About Multiple Myeloma

Disease and Treatment

 >Background  >Etiology, Epidemiology and Pathophysiology  >Evaluation and Diagnosis
 >Symptoms and Diagnosis  >Staging  >Prognosis  >Definition of Responses
 >Treatment  >Myeloma: Complications and Management 
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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.

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) and urinary immunofixation electrophoresis (UIFE). 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 fare. The typical disease course for an individual patient includes periods of symptomatic myeloma requiring treatment followed by periods of remission. 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. (Rajan et al. 2016, e451)

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.

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. In fact, today’s medications may have extended survival in many patients with myeloma upward of 10 years although an accurate measurement is unavailable due to such rapid progress.

Etiology, Epidemiology and Pathophysiology


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.


It is estimated that in 2017, approximately 30,280 new cases of 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 12,590 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.

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. View NIH Cancer Stat Facts - Myeloma.


Malignant plasma cells develop from an immune cell called a B lymphocyte. They either evolve from a single cell that can further mutate over time or from multiple unique cells whose relative frequencies change over time (Keats et al. 2012, 1067-1076). Changes in the genetic material within the myeloma cell may be seen which provide clues to the aggressiveness of the cancer.

As the myeloma cells grow in the bone marrow, they can crowd out the normal blood-making process that normally occurs there. Patients can then develop anemia and low platelets as the disease advances. The myeloma cells can cause an overproduction of certain proteins such as Interleukin 6 (IL-6) (also known as osteoclast activating factor or OAF) resulting in activation of osteoclasts which are cells in the body that break down bone. This can lead to bone destruction which is seen on X-Rays and CT scans as holes in the bones, which are called “lytic lesions”. Bone destruction results in bone weakening that predisposes the patient to fractures of long bones in the arms and legs, or even more commonly, to fractures of the bones in the spine. The same process which causes bone loss, can result in calcium to be removed from bone, causing high calcium in the blood or hypercalcemia.

The proteins manufactured and secreted by the malignant plasma cells can cause kidney damage, and can sometimes result in total renal failure. Some patients have severe renal failure needing 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 myeloma 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, the myeloma cells usually produces a single type of 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. The SPEP can identify this spike called an 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 response of the disease to 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
The FLC = assay (https://www.bindingsite.com/en/our-products/freelite-and-hevylite/freelite/overview/freelite) (The Binding Site) 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 one of the tests used to evaluate 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.

Minimal Residual Disease (MRD) Assessment
These very sensitive cell-based or sequencing-based assays are the most sensitive tests currently available to detect the presence of any residual myeloma in patients who have achieved a complete response with treatment. Complete response to therapy is associated with longer periods of disease remission and overall survival of the patient. The data suggest that patients who also achieve MRD-negative status experience even further improvements in disease remission and overall survival. It is still early days for using MRD in clinical care and its utility in patient managements needs to be formally established; however, increasingly clinicians are using MRD to assess patient status and make treatment decisions (Mailankody et al. 2015, doi:10.1038/nrclinonc.2014.239, Martinez-Lopez et al. 2015, dx.doi.org/10.1182/blood-2015-04-638742).

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 back of the hip (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 FISH (Fluorescence In-Situ Hybridization) analysis, to help with prognosis. Bone marrow tissue can also be stored in a tissue bank to facilitate research, which may not help the patient directly but can help scientists discover new therapies.

Symptoms and Diagnosis


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 2014, the International Myeloma Working Group changed the diagnostic criteria for multiple myeloma to include biomarkers. Below are the diagnostic criteria for 3 of the most common plasma cell disorders: 1) multiple myeloma, 2) smoldering myeloma, and 3) monoclonal gammopathy of undetermined significance (MGUS).



Diagnostic Criteria

Multiple myeloma

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:

Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

  • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
  • Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)
  • Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L
  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Any one or more of the following biomarkers of malignancy:

  • Clonal bone marrow plasma cell percentage ≥60%
  • Involved:uninvolved serum free light chain ratio ≥100
  • >1 focal lesions on MRI studies

Smoldering Myeloma

Both criteria must be met:

  • Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%
  • Absence of myeloma defining events or amyloidosis

Monoclonal gammopathy of undetermined significance (MGUS)

All criteria must be met:

  • Serum paraprotein <3.0 g/dL
  • Clonal plasma cells <10% on bone marrow biopsy
  • 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.


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 a simple, powerful and 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

Recently, in 2015, the ISS was improved upon by the Revised ISS (R-ISS) which includes LDH and chromosomal abnormalities (CA) in myeloma staging (Palumbo et al. 2015, 2863-9).

  • R-ISS stage I: Standard-risk CA by iFISH and normal LDH
  • R-ISS stage II: Not R-ISS stage I or III
  • R-ISS stage III: ISS stage 3 and either high-risk CA by iFISH or high LDH

At a median follow-up of 46 months, by the R-ISS, the 5-year overall survival rate was:

  • 82% in R-ISS I
  • 62% in R-ISS II
  • 40% in R-ISS III

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 system 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

Stage 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

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


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. We use the R-ISS (see above) to evaluate the prognosis of the patient while taking into consideration the genetic make-up of the myeloma cells, which 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.

Definition of Responses

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 is the IMWG criteria. The IMWG criteria are shown in the table below.


IMWG criteria


CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. While not widely used yet, measurement of Minimal Residual Disease (MRD) is a measurement of residual myeloma when a patient has already achieved a stringent complete response (sCR). It is therefore a measure of an even deeper response. There are early studies suggesting that deeper MRD’s, and especially measurements of less than 1 in a million remaining cancer cells, predict for better outcomes. The IMWG is now recognizing MRD negative CR’s.


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


Serum and urine M-protein detectable by immunofixation but not on electrophoresis
≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h


≥ 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 unmeasurable, 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


Not Applicable

No change/ Stable disease

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

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


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. 1. Development of new soft tissue plasmacytomas or bone lesions
  2. 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. 3. Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L]
  4. 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]

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


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). Recently, patients with elevated biomarkers which strongly predict for the development of symptoms, should also be treated. Therefore, patients with MGUS or smoldering myeloma can be observed, often for years, without requiring treatment.

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 therapies improved the average overall survival to approximately 4-5 years. (Attal et al. 1996, 91-97)

Current Therapy

In the last 16 years, 9 new effective agents have been approved that have resulted in significant improvement in outcomes for myeloma patients.

  • The first wave of these agents occurred between 1999-2006, with the approval of thalidomide, bortezomib, and lenalidomide. Thalidomide and lenalidomide are related drugs with strong immunomodulatory activity and drugs in this class are called IMiDs. Bortezomib is a proteasome inhibitor. These drugs 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 relapsed myeloma to treatment of newly diagnosed patients.
  • In 2012/2013, two new agents, carfilzomib (Kyprolis), a next generation proteasome inhibitor and pomalidomide (Pomalyst), a next generation IMiD, were approved for patients who have received at least 2 prior therapies, including lenalidomide and bortezomib, and whose disease did not respond to treatment and progressed within 60 days of the last treatment. These treatments have improved efficacy and reduced toxicities over the earlier generations of these therapeutics. It is anticipated that these two new agents will also ultimately move into treatment of newly diagnosed patients and in fact, carfilzomib is already in clinical trials for newly diagnosed patients.
  • At the end of 2015, daratumumab (Darzalex), a monoclonal antibody against CD38 which is highly expressed on myeloma cells, became the first monoclonal antibody approved for myeloma. Daratumumab was originally approved as a single agent therapy and in 2016 was approved for use in combination with either lenalidomide/dexamethasone or bortezomib/dexamethasone, based on the CASTOR (daratumumab/bortezomib/dexamethasone) and POLLUX (daratumumab/lenalidomide/dexamethasone) clinical trials (Palumbo et al., 2016, 754-766; Dimopoulos et al., 2016, 1319-1331). More recently, in 2017, daratumumab has also been approved in combination with pomalidomide/dexamethasone.
  • In 2015, panobinostat (Farydak), a histone deacetylase inhibitor (HDAC), was approved for patients with multiple myeloma whose cancer has progressed after treatment with at least two prior standard therapies. This drug offers an entirely new mechanism of action for patients resistant to proteasome inhibitors and IMiDs.
  • Another drug, elotuzumab (Empliciti), a monoclonal antibody against CS-1 (also known as SLAMF7) was also approved as well for myeloma in 2015. Elotuzumab in combination with lenalidomide and dexamethasone is approved for myeloma patients who have received at least 1 prior line of therapy. These drugs represent an exciting a new modality of treatment for myeloma patients.
  • Ixazomib (Ninlaro) was also approved in November 2015 as the first oral proteasome inhibitor for the treatment of myeloma patients. Ixazomib was studied in combination with lenalidomide and dexamethasone, a completely oral regimen, in patients who have received at least one prior therapy.

Most investigators believe that all these new drugs have steadily increased the overall survival substantially, although an accurate number has yet to be established.

With better treatment, 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. In fact, a study comparing early autologous stem cell transplant compared to late transplant showed that patients who got the transplant early had longer disease remission, though overall survival was the same. (Attal et al. 2017, 1311-1320) 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)

Emerging Therapies

There are many therapeutics currently being developed for multiple myeloma by a variety of companies.

Anti-CD38 antibody drugs

Isatuximab (Sanofi), another CD38 antibody has also demonstrated clinical activity as a single agent in relapsed/relapsed patients, with approximately a 30% response rate (Martin et al. 2014, (suppl; abstr 8532)) and even more robust activity when co-administered with lenalidomide and dexamethasone (60-75% response rate) (Martin et al., 2014, 83; Plesner et al. 2014, 84). This CD38 antibody is being evaluated in combination with proteasome inhibitors in relapsed/refractory myeloma patients. (www.clinicaltrials.gov) (Martin et al., 2017).

Anti-PD1 and anti-PDL1 antibody drugs

The immune system plays an important role in tumor eradication. Cells within the immune system express receptors (called immune checkpoint receptors) that balance the stimulatory and inhibitory immune responses. In many cancers, the tumor cells express molecules that preferentially activate the inhibitory receptors on immune cells, resulting in a suppressed immune response. The checkpoint inhibitor drugs, anti-PD1 and anti-PDL1 MAbs have been designed to block the tumors from inhibiting the immune system. It essentially “takes the brake off” the immune system. Two anti-PD1 MAbs (Keytruda and Opdivo) and 3 anti-PDL1 MAbs (Tecentriq, Bavencio and Imfinzi) have been approved for several solid cancers such as skin cancers, lung cancers and urothelial cancers. Given the robust activity of these drugs in other cancers, these MAbs are being studied in combination with standard therapy in multiple myeloma (www.clinicaltrials.gov).

Venetoclax (ABT-199)

Normal cells have a balance of proteins which promote cell survival and proteins which promote cell death. Myeloma has an imbalance of these proteins resulting in cancer cell survival. Anti-death proteins such as BCL2 support the survival of myeloma cells. Venetoclax inhibits BCL2. This drug is currently approved for a different cancer, chronic lymphocytic leukemia. Early studies of venetoclax in myeloma especially myeloma cells which harbor the genetic change, translocation 11;14. This drug is currently being tested in a Phase 3 clinical trial in combination with bortezomib and dexamethasone for myeloma patients (www.clinicaltrials.gov).

Newer proteasome inhibitors

Marizomib, a second generation irreversible pan-proteasome inhibitor, showed some activity in an early phase clinical trial (Richardson et al. 2016, 2693-2700) and is now being studied in combination with pomalidomide and dexamathasone for patients who were resistant to lenalidomide and bortezomib (www.clinicaltrials.gov). Another proteasome inhibitor in development, oprozomib is an oral drug related to carfilzomib. Efficacy was seen and now it is being studied in combination with pomalidomide and dexamethasone in patients with refractory myeloma (www.clinicaltrials.gov).


Selinexor is a selective inhibitor of nuclear export (SINE) compound which functions by inhibiting XPO1, a nuclear export protein. Tumor suppressor proteins become trapped in the cell nucleus, which leads to myeloma cell death. This drug has shown activity in combination with carfilzomib and dexamethasone in an early phase study. Currently selinexor is being studied in combination with dexamethasone for the treatment of myeloma patients. Another clinical study to evaluate the combination of selinexor, carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with myeloma is currently also under way (www.clinicaltrials.gov).


CAR T cells are a cell based immunotherapy approach to treating cancer. Patients T cells are collected and then are genetically reprogrammed so they can seek out and kill tumor cells. The T cells are differentially reprogrammed depending upon the tumor type. Proof of concept for this approach has been established in relapsed and refractory B-cell acute lymphoblastic leukemia in young adults, where response rates are high and in some cases the remissions go out for years. For multiple myeloma, the patients’ T cells are engineered to seek out and kill cells that overexpress B-cell maturation antigen (BCMA), a cell surface antigen which is over-expressed on MM cells. While still early in development, this therapy is showing very high response rates (over 70% achieved a very good partial response or better) in heavily pre-treated patients.

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 a chemotherapy drug called 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. A large study done in the U.S. and in France showed that transplant early in the course of the disease allows for longer cancer remission compared to transplant late but there is, as yet, no difference in overall survival (Attal et al. 2017, 1311-1320) .

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)

However, the new agents bortezomib, carfilzomib and lenalidomide, in various combinations with dexamethasone, thalidomide, or cyclophosphamide 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)


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, especially since doses of the drugs can be reduced to minimize these toxicities.

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. Several large studies have indicated increased benefit of lenalidomide maintenance in terms of duration of disease remission. However, the duration of lenalidomide maintenance, 2 years versus indefinitely is currently being studied. .

Drugs such as the proteasome inhibitor, bortezomib, are also excellent drugs for maintenance and, in fact, are mandatory in certain patients with myeloma having a translocation of t(4;14).

When patients have “high risk” disease, as defined by certain mutations such as a deletion of the short arm of chromosome 17(del(17p)), these patients may benefit from the combination of several of these drugs for their maintenance therapy.

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, carfilzomib, lenalidomide, pegylated liposomal doxorubicin (with bortezomib), thalidomide, pomalidomide, panobinostat, alkylating agents, daratumumab, elotuzumab, ixazomib 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 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.

Vertebroplasty: This 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.


Bone destruction and abnormal excretion of hormones by the myeloma cells can frequently cause high calcium or 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.


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.


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.


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)

Light-chain Amyloidosis

This is a condition in which abnormal plasma cells in the bone marrow produce misfolded light chains that are deposited in organs as amyloid fibrils. The most common organs involved include the heart, kidneys, nerves 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. (http://www.amyloidosis.org/)

Light chain MGUS of renal significance

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 Center: /

Amyloidosis Foundation: http://www.amyloidosis.org/


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