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Multiple Myeloma - 12/21/2012

posted Dec 21, 2012, 7:54 AM by Rohit Das   [ updated Dec 27, 2012, 6:36 AM by Purnema Madahar ]

An unfortunate case was presented today of a 44 year old male who initially presented with months of back pain, poor appetite and weight loss. On further evaluation, he was noted to have renal failure, hypercalcemia and pancytopenia. Various imaging modalities showed lytic lesions, and electrophoresis showed a monoclonal IgG lamda spike of nearly 10g/dL…bone marrow is pending, but overall, a highly likely case of multiple myeloma (MM). So, let’s go over some basics about this relatively common hematologic malignancy…

·         What is the pathogenesis and epidemiology of MM?

·         How does it present, and how does one go about attempting to diagnose it?

·         MM is within the “plasma cell dyscrasia” spectrum, which encompasses a few other things worth reviewing…

·         How can we prognosticate MM, and what are general approaches to treatment?

What is the pathogenesis and epidemiology of MM?

·         MM is thought to most commonly arise from a pre-malignant proliferation of monoclonal plasma cells (antibody producing factories), i.e. MGUS (monoclonal gammopathy of undetermined significance), How MM evolves from MGUS is not completely understood, unsurprisingly. Contributing factors seem to be increased Toll-like receptors (TLRs) on the surface of myeloma cells (leading to abnormal responses to antigens), enhanced expression of IL-6 (a plasma cell growth factor), and various cytogenetic abnormalities. Long-term epidemiologic studies spanning 30-35 years have led to experts concluding that MGUS à MM is a simple, but random, “two-hit” process; several oncogenic mutations have been implicated as the initiators of the “second hit,” but the cause is not really known. The attached NEJM review gives much more detail than I intend to dwell upon…

·         The annual incidence of MM in the U.S. is 4.3 per 100,000 people. Almost 20,000 new cases are diagnosed annually, nationwide. It is the most common hematologic malignancy, representing 10% of such cases. It is twice as common in blacks as compared to whites and effects males more than females. The median age at diagnosis is 66 years, with only 2% of patients younger than 40 years of age.

How does it present, and how does one go about attempting to diagnose it?

·         I love studies like the one I attached – large cases series that allow clinicians to really get a handle of the most common clinical presentations of a particular diagnosis. This study from Mayo had 1000+ patients enrolled from 1985 to 1998 and specifically looked at the distribution of symptoms and laboratory data within 1 month of newly diagnosed MM; some important findings:

·         Bone pain was the most common symptom, occurring in 60% of patients; 70% had such symptoms for <6 months, and 90% had symptoms for <12 months. Other less common symptoms were fatigue (30%) and weight loss (20%). Osteolytic lesions generally present chronically, but pain can present acutely in the setting of a pathologic compression fracture. The pathogenesis of lytic lesions is due to cytokine induced inhibition of osteoBLASTS (less bone building) and overactivity of osteoCLASTS (more bone resorption).

·         Anemia is the most common laboratory finding, present in 70% of patients with MM, with an overall median value of 10.9 g/dL; 40% of patients have renal failure and around 30% of patients are hypercalcemic. Corresponding to the incidence of pain symptoms, around 67% of patients had lytic lesions on initial radiographic evaluation. Renal failure in multiple myeloma is a diverse, interesting topic...the main causes include myeloma cast nephropathy (tubular disease - effecting 40-60% of cases), light chain deposition disease (glomerular disease - around 20% of cases), amyloid protein deposition, and various other miscellaneous causes (hypercalcemia is also particularly important)...I think I'll leave further details for another day...

·         The diagnostic criteria are reviewed in the upper panel of Table 1 in the attached NEJM review paper. I’d like to touch one aspect of this schema – the detection of monoclonal immunoglobulins (M proteins). Up to 80% patients will have M protein detected by SPEP, but very importantly, “light-chain” myeloma (a variant where plasma cells are predominantly secreting only the light chain portion of their respective antibody) may be missed in the serum, but usually detected in the urine. Checking both a SPEP and UPEP increases the sensitivity of detecting M proteins to 97%.

·         There is a small portion of patients who will not have M proteins detected in their serum OR urine. In such cases where MM is highly suspected, serum free light-chain assays are the next step; the normal kappa/lamba ratio is 0.26 to 1.65 – abnormalities one way or the other are very suggestive of a monoclonal plasma cell expansion. FINALLY, there is a small minority of patients, 1 to 2%, who have no M protein detected on ANY of these tests – thus the term “nonsecretory” myeloma.

MM is within the “plasma cell dyscrasia” spectrum, which encompasses a few other things worth reviewing…

·         This spectrum encompasses asymptomatic disorders like MGUS and Smoldering Multiple Myeloma, and then some bad stuff, like AL amyloidosis, Waldenstrom’s macroglobulinemia, solitary plasmacytomas, and POEMS Syndrome. The definitions of the above syndromes are reviewed in Table 110-1 of the attached chapter from Clinical Oncology.

·         MGUS is pretty prevalent in our population – 3% of people 50 years or older, increasing to around 7% in people 85 years or older. MGUS is classified into different risk stratifications based on 3 factors – abnormal serum free light chain ratio, high M protein level (≥1.5g/dL), and non-IgG MGUS. Three of these risk factors give a 60% chance of progression over 20 years, 40% change with 2 risk factors, 20% with 1, and 5% with no risk factors. Smoldering MM is a much higher risk syndrome, with 75% progression to MM in 15 years.

How can we prognosticate MM, and what are general approaches to treatment?

·         Staging of MM is pretty simple actually, and done via the International Staging System (ISS). It depends only on the Beta-2 Microglobulin (B2M) level and serum albumin. Stage 1 = B2M < 3.5 mg/L and albumin ≥3.5 g/dL, Stage III = B2M ≥ 5.5 mg/L, and Stage II fits neither I or III. The median survivals for Stages I, II and III are 62, 44 and 29 months respectively --- BAD DISEASE. Table 16 of the attached Mayo study lists some additional CLINICAL risk factors for poor prognosis, based on a univariate analysis of their 1,027 patients.

·         The main decision in the treatment of myeloma is one’s eligibility for autologous stem cell transplant (ASCT), and this decision is based on age, performance status and comorbidities. From there, patients are then risk stratified based on cytogenetics obtained via fluorescence in situ hybridization (FISH). Everything after these assessments is totally beyond me…of note, though, there is emerging data that double (tandem)-ASCT may lead to better outcomes in patients with an incomplete response after their first ASCT.

That does it for this week, hope you guys learned a thing or two. Have a good weekend and happy holidays!!


Medical Progress: Multiple Myeloma
Palumbo et. al., NEJM 2011, Volume 364: 1046-60

Kyle et. al., Mayo Clin Proc 2003, Volume 78: 21-33

Rajkumar et. al., Abelhoff's Clinical Oncology 4th Edition, Chapter 110
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