2mg/dL

Prognosis

There is a clear heterogeneity amongst patients with myeloma as some individuals have a slow disease pace and can live decades and others have rapid disease progression, unresponsiveness to multiple therapies and short survival. Therefore, it is increasingly important to identify biomarkers and/or disease characteristics that can help select the optimal management of patients with good or poor-prognosis myeloma. Many studies have attempted to identify these prognostic features in patients with myeloma.  Probably the most predictive prognostic marker is serum β2-microglobulin as described for the ISS above. However, many other markers have been used. High-risk characteristics associated with worse prognosis include extramedullary (disease outside the bone marrow) disease, IgA heavy chain, lack of bone disease, elevated serum LDH (lactase dehydrogenase) at diagnosis, low platelets, and abnormal cytogenetics (see below).  Some features associated with a good prognosis include IgG kappa myeloma, advanced bone involvement, and cytogenetics showing hyperdiploidy (more than the normal number of chromosomes).

The genetic make up of the myeloma cells has a very significant effect on outcome. Up to 40 or 50% of patients with myeloma may have acquired defects in the chromosomes. Frequent abnormalities include translocations, or losses and gains of various chromosomes of the myeloma cells. Loss or deletions of chromosome 13, and translocations from chromosome 4 and 14 or 14 and 16 have been associated with median survival of less than 2 years. Translocations involving chromosome 11 and 14 [t(11,14)] or multiple gains of chromosomes (hyperdiploidy) have been associated with a good prognosis.  Another exciting strategy for evaluating prognosis is the use of gene expression profiles. Researchers at the University of Arkansas have determined a pattern of gene expression (GEP) in the myeloma cells that can be associated with a good or poor prognosis. Although this strategy is currently experimental, it will likely prove useful in the future for classifying good or poor risk patients and may even be used to help select the best initial therapy for individual patients. (Rajkumar and Buadi 2007, 665-680)

 

Blade Criteria and International Myeloma Working Group (IMWG) Criteria

(Rajkumar and Buadi 2007, 665-680):

Once therapy is initiated for myeloma standard criteria are used to follow response to treatment. The most widely used response criteria are Blade Criteria and the IMWG criteria. Response definitions in the past have not followed a uniform set of criteria, and thus have differed from one report to the next, making it very difficult to compare results across various studies. The myeloma community is attempting to rectify this by consistently using the same response definitions (e.g., Blade criteria and IMWG). The IMWG criteria are shown in the table below. It differs from the Blade criteria only by its inclusion of the results from FLC assays.

 

Response

IMWG criteria

sCR

CR as defined below plus normal FLC ratio and absence of clonal cells in bone

marrow by immunohistochemistry or immunofluorescence

CR

Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow

VGPR

Serum and urine M-protein detectable by immunofixation but not on electrophoresis

or

≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h

PR

≥ 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by ≥90% or to < 200 mg/24 h

 

If the serum and urine M-protein are un-measurable, a ≥ 50% decrease in the

difference between involved and uninvolved FLC levels is required in place of the M-protein criteria

 

If serum and urine M-protein are not measurable, and serum free light assay is also not measureable, ≥ 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥ 30%

 

In addition to the above listed criteria, if present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required

MR

NA

No change/ Stable disease

Not meeting criteria for CR, VGPR, PR, or progressive disease

Plateau

NA

Progressive disease

Increase of ≥ 25% from lowest response value in any one or more of the following:

 

Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)

 

Urine M-component and/or (the absolute increase must be ≥200 mg/24 h)

 

Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL

 

Bone marrow plasma cell percentage; the absolute percentage must be ≥10%

 

Definite development of new bone lesions or soft tissue plasmacytomas or

definite increase in the size of existing bone lesions or soft tissue

plasmacytomas

 

Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder

Relapse

Clinical relapse requires one or more of:

 

Direct indicators of increasing disease and/or end organ dysfunction (CRAB features). It is not used in calculation of time to progression or progression-free survival but is listed here as something that can be reported optionally or for use in clinical practice

 

  1. Development of new soft tissue plasmacytomas or bone lesions
  2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
  3. Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L]
  4. Decrease in haemoglobin of ≥ 2 g/dL [1.25 mmol/L]
  5. Rise in serum creatinine by 2 mg/dL or more [177 ­µmol/L or more]

Relapse from CR (To be used only if the end point studied is DFS)

Any one or more of the following:

 

Reappearance of serum or urine M-protein by immunofixation or electrophoresis

 

Development of ≥ 5% plasma cells in the bone marrow

 

Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcaemia)

Source: http://myeloma.org/pdfs/IMWG_Response_criteria.pdf

 

Treatment

Who Should Be Treated and Who Should Not

Since it is not at all clear that patients with myeloma can be cured, standard practice is to reserve treatment for patients who have symptoms (i.e., pain, infections, neurologic sequelae, or any of the CRAB features).  Therefore, patients with MGUS or asymptomatic (smouldering) myeloma can be observed, often for years, without requiring treatment.  In addition, there is no data to suggest that early treatment of asymptomatic patients will prolong overall survival.

Historical Therapy

For decades, treatment of myeloma was based on oral alkylator drugs and steroids, typically melphalan (phenylalanine mustard) or cyclophosphamide with prednisone.  This therapy was effective, with 50-60% of patients achieving at least a partial remission. However, for decades overall survival remained approximately 2-3 years after diagnosis.

In the 1990’s, infusional intravenous therapy with doxorubicin, vincristine, and pulses of very high dose dexamethasone (VAD therapy) was introduced, and multiple large trials (primarily European) showed an added efficacy of autologous stem cell transplantation. The combination of VAD, autologous stem cell transplantation, and various salvage therapies improved the average overall survival to approximately 4-5 years. (Attal et al. 1996, 91-97)

Current Therapy

Between 1999 and 2006, 3 new effective agents were introduced:  thalidomide, bortezomib, and lenalidomide. These drugs have changed the face of myeloma therapy at a very rapid pace and new studies have made it very difficult to identify one “standard of care” therapy.  In general though, all 3 of these agents have quickly moved from treatment of relapse myeloma to treatment of newly diagnosed patients.  Very recently, two new agents, carfilzomib (Kyprolis) and pomalidomide (Pomalyst) were approved for patients who have received at least 2 prior therapies, including lenalidomide and bortezomib, and whose disease did not respond to treatment or progressed within 60 days of the last treatment.  It is anticipated that carfilzomib will also ultimately move into treatment of newly diagnosed patients.  Most investigators believe that all these new drugs have increased overall survival substantially, although an accurate number has yet to be established. 

With better up-front therapy, the role of autologous stem cell transplantation has been questioned. However, it remains the most potent therapy against myeloma and continues to provide the best odds for achieving complete remission. The role of allogeneic therapy remains experimental including the combined use of autologous stem cell transplantation followed by “mini” allogeneic stem cell transplantation. (Mitsiades et al. 2007, 797-816)(Corso and Varettoni 2007, 1-11)

Initial Therapy

Determining Transplant Eligibility

In determining appropriate initial therapy, patients are commonly separated into those who are eligible for autologous transplantation and those who are not.  Many centers determine transplant eligibility based on an age cut-off of less than 65 years of age, whereas other programs use a more qualitative approach, often including patients into their early 70’s as transplant eligible if they are relatively healthy.  The only real difference in initial therapy for those eligible for transplant and those not eligible is the preference for avoiding melphalan in those who are eligible, since melphalan can make it difficult to collect stem cells. 

Another approach to selecting initial therapy is to divide patients based on prognostic features (such as those with chromosomal abnormalities) into those with “high risk” (difficult to treat) myeloma and those with “low-risk” disease.  Based on these distinctions, therapy can be chosen accordingly, using certain drugs and avoiding others.  This concept is still in its early development, and will certainly evolve over the next few years as we learn which of the newer drugs are better for subsets of patients.

Overall, most patients will receive some combination of newer drugs with dexamethasone as initial therapy and the response to these drugs will be monitored. Transplantation can be utilized after patients have received 3-4 months of initial therapy. The new goal of initial therapy is to achieve a complete remission. Many physicians will continue with initial therapy including transplantation until a complete remission is achieved.  (Mitsiades et al. 2007, 797-816)

Patients Eligible for Transplantation

As discussed above, patients eligible for transplantation should not receive melphalan prior to collection of peripheral blood stem cells.  Initial therapy should be aimed at maximum response and achieving complete remission (CR), since evidence is mounting that patients who achieve a CR will have longer disease-free and overall survivals.  Many studies continue to demonstrate that the addition of transplant enhances the number of patients achieving CR.  There is some debate, however, as to whether the transplant must occur immediately after initial therapy, or whether it can be delayed.  For patients who achieve a CR with initial therapy, some institutions are beginning to collect and store the stem cells for future use.  Other institutions are recommending proceeding immediately to transplant even after achieving CR to initial therapy. A few institutions are doing neither transplant nor collection and storage.  New Phase III studies in Europe and the U.S. will hopefully settle these questions.

In approximately the year 2000, most physicians switched to the combination of thalidomide and dexamethasone for patients who had symptomatic myeloma and were transplant eligible.  This combination was entirely oral and therefore less cumbersome than the infusions of vincristine and doxorubicin.  The results (RR 66%, CR <5%) were similar. (Weber et al. 2003, 16-19)

Over the last 10 years, however, the new agents bortezomib and lenalidomide, in various combinations with dexamethasone, thalidomide, cyclophosphamide, doxorubicin, or pegylated liposomal doxorubicin, have demonstrated remarkably better results (RR 80% to 90%, CR and nCR 30-50%). (Oakervee et al. 2005, 755-762; Wang et al. 2007, 235-239)

Which of these combinations is best and whether such response will make it unnecessary to proceed to autologous transplant is yet to be determined, but it is certainly clear that some of these initial combinations should become standard. The National Comprehensive Cancer Network (NCCN) Drug and Biologics Compendium (www.NCCN.org) has listed them as appropriate first line therapies.  (Bensinger 2008, 480-492; Harousseau 2006, 577-589; Lacy et al. 2007, 1179-1184; Oakervee et al. 2005, 755-762; Srikanth, Davies, and Morgan 2008, 1-12)

Transplantation

Autologous Transplantation

Autologous transplantation is a process by which a patient’s own blood stem cells are harvested in anticipation of very intensive chemotherapy for the treatment of their cancer.  The chemotherapy damages the bone marrow to a point that it will not recover.  Without bone marrow, the body is incapable of producing more blood cells. Peripheral blood stem cells, collected through the veins in a procedure known as pheresis and stored in liquid nitrogen, are infused intravenously a day or two after the chemotherapy.  These cells will re-populate the obliterated bone marrow and within 10-12 days will allow recovery of white cells, with platelets and red cells recovering soon after.

In the early 1990’s, Phase II trial results in myeloma looked very promising and through the 1990’s a number of randomized, Phase III trials showed that patients receiving a transplant after initial therapy had increased CRs, increased median durations of remission, and most importantly, an increase in median survival by approximately 18 months.  This approach, therefore, became standard and remains an important part of the therapy of myeloma even today. (Attal et al. 1996, 91-97; Child et al. 2003, 1875-1883)

Tandem transplants, 2 autologous transplants performed within 3 months of each other, were studied in Phase III fashion as well, but since the results were mixed, is rarely used, and has not become standard.  A second, or even a third autologous transplant, may be considered, and may be very helpful at subsequent points in the illness, especially if the first transplant was very effective, resulting in many years of disease control. (Attal et al. 2003, 2495-2502; Moreau et al. 2006, 397-403)

Allogeneic Transplantation

Allogeneic transplantation is a process, in which the patient receives chemotherapy just as in autologous transplantation, but the stem cells are obtained from a sibling (brother or sister), an unrelated matched donor, or even potentially from stored umbilical cord blood cells.  These donor stem and immune cells can provide potent immune effects in the recipient. On a positive note, the donor cells may provide a so-called “graft-versus-myeloma effect” wherein these new immune cells can recognize the patient’s cancer as “foreign” and help to eliminate the myeloma cells.

In the 1990’s, all attempts at allogeneic transplantation for myeloma failed miserably because of a 50% or higher incidence of death from infections and other complications.  This process of allogeneic transplant for myeloma has been revived, however, in the form of reduced intensity conditioning (RIC) transplants, using much lower doses of chemotherapy as immunosuppression alone.  This reduced intensity, combined with better anti-infective agents, has led to a much lower treatment-related mortality of only 10-15%.  Nevertheless, this mortality rate, the high incidence of chronic graft versus-host disease (50%-70%), and the continued evidence of relapses, even 4 or 5 years after transplant, continues to make this approach experimental. (Maloney et al. 2003, 3447-3454; van Dorp et al. 2007, 178-184)   

Patients Not Eligible for Transplant

For years, the approach in patients ineligible for transplant has been to treat with a combination of melphalan and prednisone (M+P) therapy.  However, a number of Phase III studies have confirmed the superiority of combinations of these 2 agents with either thalidomide or bortezomib. 

In the studies combining thalidomide with M+P, response rates (defined as a 50% or greater reduction in para-protein) were increased from 60% (M+P alone) to 90% (MPT) and complete responses (disappearance of positive Immunofixation test) from 0% to 25%.  In addition, overall survival was improved with MPT versus MP from 27 months to 45 months.  These studies have promoted the use of MPT and MPV as primary therapy for adults not undergoing autologous stem cell transplantation. (Facon et al. 2007, 1209-1218)  In the bortezomib combination study (Vista), response rates (RR) were increased to 90% and complete responses (CR) to 32%.

The evidence is now convincing that if the physician is aiming for prolonging survival in older patients or those unable to tolerate transplantation, the new combination therapies should be tried if the patient is able to tolerate the additional side effects of the added drug.

The Eastern Cooperative Oncology Group (ECOG) investigators have presented results from a randomized trial using lenalidomide with high-dose versus low-dose dexamethasone. Approximately 30% of patients were >65 years old and these patients tolerated the therapy well. Single weekly dosing of dexamethasone was associated with improved survival and the overall survival at 1 year in the >65 years old group was 93%. This suggests that lenalidomide or dexamethasone may also be an active regimen in patients ineligible for stem cell transplantation.

Maintenance Therapy

There have been a number of studies of continuation therapy, or maintenance. This therapy, begun after transplantation or after a response has been obtained, is intended to prolong responses and hopefully, survival.  Although several studies have suggested benefit, others have not.  The role of maintenance therapy for myeloma is therefore unresolved.  A number of large, ongoing randomized clinical trials will provide answers to this question.  (CALGB link http://myeloma.org/pdfs/McCarthy_8017.pdf)

Treatment at Relapse

After initial therapy, and perhaps transplant, and possibly even after maintenance therapy, patients are likely to relapse with recurrent disease.  At this point in their course they will be treated with further therapy.  Approved therapies for this circumstance include dexamethasone, bortezomib, lenalidomide, pegylated liposomal doxorubicin (with bortezomib), thalidomide, alkylating agents, and all combinations of these.  The choice of therapy, of course, will be dictated by which therapies the patient has already had. Most clinicians will choose a new agent, bearing in mind that some drugs, such as bortezomib, might be used again if the patient tolerated this well and if the therapy was stopped for reasons other than disease progression.

Third and fourth line therapies (and more) can be considered with each relapse.  Most of these will work, some even better than earlier therapies.  Finally, the patient may be eligible for newer, experimental agents that are just entering Phase I or Phase II testing.  Some of these drugs may not work, and others may be only partially effective. Every once in a while a drug proves to work very well, as has been the case with bortezomib or lenalidomide.  Patients should seriously consider these studies when they are offered. (Hayden et al. 2007, 609-615; Ning et al. 2007, 1503-8; discussion 1511, 1513, 1516 passim; Palumbo et al. 2007, 2767-2772; Palumbo et al. 2008)

 

Myeloma: Complications and Management

Bone Disease

Myeloma causes a wide spectrum of complications, including significant bone destruction in the form of osteoporosis and lytic lesions.  Often these lesions are in the spine, ribs, clavicles (collarbone), pelvis, or in a long bone such as the humerus (arm) or femur (leg).  Small fractures or even major fractures may occur, causing pain, loss of height, more difficulty breathing, or difficulty walking.  Although specific therapy for myeloma may slow this process down, specific agents have also been developed which are intended to slow down the destructive process, heal the bones, and even prevent fractures.   Supportive medications for improving bone metabolism include supplemental calcium and vitamin D.

BisphosphonatesPamidronate (ArediaTM) and zoledronate (ZometaTM) are drugs which are approved for the treatment of the bone disease associated with myeloma.  They are usually administered intravenously on an every 4 week schedule. They have been shown in Phase III randomized trials to reduce the risk of fracture, such that for every 10 patients treated, 1 fracture is prevented.

These agents can also be used very effectively to treat hypercalcemia.

Long-term utilization of these drugs does have moderate risk. Kidney function must be monitored constantly and there is also a risk of osteonecrosis of the jaw, a condition in which the bone supporting the teeth becomes eroded.  Symptoms include pain, swelling, loose teeth, exposed bone, drainage, and infection. This occurs in somewhere between 1 % and 5% of people who have been on the drugs for many years. (Chaudhry and Ruggiero 2007, 199-206; Ruggiero and Drew 2007, 1013-1021)

The recommendations recently include reducing the utilization of these agents after 2 years of stable disease, and possibly not using them where there is no bone involvement.  Dental exams before utilization, and routinely during use are advised.

Therapy for the Spine

As the vertebral bodies become more involved with myeloma, small fractures, large lytic lesions, and compression (collapse) with significant pain may occur.  Surgical procedures may be used to stabilize the worst areas, but non-surgical approaches have also been developed to stabilize the vertebrae, relieve pain, and prevent further compression.

VertebroplastyThis is a procedure in which a radiologist or orthopedic surgeon inserts a needle under x-ray guidance into the bone and injects methylmethacrylate (similar to CorianTM), to help support the bone and relieve pain.

KyphoplastyThis is a similar procedure to vertebroplasty, but in this approach a balloon is used to open up more space in the vertebrae prior to the injection of the methylmethacrylate.  Kyphoplasty helps to support bone structure and relieve pain but can also preserve and improve height.  (www.Kyphon.com)

RadiationAlthough radiation is remarkably effective in controlling malignant plasma cells, it cannot be used for the entire body (except in the case of stem cell transplantation), and therefore must be used in specific locations.  This modality of therapy is very effective in controlling localized pain caused by myeloma and in treating large plasmacytomas, especially in the sacrum.  Any area of fracture should be treated with radiation as well, to control the cancer and promote healing.  The number of doses may be as low as a single fraction or may range up to ten fractions.

In the case of a Solitary Plasmacytoma, radiation is used as the sole treatment and should be increased to a maximum dose tolerated in order to potentially cure this myeloma variant.

Hypercalcemia

Bone destruction and abnormal excretion of hormones by the myeloma cells can frequently cause hypercalcemia. Symptoms of hypercalcemia include fatigue, altered mental status, gastrointestinal upset and weakness.  Hypercalcemia can result in kidney failure and rarely heart rhythm abnormalities. The mainstay of treatment for hypercalcemia includes intravenous fluids with lasix, bisphosphonates, calcitonin injections and corticosteroids. Effective treatment of the myeloma will also help to improve the hypercalcemia and prevent its recurrence.

Renal Failure

Patients with myeloma often present with renal failure and the cause of the kidney injury is often multifactorial. Hypercalcemia and hyperuricemia can occur as a result of myeloma and can contribute to renal failure. In addition, the myeloma cells can directly infiltrate the kidneys resulting in dysfunction.  Abnormal proteins made by the myeloma cells, especially lambda light chains, can infiltrate the tubules of the kidney causing renal failure. Finally, the myeloma cells can produce other abnormal proteins called amyloid proteins that destroy the glomerulus or filter part of the kidney.  Treatment of renal failure consists of correction of hypercalcemia, hyperuricemia, installation of intravenous fluids and avoidance of any further toxins. Usually, with effective treatment of the myeloma, kidney failure will improve. Occasionally, permanent kidney failure results and lifelong hemodialysis is necessary.

Infection

Patients with myeloma have defective immunity and are at risk for severe and life-threatening infection.  As a result of myeloma, the normal defense system lacks protective antibodies and infection caused by encapsulated bacteria and other opportunistic organisms are common.  Patients showing signs of infection need to be evaluated and treated aggressively if there’s suspicion of serious bacterial or fungal infection. Viral infections are also common including herpetic outbreaks or reactivation of chicken pox (shingles).  Commonly, preventative antivirals (acyclovir or Valtrex) and anti-Pneumocystis carinii (Septra or dapsone) medications are given if corticosteroids are used in the treatment regimen. Certainly, all patients should receive vaccines including pneumovax, hemophilus influenza B, meningococcal, and tetanus.

Neuropathy

Upward of 30% of patients with myeloma have neuropathy, at baseline, before starting treatment.  In addition, multiple agents used to treat myeloma are associated with neuropathy including thalidomide, lenalidomide, bortezomib, and vincristine. Therefore, patients and physicians alike need to be proactive about preventing and treating neuropathy. Several supplements have been recommended for their ability to ameliorate symptoms of neuropathy. These include vitamins B6, B12, alpha-lipoic acid and L-carnitine.  Message, warm baths, and cocoa butter rubs have also been used. For patients who have neuropathy, pain can be a debilitating symptom.  Prescription medications used to treat painful neuropathy include Neurontin (gabapentin), Lyrica (pregabalin), Cymbalta (duloxetine), Elavil (amitriptyline), and various narcotics. Trial and error of combinations of these medications often provides some relief.

Plasma Cell Dyscrasias

Solitary Plasmacytoma

Plasma cells live in the bone marrow and lymph nodes and thus have ready access to the blood stream. Therefore, most plasma cell disorders have already spread throughout the body by the time of diagnosis. Rarely, plasma cells can grow in one area and form one or several localized tumors in the bones. When a localized plasma cell tumor is found (with no evidence of distant spread) it is called a solitary plasmacytoma. These tumors can be located in the bones (most common) or rarely, outside the bone called extramedullary plasmacytoma.  Anyone with a plasmacytoma needs to undergo an extensive work-up for myeloma to prove that distant spread of plasma cells is not present. Despite a “clean” work-up, these patients often recur in other areas years later, due to microscopic tumor spread within the body.  Treatment of plasmacytoma includes high-dose radiotherapy aimed at curing the disorder.

MGUS

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a plasma cell abnormality in which the patient has less than 10% plasma cells in the bone marrow, the IgG para-protein in the blood is less than 3.0 gms/dL, and there is no evidence of myeloma-related organ damage.  Approximately 1-2% of these patients each year progress to a more malignant condition, including myeloma, Waldenstrom’s Macroglobulinemia, chronic lymphocytic leukemia (CLL), and amyloidosis.  There is some evidence that the serum free light chain test can help stratify these patients by risk, ranging from low risk with only a 2% chance of progression at 20 years, to high risk with a 27% chance of progression at 20 years. (Rajkumar 2005, 340-345)

Amyloidosis

This is a condition in which abnormal plasma cells in the bone marrow produce light chains that are deposited in organs. The most common organs involved include the heart, the kidneys, nerves and the muscles of the tongue and bowel. Manifestations of this disease include thick tongue, hoarse voice, congestive heart failure, dizziness upon standing, tingling or pain in the toes and fingers, and diarrhea. (Link to amyloid http://en.wikipedia.org/wiki/Amyloid)

Plasma Cell Dyscrasia

This is a myeloma variant in which the problem is limited to elevated proteins (usually light chains only) and renal dysfunction, including renal failure requiring dialysis.  There is some debate as to whether plasma exchange (pheresis) is helpful in this setting.

 

POEMS Syndrome

This is a myeloma variant in which the patient presents with Polyneuropathy peripheral nerve damage), Organomegaly (large liver or spleen), Endocrinopathy (abnormal hormone-producing glands), M-protein (elevated proteins in blood), and Skin abnormalities (hyperpigmentation or hypertrichosis {increased hair on body}).  It is a form of myeloma and should be treated aggressively, including with autologous stem cell transplantation.

Links for Patients, Clinicians and Researchers

Multiple Myeloma Research Foundation: www.themmrf.org

Multiple Myeloma Research Consortium: http://www.themmrc.org/

The Leukemia and Lymphoma Society: http://www.leukemia-lymphoma.org/hm_lls

International Myeloma Foundation: http://myeloma.org/

Helen Diller Family Comprehensive Cancer Centerhttp://cancer.ucsf.edu/

 

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