EVALUATION OF RESPONSE TO THERAPY

 

EBMT (BLADE') CRITERIA (old)

Progressive Disease (PD)
   M increased of > 25% or
   PCs in BM increased of 25% or
   New/increased bone lesions at x-rays

Stable Disease (SD)
  
No MR and no PD

Minimal response (MR)
  
M reduced of ≥ 25%

Partial response (PR)
  
M reduced of ≥ 50%

Complete Response (CR)
  M reduced to 0% and
  IFE/UIFE negative and
  < 5% PCs in BM

 

The European Group for Blood and Marrow Transplantation (EBMT), published by Blade' et al in 1998, considered relapse the conversion from negative IFE to positive IFE, despite the fact that this conversion may not represent a symptomatic relapse requiring treatment. Therefore, with this definition of CR, TTP in patients with CR may paradoxically be shorter than that in patients with PR.

 

 

INTERNATIONAL UNIFORM RESPONSE CRITERIA (2006)

 

Progressive Disease (PD)
 
M increased of ≥ 25% or
  PCs in BM increased of 25% or
  New/increased bone lesions at x-rays or
  New/increased soft tissue plasmacytomas or
  Development of hypercalcemia

Partial response (PR)
 
Serum M reduced of ≥ 50% and
  Urine M reduced of ≥ 90% or <200 mg/24h

Very Good Partial Response (VGPR)
 
Serum M reduced of ≥ 90% and
  Urine M <100 mg/24h 

Complete Response (CR)
 
IFE/UIFE negative and
  ≤ 5% PCs in BM

Stringent Complete Response (sCR)
 
CR and
  Normal free light chain ratio and
  Absent clonal cells in BM by IHC/immunofluorescence

 

International uniform response criteria for multiple myeloma.
Leukemia. 2006 Sep;20(9):1467-73.
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadoro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group.
These International uniform response criteria added 2 categories of response, i.e., "stringent complete response" and "very good partial response".

 

 


 

ASSESSMENT OF DISEASE STATUS

 

 - REFRACTORY MYELOMA = Disease that is unresponsive while on therapy, or
                        Disease that progresses within 60 days of last therapy.

       - "Primary refractory myeloma" =
                        Disease that does not demonstrate a minimal response or better with therapy.

       - "Relapsed and refractory myeloma" =
                        Disease unresponsive while on salvage therapy, or
                        Disease that progresses within 60 days of last therapy.

 - RELAPSED MYELOMA   = Disease previously treated and in progression.

 

Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.
Blood. 2011 May 5;117(18):4691-5.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J; International Myeloma Workshop Consensus Panel 1.

 

 

Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation.
Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant.
Br J Haematol. 1998 Sep;102(5):1115-23.
Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D.

Minimal residual disease monitoring in multiple myeloma.
Best Pract Res Clin Haematol. 2002 Mar;15(1):197-222.
Davies FE, Rawstron AC, Owen RG, Morgan GJ.
[Review]

Bone marrow trephine combined with immunohistochemistry is superior to bone marrow aspirate in follow-up of myeloma patients.
J Clin Pathol. 2008 Feb;61(2):213-6.
Joshi R, Horncastle D, Elderfield K, Lampert I, Rahemtulla A, Naresh KN.
This is a study of 106 bone marrow samples, comparing conventional 500-cell differential count in the bone marrow aspirate vs the IHC of the bone marrow biopsy. The mean plasma cell number was 13% in the bone marrow aspirate and 32% in the bone marrow biopsy with IHC. While the positive predictive value was 100% with both tests, the negative predictive value was higher with the biopsy + IHC than the aspirate (57% vs 22%).

Eliminating the complete response penalty from myeloma response criteria.
Blood. 2008 Jun 15;111(12):5759-60.
Rajkumar SV, Durie BG.

Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients' monitoring after transplantation.
Bone Marrow Transplant. 2013 Mar;48(3):419-24.
Zamarin D, Giralt S, Landau H, Lendvai N, Lesokhin A, Chung D, Koehne G, Chimento D, Devlin SM, Riedel E, Bhutani M, Babu D, Hassoun H.
After a retrospective study of 368 autologous stem cell transplant for myeloma done at MSKCC between 2001 and 2009, the authors found the first sign of relapse or progression after transplant is an increase of the myeloma markers in the serum in asymptomatic patients (85% of cases). Only 15% of patients had an aggressive disease that became clinically manifested by symptoms. Annual skeletal surveys were not useful in predicting disease relapse/progression.

 

 


 

EFFICACY MEASURES

 - Overall survival (OS)
 - Progression-free survival (PFS)
           = Duration from start of therapy to progression or death (from any cause)
 - Time to progression (TTP)
           = Duration from start of therapy to progression,
             but deaths due to causes other than disease progression are censored.
 - Event-free survival (EFS)
           = Duration from start of therapy to event.
             If event is defined as progression, EFS = PFS.
             An event can be defined as progression, death, or toxicity.
 - Disease-free survival (DFS)
           = Duration from start of CR to the time of relapse.
 - Duration of response (DOR)
           = Duration from start of response (PR or CR) to the time of progression.
             Deaths due to causes other than disease progression are censored.

 

 


 

SERUM FREE LIGHT CHAINS

Due to the short serum half life of free light chains (approximately 3-4 hours), the FLC assay can provide a rapid indication of the response to treatment.

Serum free light chains for monitoring multiple myeloma.
Br J Haematol. 2004 Aug;126(3):348-54.
Mead GP, Carr-Smith HD, Drayson MT, Morgan GJ, Child JA, Bradwell AR.

The tumor kinetics of multiple myeloma following autologous stem cell transplantation as assessed by measuring serum-free light chains.
Leuk Lymphoma. 2006 Jan;47(1):21-8.
Pratt G, Mead GP, Godfrey KR, Hu Y, Evans ND, Chappell MJ, Lovell R, Bradwell AR.

Monitoring serum free light chains in patients with multiple myeloma who achieved negative immunofixation after allogeneic stem cell transplantation.
Haematologica. 2007 Feb;92(2):275-6.
Mösbauer U, Ayuk F, Schieder H, Lioznov M, Zander AR, Kröger N.
In 26 myeloma patients treated with allogeneic stem cell transplant, serum free light chains anticipated the achievement of remission (they decreased at a median of 128 days before IFE became negative), and they anticipated disease relapse (a 25% increase of FLC was observed at a median of 98 days before IFE became positive).

Abnormal serum free light chain ratio in patients with multiple myeloma in complete remission has strong association with the presence of oligoclonal bands: implications for stringent complete remission definition.
Blood. 2009 Dec 3;114(24):4954-6.
de Larrea CF, Cibeira MT, Elena M, Arostegui JI, Rosiñol L, Rovira M, Filella X, Yagüe J, Bladé J.
Despite the status of CR in 34 myeloma patients after stem cell transplantation, the FLC ratio was abnormal in 14 of them (41%). This was related to the presence of oligoclonal bands, which are commonly seen after SCT, and usually indicate a good outcome. These results have important implications for the definition of "stringent" CR, which includes normalization of the FLC ratio.

 

In "light-chain escape", myeloma progresses with increase of the light chains only, without a concomitant increase of the original entire monoclonal immunoglobulin.

 

 

PCR

PCR for CDR3 is occasionally used for determining the presence of minimal residual disease after therapy. CDR3 is the Complementary Determining Region 3, which consists of the V-N-D-N-J region. The sequence and length of N varies in each clone, because N is inserted by the enzyme terminal deoxynucleotidyltransferase during the VDJ rearrangement.
The median length of the CDR3 region is about 15 amino acids.

Although PCR can be more sensitive and specific than flow cytometry for the detection of minimal residual disease, it is more expensive, more time consuming, and less readily available. When compared with flow cytometry, the feasibility of PRC for assessing minimal residual disease is limited by:
  - Need for a baseline sample
  - Inability to obtain adequate primers in many patients

Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects.
Leukemia. 2003 Jun;17(6):1013-34.
van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ.
[Review]

Levels of minimal residual disease detected by quantitative molecular monitoring herald relapse in patients with multiple myeloma.
Haematologica. 2004 May;89(5):557-66.
Fenk R, Ak M, Kobbe G, Steidl U, Arnold C, Korthals M, Hünerlitürkoglu A, Rohr UP, Kliszewski S, Bernhardt A, Haas R, Kronenwett R.
This study evaluates the use of PCR for IgH to detect minimal residual disease after stem cell transplantation in 11 patients with multiple myeloma. Monitoring of quantitative PRC was predictive of disease remission and relapse.

Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response.
Br J Haematol. 2008 Sep;142(5):766-74.
Martínez-Sánchez P, Montejano L, Sarasquete ME, García-Sanz R, Fernández-Redondo E, Ayala R, Montalbán MA, Martínez R, García Laraña J, Alegre A, Hernández B, Lahuerta JJ, Martínez-López J.
Fluorescent PCR (F-PCR) of DHJ and light chain rearrangements was used for the detection of minimal residual disease after stem cell transplantation in 53 patients with multiple myeloma. The results of F-PCR were similar to those of flow cytometry. Molecular response by PCR had prognostic value. PCR could identify a subset of patients with better prognosis, even amongst patients in CR by IFE.

 

 

OTHER

Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma.
Blood. 2014 May 15;123(20):3073-9.
Martinez-Lopez J, Lahuerta JJ, Pepin F, González M, Barrio S, Ayala R, Puig N, Montalban MA, Paiva B, Weng L, Jiménez C, Sopena M, Moorhead M, Cedena T, Rapado I, Mateos MV, Rosiñol L, Oriol A, Blanchard MJ, Martínez R, Bladé J, San Miguel J, Faham M, García-Sanz R.

 

 

BONE MARROW BIOPSY

FLOW CYTOMETRY - See specific section.

The importance of bone marrow examination in determining complete response to therapy in patients with multiple myeloma.
Blood. 2009 Sep 24;114(13):2617-8.
Chee CE, Kumar S, Larson DR, Kyle RA, Dispenzieri A, Gertz MA, Colby CL, Rajkumar SV.
This study evaluated the role of bone marrow biopsy in 92 myeloma patients in good remission after therapy, i.e., with negative immunofixation in both serum and urine. Bone marrow was found to contain residual disease (defined as presence of 5% or more plasma cells) in 14% of cases. Even after including a normal serum free light chain ratio to negative IFE and UIFE, the BM biopsy retained its importance, as it was positive in 10% of cases. Therefore, the bone marrow biopsy should not be eliminated from the criteria used to define complete remission in MM. Bone marrow involvement with 5% or more plasma cells was found to have a prognostic impact for overall survival.

 

 


Giampaolo Talamo, M.D.