Multiple Myeloma


MM: 
Mostly Secrete M protein or Free light Chain Alone (16%) or Rarely No Immunoglobulin (Ig
    • M-Protein: (Consist of an intact Ig composed of Heavy Chain (IgG, IgA, IgD) and a kappa or lambda light chain
      • Misc
    • Diagnosis: 3 ways to diagnose MM if End-Organ Damage is present Lancet 2014
      • 1. M Protein (any level) with ≥  10% BM Plasma Cells 
      • 2. M protein more than or equal to 3 g/100 mL even if less than 10% BM Plasma Cells 
      • 3. Non-secretary MM:  if greater than 30% BM Plasma Cells or detection of Plasmacytoma on BM biopsy  
        • CRAB Criteria)
          • Hypercalcemia (28%) (>10.5 mg / dL)
          • Renal Failure (48%) (S-Cr: > 2 mg/dL)
          • Anemia (73%) (<10g/dL or 2 g/dL below baseline) Leukopenia (20%) Thrombocytopenia (5%)
          • Bony Lytic Lesions (58% of newly diagnosed pt): Bone Pain, Back Pain, Spinal Cord Compression, Vertebral Body Compression Fractures
          • Hyper-viscosity / Recurrent Bacterial Infections / AL
    • Diagnostic Tests:
      • UA: Will not identify M protein; Will detect Albumin if complicated by Amyliodosis
      • SPEP / 24 hr Urine UPEP / IFA : Detect M protein in 97% of the time ; Can be negative if specimen is at room temperature for long time; can lead to precipitation of M component as a part of cryoprecipiate
      • Serum Free Light Chain Testing: (For remaining 3 % who may have non-secretory disease)
      • 16 % of MM have Free Light Chain Alone: Abnormal Serum Free Light Chain Ratio is associated with Monoclonal Gammopathy; most sensitive test for the detection of abnormal Igb secreting B-clones; better test 24 hr FLC assay
      • Bone Survey (Lytic Lesions and Osteopenia) and Not Bone Scan. MRI may be needed in suspected patients despite unrevealing radiographs
      • CMP (High Calcium, Albumin to correct Calcium (Low if proteinuria), Cr)
    • Prognosis: B2 Microglobulin (<3.5 mg/L, >5.5 mg/L) and Serum Albumin (> or < 3.5 g / dL)
    • Treatment Principle: 
    • Eligibility of BM transplantation 
Case based Learning  
Case 1 - New diagnosis 
73 yo F is seen for weakness. Lab shows Ca of 13.5, Alb of 2.9, iCa of 7.16. PTH is 17, Vit D is 60, 1,25 Vitamin D is 7. Cr is normal. 24 hr proteinuria is around 2 gm. Hgb is 8.6, MCV is 106. B12, and FA is normal. Does not have any history of liver disease. SPEP and S-IFA is negative for any monoclonal proteins. FLC shows less than normal lab, but abnormal labs. Skeletal survey shows diffuse osteopenia. PTHrp is 5.7. Breast exam and lymph node exam is normal. Patient has previously had TAH with BSO. What is the next step in the management. 




  • 1. CT chest and abdomen and pelvis to look for malignancies producing PTHrp. 
  • 2. BM biopsy for the concern of MM
  • 3. BM biopsy for the concern of BM lymphoma
BM biopsy shows 25 % plasma cells producing Kappa light chain. 
24 Hr urine protein is: 
LDH: 
B2-Microgluobulin:
S-Albumin: 3.1
Now that MM is diagnosed, how to treat. 

Case 2 - MM Relapse 
60 yo AAM is seen for AKI/CKD. 
Patient was diagnosed with MM in 01/2011. Kappa LC Myeloma, unknown stage

Baseline serum M-spike of 1.09 IgG kappa
Baseline urine M-spike unknown
Plasma cell marrow: 50%
Anemia: present
Renal failure: absent
FISH: Hyperdiploid
Bone disease: present

Baseline B2-Miroglobulin : 3 (10/2011), 2.4 (6/2011)

Baseline Albumin : 3.4



Prognosis factors: B2 Microglobulin (<3.5 mg/L, >5.5 mg/L) and Serum Albumin (> or < 3.5 g / dL)

How would you treat the patient. 

  • Depends on if patient is transplant eligible or not. The most commonly used criteria for eligibility are 
    • the patient’s preference, 
    • a biological age up to 65–70 years, 
    • the absence of substantial heart, lung, kidney, or liver dysfunction, or other uncontrolled comorbidities such as diabetes. 
Based on these features patient is eligible for BMT. How should the patient be treated. 

Patient was treated with VCD x 24 weeks : 
bortezomib, Cyclophosphamide, dexamethasone ("VCd")
Other regimens:
bortezomib, lenalidomide, dexamethasone ("VRd")
carfilzomib, lenalidomide, dexamethasone ("KRd")

PR was achieved. 
How is remission defined? 

Subsequently, patient underwent Autologous HSCT with Mel 200 in 11/1/11 -VGPR

BMT Eligible patients should receive myeloablative treatment with melphalan 200 mg/m2 after remission induction by standard first-line treatment. Hence, our patient received Mel 200 mg / m2. 

BMT Trans Date: 11/1/2011 
Conditioning: Melphalan 200 
Donor Info-BMT: M CMV Pos ABO Neg self: 

Now BMT is done, how should this patient be managed further

  • Maintenance therapy. 
  • Studies supporting maintenance therapy using Lenalidomide  
  • IFM 2005-02  (41 months vs 23 months of Progression free survival
  • CALGB 100104  (46 months versus 27 months of progression free survival)  
Hence, patient received Lenalidomide 15mg for maintenance. 


How long to give. 

The preliminary results of the FIRST trial showed a statistically significant improvement in progression-freesurvivalandoverallsurvivalwhenfirst- line lenalidomide plus dexamethasone treatment was given continuously until progression compared with a fixednumberofcycles. 


What else can be given for maintaince? Ans: Bortezomib

Dutch-German randomised trial, which compared bortezomib maintenance after bortezomib-based induction and thalidomide maintenance after induction with vincristine, doxorubicin, and dexamethasone. Bortezomib was given intravenously every 2 weeks for 2 years. Bortezomib maintenance was better tolerated than thalidomide. The main adverse events during maintenance were infections, polyneuropathy, and gastrointestinal symptoms. After a median follow-up of 41months,progression-freesurvivalwassignificantly prolonged in the bortezomib group (35 months vs 28 months, p=0·002) 

Ref: Lancet 2014

Patient was doing well until 2016, when in late 2016 patient had low back pain. Work up revolved the compression fracture of T11. Further evaluation revealed patient had relapse of MM. 






What to treat the patient with now?

Lancet 2014

 

Patient still remans transplant eligible. 

Since, time of previous transplant is > 12-18 months, Consider reinfection and autologus stem cell transplant. 

In addition, patient undergoes PET scan, and is seen to have

Newly increased uptake within a fractured left anterior fifth rib with maximum SUV of 3.4. Increased uptake is also seen with the known T12 compression deformity

How should this be managed. 
Radiation therapy. 

Case 3 - MM presenting with complications 

77 y/o Male is seen for Syncope. Work up reveals BUN/Cr of 96/2.72. UA shows Specific Gravity of 1.013 and Protein 3 +. Ur Pr/Cr > 10 gm. 24 hr urine shows protein of 20 gm (s-albumin was 2.5). SPEP, SIFA, FLC is done and a result is as below. No DM, HIV -ve. 

What is the next step in the work up for Nephrotic Syndrome?

Ans: Look for Monoclonal Protein. 

M-spike is present. FLC ratio is abnormal. This is consistent with M-protein being present. 

What is the likely diagnosis?

It is likely, MM causing Amylodiosis. (data below on incidence of M-protein in Amyloidiosis), 
  • SPEP: 50 % 
  • SPEP, S-IFA, FLC: 97 %
  • SPEP, S-IFA, FLC, 24 hr UPEP with U-IFA: 99 % 
But, once M-spike is present, we need a tissue diagnosis to confirm the Amyloidiosis. Hence, Renal biopsy is performed and shows the following. 


Biopsy, confirms Amyliodiosis. What are the types of Amyloidiosis?
Ans: 3 Types
  • AL
  • TTR
  • Wild Type or Age-related
What are the clinical manifestation of Amyloidiosis?

It is the great imitator. See above. 

What other work up will be needed? ECHO and EKG. What do you expect to see on ECHO and EKG. 

ECHO of the heart is normal. 
EKG is as shown below with relatively low voltage in limb leads. 
 

What is the other test that helps in looking for Caridac AL?
BNP. It was 17 in out patient.

Cardiac AL amyloid deposition is accompanied by marked elevation of the biomarkers BNP and cardiac troponin, even at an early stage. Involvement of the heart is the commonest cause of death in AL amyloidosis and is a major determinant of progno- sis; without cardiac involvement, patients with AL amyloidosis have a median survival of around 4 years,26 but the progno- sis among affected patients with markedly elevated BNP and cardiac troponin (Mayo stage III disease)27 is on the order of 8 months. 

Once we have confirmed the AL-Type Amyliodiosis, what is the next step?
Ans: Confirm the nature of Amyloid. There are > 20 types in total, but 3 major subtypes in Cardiology literature. 

Next, could this patient have Amyloidiosis due to MM?

CRAB
Hypercalcemia is not seen
Renal Failure is present
Hgb is 10.5 with MCV of 88 
Bone surgery is negative for MM kind of lessons. 

Next step. 
BM biopsy. Results are as below. 

What are the 3 ways to diagnose MM? Does this patient have MM? 
  • Diagnosis: 3 ways to diagnose MM if End-Organ Damage is present Lancet 2014
    • 1. M Protein (any level) with ≥  10% BM Plasma Cells 
    • 2. M protein more than or equal to 3 g/100 mL even if less than 10% BM Plasma Cells 
    • 3. Non-secretary MM:  if greater than 30% BM Plasma Cells or detection of Plasmacytoma on BM biopsy  
      • CRAB Criteria)
        • Hypercalcemia (28%) (>10.5 mg / dL)
        • Renal Failure (48%) (S-Cr: > 2 mg/dL)
        • Anemia (73%) (<10g/dL or 2 g/dL below baseline) Leukopenia (20%) Thrombocytopenia (5%)
        • Bony Lytic Lesions (58% of newly diagnosed pt): Bone Pain, Back Pain, Spinal Cord Compression, Vertebral Body Compression Fractures
        • Hyper-viscosity / Recurrent Bacterial Infections / AL
Yes, based on the criteria of Presence of M protein and > 10 % plasma cell this patient does have MM. 

How do you prognosticate a patient with MM? 
  • Prognosis: B2 Microglobulin (<3.5 mg/L, >5.5 mg/L) and Serum Albumin (> or < 3.5 g / dL)

Prognosis in myeloma depends on several variables: 
  • host factors (age, performance status, co-morbidities), 
  • stage, 
  • response to therapy, and 
  • disease biology. Disease biology is dictated by the underlying cytogenetic abnormalities in the myeloma clone. It is a major predictor of outcome and also influences the choice of therapy. Thus, all myeloma patients are risk-stratified at initial diagnosis based on FISH studies on the bone marrow. If FISH is unavailable, conventional cytogenetics can be used as an alternative but is much less sensitive.
  • Ref: Uptodate 
How is the risk stratification done after reviewing the above?
  • High risk
  • Intermediate risk
  • Low risk 
How is MM treated? 
 
Multiple myeloma Lancet 2014

When compared with chemotherapy alone, intensified chemotherapy followed by HCT appears to prolong both event-free and overall survival in previously untreated patients with standard risk myeloma. Hence, SCT would be offered. 

But, 
What decides the Transplant eligibility? Does this patient qualify? 

In most centers in the United States, patients with one or more of the following factors are not considered eligible for autologous HCT in myeloma:

●Age >77 years

●Direct bilirubin >2.0 mg/dL (34.2 µmol/liter)

●Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain

●New York Heart Association functional status Class III or IV


Ref: Uptodate


Our patient does not meet these criteria except for Age. Hence, our patient is not a Transplant eligible in most centers of US. Our patient is a candidate for chemotherapy alone. 
For most patient, Lenalidomide and dexamethasone is the preferred regimen. 
see algorithm.



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