CLINICAL MANIFESTATIONS

 

 

SMOLDERING MYELOMA

If myeloma is smoldering (asymptomatic), it does not require treatment. In this case, risk of progression to symptomatic myeloma is approximately 10% per year in the first 5 years, then it declines.

Although a trial with lenalidomide and dexamethasone has demonstrated a survival advantage in high-risk patients, many experts believe that patients with smoldering myeloma should not be treated, unless they have >60% plasma cells in the bone marrow, or a serum free light chain ratio >100.

 

Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.
N Engl J Med. 2007 Jun 21;356(25):2582-90.
Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV.
This is a study of 276 patients with smoldering myeloma. The risk of progression to symptomatic myeloma was:
  - 10% per year for the first 5 years
  - 3% per year for the following 5 years
  - 1% per year for the following 10 years
The cumulative probability of progression to symptomatic myeloma was 73% at 15 years.

Diagnosis of smoldering multiple myeloma.
N Engl J Med. 2011 Aug 4;365(5):474-5.
Rajkumar SV, Larson D, Kyle RA.
[Letter]
After reviewing data from 655 patients with smoldering myeloma seen at the Mayo Clinic between 1996 and 2010, the authors noticed that patients with 60% of more plasma cells in the bone marrow had a very high rate of progression to symptomatic myeloma. This high percentage of plasma cells in the bone marrow was seen in 21 patients (3%), and their median progression to symptomatic myeloma was only 7 months. The authors propose immediate therapy of all myeloma patients having >60% plasma cells, regardless of the presence of symptoms.

Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form.
Cancer. 2012 Nov 15;118(22):5544-5549.
Rago A, Grammatico S, Za T, Levi A, Mecarocci S, Siniscalchi A, De Rosa L, Felici S, Bongarzoni V, Piccioni AL, La Verde G, Pisani F, Franceschini L, Paviglianiti AL, Caravita T, Petrucci MT, De Stefano V, Cimino G; on behalf of the Multiple Myeloma GIMEMA-Latium Region Working Group.
This is a study of 397 patients with smoldering myeloma. Progression to symptomatic myeloma occurred in 45% of cases at 10 years, and 75% of cases at 20 years. In 10 patients (2.5%) having >60% plasma cells in the bone marrow, risk of progression to symptomatic myeloma was higher, and the authors recommended starting therapy in those patients soon after diagnosis.

Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.
Leukemia. 2013 Apr;27(4):941-6.
Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV.
After a retrospective review of 5865 patients with smoldering myeloma seen at the Mayo Clinic between 1970 and 2010, the authors found that a serum involved/uninvolved FLC ratio >100 (seen in 15% of cases) had a 98% chance to progress to symptomatic myeloma within a median follow-up of 52 months (vs 56% in all patients), and a 72% risk of progressing to symptomatic myeloma within 2 years.

 

TREATMENT

Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.
N Engl J Med. 2013 Aug 1;369(5):438-47.
Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF.
This is the first clinical trials which showed a survival advantage in the treatment of smoldering myeloma. 119 patients with high-risk smoldering myeloma were randomized to either observation (the historical standard of care) vs treatment with lenalidomide + dexamethasone.
High-risk myeloma was defined as:
  1- Plasma cells 10% in bone marrow
  2- IgG 3000 mg/dL or IgA 2,000 mg/dL or urine M >1000 mg/24 hours
  3- Only one of the two criteria above + at least 95% phenotypically aberrant plasma cells in the bone marrow aspirate
       and >25% reduction in one or two uninvolved immunoglobulins
The treatment was divided into:
  - Induction phase: lenalidomide 25 mg on days 1-21 and dexamethasone 20 mg on days 1-4 and 12-15 every 28 days, x 9 cycles
  - Maintenance phase: lenalidomide 10 mg on days 1-21 every 28 days, for 2 years
Median follow-up was 40 months.
Results:
  - Response rate: 79% in the induction phase, and 90% in the maintenance phase
  - Progression-free survival at 3 years: 30% in the observation group, and 77% in the treatment group
  - Overall survival at 3 years: 80% in the observation group, and 94% in the treatment group
There are 4 aspects that could be criticized: 1) the definition of high-risk myeloma as used in this trial is arbitrary/controversial; 2) the trial compared Len-Dex upfront vs observation, but we do not know the outcome of Len-Dex upfront vs Len-Dex delayed; 3) only 28% of patients received autologous stem cell transplantation at progression; 4) in a world with limited resources, the use of a drug with a cost exceeding 10,000$ a month in asymptomatic persons (and with risk of side effects like rash, thrombosis, and second malignancies) is debatable.

A published comment by Dr. Gertz explained in detail the reasons why patients with smoldering myeloma should not receive lenalidomide, outside of the context of clinical trials [Gertz MA. Chemoprevention for smoldering multiple myeloma: not ready for prime time. Leuk Lymphoma, 2013; 54:2331-2].

 

 


 

Symptomatic myeloma is typically manifested by CRAB symptoms:
  - HyperCalcemia
  - Renal insufficiency
  - Anemia
  - Bone lesions

 

Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2010 Dec 1;10(6):464-8.
Talamo G., Farooq U., Zangari M., Liao J., Dolloff N.G., Loughran T.P. Jr., Epner E.

 

 

HYPERCALCEMIA

Hypercalcemia is an oncologic emergency.
Symptoms and signs of hypercalcemia:
 - Nausea, vomiting
 - Polyuria
 - Constipation
 - Altered mental status , somnolence

 

 

RENAL INSUFFICIENCY (50%)

Some patients will eventually require dialysis.
The causes of renal failure in MM include:
 - Myeloma kidney (obstruction of distal and collecting tubules by casts containing Ig and light chains, surrounded by giant cells)
 - Hypercalcemia
 - Hyperuricemia
 - Plasma cell infiltration
 - Amyloid deposition
 - Pyelonephritis
The most frequent causes of renal failure are myeloma kidney and hypercalcemia. In patients with hypercalcemia, normalization of serum Ca can reverse the renal dysfunction.
Renal failure develops more commonly with lambda chains than with kappa chains.
Light chains can damage tubular cells and lead to proximal or distal renal tubular dysfunction → Fanconi’s syndrome, distal RTA, nephrogenic DI.
MM is the most common cause of Fanconi's syndrome in adults. Fanconi syndrome should be suspected when a patient with monoclonal gammopathy (especially of kappa type) has glycosuria (with normal glycemia), hypouricemia, and hypophosphatemia.

 

Monoclonal gammopathy: significance and possible causality in renal disease.
Am J Kidney Dis. 2003 Jul;42(1):87-95.
Paueksakon P, Revelo MP, Horn RG, Shappell S, Fogo AB.
This study reviews data from 121 patients who had monoclonal gammopathy on serum and/or urine electrophoresis and underwent a renal biopsy.
Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were:
 - Cryoglobulinemic glomerulonephritis (CG) (30.3%)
 - Monoclonal immunoglobulin deposition disease (MIDD) (28.8%)
 - Light chain cast nephropathy (CN) (19.7%)
 - Light chain amyloidosis (AL) (19.7%)
 - CN + MIDD (1.5%)
Among 55 patients with renal disease unrelated to monoclonal gammopathy (63.2% of all patients with monoclonal gammopathy), diagnoses were:
 - Diabetic nephropathy (18.1%)
 - Focal segmental glomerulosclerosis (18.1%)
 - Arterionephrosclerosis (12.7%)
 - Membranous glomerulonephritis (9.0%)
 - Minimal change disease (7.3%)
 - Various immune complex diseases, interstitial nephritis, or nonspecific changes
Authors conclude that most patients with monoclonal gammopathy who undergo renal biopsy have findings unrelated to the monoclonal gammopathy, probably because of the high frequency of MGUS in older patients.

Renal crystal storing histiocytosis in a patient with multiple myeloma.
Ann Hematol. 2009 Jan 3.
Farooq U, Bayerl MG, Abendroth CS, Verma N, Talamo G.

Kidney disease associated with plasma cell dyscrasias.
Blood. 2010 Sep 2;116(9):1397-404.
Heher EC, Goes NB, Spitzer TR, Raje NS, Humphreys BD, Anderson KC, Richardson PG.
[Review]

Outcomes of newly diagnosed myeloma patients requiring dialysis: renal recovery, importance of rapid response and survival benefit.
Blood Cancer J. 2017 Jun 16;7(6):e571.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Fotiou D, Ziogas DC, Migkou M, Panagiotidis I, Eleutherakis-Papaiakovou E, Kanellias N, Psimenou E, Marinaki S, Bacharaki D, Mparmparoussi D, Matsouka C, Giannouli S, Terpos E, Kastritis E.
This is an interesting study, that analyzed outcomes of patients with multiple myeloma with renal failure, and in particular those who required hemodialysis at the time of diagnosis (52 patients). Of note, after response to chemotherapy, 26 (50%) patients had an improvement of their renal function to the point that they could discontinued dialysis, even without the use of special filters.

 

 

IMPAIRED HEMATOPOIESIS

 - Anemia (60%)
 - Leukopenia
 - Thrombocytopenia

Anemia is another common symptom, and it induces fatigue, dizziness, palpitations, etc.
The causes of anemia in MM include BM infiltration by tumor cells, renal failure, and myelosuppression induced by chemotherapy.

 

 

BONE LESIONS

 - Osteolytic lesions (80%)
 - Bone pain
(70%)
 - Osteopenia, osteoporosis
Bone pain is a common symptom.
Bone lesions in myeloma usually involve spine, pelvis, ribs, and skull. They are "osteolytic". Bone lesions are "osteoblastic" in 1% of patients, often in the context of POEMS syndrome.
Bone fractures may occur even in the absence of trauma ("pathologic fractures"). Vertebral collapse are common.
Types of vertebral fractures are: biconcave (55%), wedge (32%), and crush (13%). The most commonly involved site is the thoracic spine.
If myeloma involves the spine, it may compress the spinal cord and compromise the ability to move arms and legs, and the urinary function.

 

 

Lytic bone lesion in the midshaft of the left humerus, at risk for pathologic fracture (my personal archive):

 

 

Lytic bone lesion in the midshaft of right humerus in a patient with multiple myeloma (my personal archive). Note the thinned bone cortex:

 

 

Pathologic fracture of the right humerus in the same patient, after orthopedic surgery (my personal archive): 

 

 

Lytic lesions of the skull seen at the CT scan in a patient with multiple myeloma (my personal archive):

 

 

Fracture of the dens (C2) in a patient with multiple myeloma - CT scan (my personal archive):

 

 

 

Association between diffuse idiopathic skeletal hyperostosis and multiple myeloma.
Skeletal Radiol. 1995 Oct;24(7):489-92.
Scutellari PN, Orzincolo C, Castaldi G.
This study includes 97 consecutive MM patients. Radiologic studies found both myelomatous bone lesions and hyperostosis similar to DISH. 21 male and 8 females patients had DISH in association with multiple myeloma, and the prevalence was higher (29.8%) than in the control group (973 patients) or in the general population (15-20%). The involved segments of the column were thoracic in 18 patients, cervical in 10 patients, and lumbar in 9 patients. It is possible that the coexistence of DISH and multiple myeloma is only an association.

Effect of pathologic fractures on survival in multiple myeloma patients: a case control study.
J Exp Clin Cancer Res. 2008 Jun 10;27:11.
Sonmez M, Akagun T, Topbas M, Cobanoglu U, Sonmez B, Yilmaz M, Ovali E, Omay SB.

Among 49 patients with MM, pathologic fractures (PFs) were observed in 24 patients (49%) and absent in 25 patients (51%). The risk of death was increased in the patients with PFs compared with patients without PFs. OS was 17.6 months in patients with PFs and 57.3 months in patients without PFs.

The impact of osteoporosis (as measured by lumbar spine quantitative computed tomography) on disease activity and survival in myeloma patients: A 13-year prospective study.
Am J Hematol. 2011 Jul;86(7):617-9.
Diamond T, Golombick T, Manoharan A, Kwan Y, Bryant C.
Data collected on 108 myeloma patients followed for 13 years showed that patients with severe osteoporosis (defined as a T-score > -3.5 at lumbar spine quantitative CT) had a median survival 18 months shorter than the rest of the patients. 

Radiologic and clinical characteristics of vertebral fractures in multiple myeloma.
Spine J. 2015 Oct 1;15(10):2149-56.
Miller JA, Bowen A, Morisada MV, Margetis K, Lubelski D, Lieberman IH, Benzel EC, Mroz TE.
This is a retrospective study of 124 vertebral fractures in 50 patients with multiple myeloma. The most commonly involved site is the thoracic spine. Types of vertebral fractures are: biconcave (55%), wedge (32%), and crush (13).

 

 


Giampaolo Talamo, M.D.