Multiple Myeloma
 

NCCN Guidelines for Multiple Myeloma


WHO criteria for the diagnosis of multiple myeloma


Major criteria (3)

  1. 1. Bone marrow plasmacytosis >30 percent

  2. 2. Plasmacytoma on biopsy

  3. 3. Presence of a monoclonal protein (M-component) in serum or urine


  1. • Serum IgG >3.5 g/dL, or


  1. • Serum IgA >2 g/dL, or


  1. • Urine Bence-Jones protein >1g/24 hours



Minor criteria (4)

  1. 1.Bone marrow plasmacytosis of 10 to 30 percent

  2. 2.Monoclonal protein present but less than the above concentrations

  3. 3.Presence of lytic bone lesions

  4. 4.Reduced normal immunoglobulins to <50 percent of normal


  1. •IgG <600 mg/dL, or


  1. •IgA <100 mg/dL, or


  1. •IgM <50 mg/dL


Diagnostic requirements

The diagnosis of multiple myeloma requires a minimum of one major criterion and one minor criterion, or three minor criteria which must include bone marrow plasmacytosis of 10-30 percent and the presence of a monoclonal protein. These criteria must be manifest in a symptomatic patient with progressive disease.


Adapted from Grogan, TM, et al. Plasma cell neoplasms. In: Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW, editors. World Health Organization Classification of Tumours.


Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001, p. 142. Permission granted from Harris, NL and Vardiman, JW.


Diagnostic criteria for multiple myeloma and Related Disorders


Multiple Myeloma (all 3 criteria must be met)


  1. 1.Presence of a serum or urinary monoclonal protein

  2. 2.Presence of clonal plasma cells in the bone marrow or a plasmacytoma

  3. 3.Presence of end organ damage felt related to the plasma cell dyscrasia, such as:


  1. •Increased calcium concentration

  2. •Lytic bone lesions

  3. •Anemia, or

  4. •Renal failure


Asymptomatic (smoldering) multiple myeloma (SMM, both criteria must be met)


  1. 1. Serum monoclonal protein >3 g/dL and/or bone marrow plasma cells >10 percent

  2. 2. No end organ damage related to plasma cell dyscrasia (see list above)


  1. BulletMonoclonal gammopathy of undetermined significance (MGUS, all 3 criteria must be met)

  2. 1. Serum monoclonal protein <3 g/dL

  3. 2. Bone marrow plasma cells <10 percent

  4. 3. No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative        disorder (see list above)


Adapted from Br J Haematol 2003;121:749 and Rajkumar, SV et al. Leukemia 2001;15:1274.


MGUS Risk of Progression

Patients with an abnormal serum FLC ratio, non–immunoglobulin G (non-IgG) MGUS, and a high serum M protein level ( 15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with one risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk).

Blood, 1 August 2005, Vol. 106, No. 3, pp. 812-817


The International staging system (ISS)


An International Staging System (ISS), based on 10,750 previously untreated patients with myeloma from over 17 institutions worldwide has been developed. It is based on the levels of serum beta-2 microglobulin (B2M) and serum albumin alone [10]:

        Stage I — B2M <3.5 mg/L and serum albumin 3.5 g/dL

        Stage II — neither stage I nor stage III

        Stage III — B2M 5.5 mg/L

The ISS does not distinguish MGUS and SMM from multiple myeloma, and therefore has no known value in MGUS or SMM. Unlike the Durie-Salmon staging system, the ISS is not a reliable indicator of tumor burden. However, the lSS is of prognostic value; median survivals for patients with ISS Stages I, II, and III are 62, 44, and 29 months, respectively, see below.



Stage Criteria             Median Overall Survival

I Serum Beta 2-microglobulin < 3.5 mg/L62 months

AND

Serum albumin > 3.5 g/dL

II Neither stage I or stage III         44 months

III Serum Beta2-microglobulin > 5.5 mg/L         29 months


Median Overall Survival     Median Overall Survival

Stage Age < 65 years             Age > 65 years

I    69 months                               47 months

II  50 months                               37 months

III 33 months                                       24 months


Median Overall Survival     Median Overall Survival

High-Dose Chemotherapy            Conventional-Dose

Stage                        Chemotherapy

I   111 months                                     55 months

II   66 months                             40 months

III 45 months                            25 months




Risk Group Cytogenetics

Poor                                                                Median Overall Survival

t(4;14)                                       24.7 months

t(14;16)

–17p13

Intermediate –13q14                                42.3 months

Good All others and                      50.5 months

Hyperodiploidy t(11;14), t(6;14)


Regimen Dosing and Schedule for Non Transplant Candidates                   References in 2006 ASH Ed


MDT Induction: Melphalan 8 mg/m2 orally on days 1-4 +         30

Dexamethasone 12 mg/m2 orally on days 1-4 and 17-20 +

Thalidomide 300 mg orally on days 1-4 and 17-20;

Given on an every 5 week schedule for 3 cycles

Maintenance: Melphalan 8 mg/m2 orally on days 1-4 +

Dexamethasone 12 mg/m2 orally on days 1-4 +

Thalidomide 300 mg orally on days 1-4;

Given every 5 weeks for 9 cycles


MPT Italian Multiple Myeloma Network Phase II Study 29

Induction: Melphalan 4 mg/m2 orally on days 1-7 +

Prednisone 40 mg/m2 orally on days 1-7 +

Thalidomide 100 mg orally each day;

Given on a monthly schedule for 6 months

Maintenance: Thalidomide 100 mg orally each day until progression

Supportive care: At physician’s discretion


Italian Multiple Myeloma Network Phase III Study           31

Induction: Same as in phase II study above

Maintenance: Same as in phase II study above

Supportive care: Enoxaparin 40 mg subcutaneously each day

during the first four cycles; Other agents at physician’s discretion


Intergroupe Francophone du Myélome Phase III Study 32

Induction: 12 courses of standard MP at 6-week intervals with

thalidomide at up to 400 mg daily

Maintenance: None; thalidomide was stopped

at the end of therapy with MP

Supportive care: At physician’s discretion

R-MP Induction: Melphalan 0.18 or 0.25 mg/kg orally on days 1-4 +  36

Prednisone 2 mg/kg orally on days 1-4 +

Lenalidomide 5 or 10 mg orally for 21 days;

Given on an every 4-6 week schedule

Supportive care: Ciprofloxacin and aspirin


VMP Induction: Melphalan 9 mg/m2 orally on days 1-4 + 43

Prednisone 60 mg/m2 orally on days 1-4 +

Bortezomib 1.0 or 1.3 mg/m2 intravenously

days 1, 4, 8, 11, 22, 25, 29, and 32;

Given on an every 6 week schedule for four cycles

Maintenance: Melphalan 9 mg/m2 orally on days 1-4 +

Prednisone 60 mg/m2 orally on days 1-4 +

Bortezomib 1.0 or 1.3 mg/m2 intravenously days 1, 8, 15, and 22;

Given on an every 5 week schedule for five cycles

Supportive care: Intravenous bisphosphonates every 4 weeks;

other measures at physician’s discretion



Supportive care: Warfarin 1.25 mg orally each day +

vitamin B6 + ciprofloxacin 250 mg orally twice daily +

intravenous zoledronate + erythropoietic and

hypoglycemic agents as needed


Regimen dosing and schedule for Transplant Candidates


  2. VTD  Bortezomib, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration, Thalidomide 200 mg/d through d 1 to 63. Three 21 days cycles.

  3.          http://www.ncbi.nlm.nih.gov/pubmed?term=21146205


  5. vtD   Bortezomib (1 mg/m2 days 1,4,8, and 11), low dose thalidomide (100 mg daily), and dexamethasone (40 mg days 1 to 4 in all cycles and days 9 to 12 in cycles 1 and 2) 

  6.         http://www.ncbi.nlm.nih.gov/pubmed?term=21849487


  8. VRD  Bortezomib 1.3 mg/m2 once a week, lenalidomide 25 mg days 1 to 14, and dexamethasone 40 mg once a week. Treatments are repeated every three weeks as tolerated.

  9.          http://www.ncbi.nlm.nih.gov/pubmed?term=21181954


  11. VD    Bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration for the first 2 of the 4 Induction Cycles, the second two cycles Decadron is given only the days of Velcade administration.


  13.        

  14.         Recent Review of chemotherapy regimens for myeloma patients who are ransplant candidates. IMWG MM PreBMT Blood 2011 Cavo.pdf



Response Criteria


  1.         Stringent complete response (sCR): In addition to CR criteria (defined below), these patients have a normal free light chain ratio and have no clonal cells by bone marrow immunohistochemistry or immunofluorescence. Clonal cells detected in the bone marrow by immunohistochemistry or immunofluorescence are considered abnormal if there is a kappa/lambda ratio of >4:1 or <1:2 after examination of a minimum of 100 cells.


  3.          Complete response (CR): Absence of monoclonal protein in serum and urine by immunofixation with no current evidence of soft tissue plasmacytoma. Bone marrow aspirate and biopsy with less than five percent plasma cells.

  4.          Very good partial response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or at least a 90 percent reduction in serum M-protein with a urine M-protein <100 mg/24 hours.


  6.          Partial response (PR): ≥ 50 percent reduction in serum M-protein and reduction of 24 hour urinary M-protein by 90 percent or to <200 mg/24 hr. In nonsecretory myeloma, FLC levels can be used to determine a PR; a 50 percent decrease in the difference between kappa and lambda FLC levels denotes a PR. If the FLC levels were unmeasurable at baseline, a 50 percent reduction in bone marrow plasma cells is acceptable as long as the original bone marrow contained at least 30 percent plasma cells. All PR require a 50 percent reduction in size of any soft tissue plasmacytomas.


  8.          Stable disease (SD): does not meet criteria for CR, VGPR, PR, or PD


  1.          Progressive disease (PD): 25 percent increase from lowest response value in any of the following: serum M-protein (absolute increase ≥ 0.5 g/dl), urine M-protein (absolute increase of ≥ 200 mg/24hr), bone marrow plasma cell percentage (at least 10 percent difference), or difference in the kappa and lambda FLC (absolute increase must be >10 mg/dl). The FLC criteria should only be used for patients with nonsecretory myeloma or unmeasurable M protein in the serum and urine. PD is also diagnosed when there is an increase in the size or development of new bone lesions or soft tissue plasmacytomas or the development of a serum calcium >11.5 mg/dl without other cause.


Durie, BG, Harousseau, JL, Miguel, JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20:1467.