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Dept of Orthopedics
Med College, Calicut

 

 

 

 

 

 

ORIGINAL ARTICLE

Study Of Factors Predicting Therapeutic                   Response In Multiple Myeloma

 Binu sasidharan 1, Prem Kotian 2, Jagannath Kamath B 3, Deepak Jayaram 4,  Krishnaprasad 5, Vandana Vamadevan 6, Muralikrishnan, Kannampillil 7, Vijay Tubaki 8, Vishal Mangrolia 9,  Anup Kumar 10

1. Senior Resident, Dept. of Orthopaedics, 
2. Professor, Dept. of Orthopaedics, 
3. Professor,Dept. of Orthopaedics, 
4. Specialist Registrar, General internal
    medicine, Lancaster Royal Infirmary, Lancaster,United Kingdom.
5. Associate professor, Dept of Medical Oncology,
6. Junior resident, Dept of Otorhinolaryngology
 and head and neck surgery,
7. Final MBBS Student
8.  Consultant Orthopaedic Surgeon, Unity Hospital, Mangalore.
9.  Consultant orthopaedic surgeon, G T Sheth  orthopaedic hospital, Rajkot, Gujarat.
10. Assistant professor, Dept. of orthopaedics, Kasturba Medical College, Mangalore.

Address for Correspondence:  

Binu sasidharan,
Kottarathil, No.37, Maithrinagar, 
Kottarakkara, Kollam, Kerala. 
Email: binunirmal2000@yahoo.com
Tele: 09845800912

J.Orthopaedics 2008;5(1)e19

 
Introduction:

Ever since William McIntyre 1 gave the first description of multiple myeloma(MM) in 1850,this disease has been an area of constant research because of the plethora of symptoms by which the disease can present, lack of effective treatment and poor prognosis.Multiple myeloma which accounts for 1% of all malignancies represents an unrestrained proliferation of a single clone of plasma cells leading to increased production of immunoglobins which are structurely abnormal and functionally incompetent. Last four decades has seen great progress in understanding the diagnosis and treatment of this deadly condition.A major breakthrough happened in 1958 when Blokhin of Russia reported the successful use of a racemic mixture of D and L phenylalanine mustards (Melphalan) in the management of myeloma 1.  

The most widely used staging system in multiple myeloma is the Durie Salmon staging 2which was introduced in 1975.In 2003, Griepp et al proposed a new staging system named as International Staging System(ISS) 3,4 which is a simpler one.In our study we used this new staging system and analyzed the significance of various  parameters in predicing therapeutic response in myeloma.

Material and Methods :

This is a prospective study that includes 35 newly daignosed cases of symptomatic myeloma  treated in our institution  between January 2005 and April 2007. Permissionto conduct the study was taken from local ethical committee.We used the diagnostic criteria proposed by International myeloma working group 2003 4,5(Table 1).

Patients who were not willing (financial constraints) or not eligible(age, medical contraindications) to receive high dose chemotherapy and autologous stem cell transplantation (SCT) were included. Patients with non secretory myeloma, monoclonal gammopathy of unknown significance, smouldering myeloma and those patients who were willing/eligible to undergo autologous SCT and those with a serum creatinine >3 mg/L after adequate hydration were excluded from the study .Patients with associated hepatic, cardiac or pulmonary disease and the immunocompromised were also excluded.  

           Table 1  
==================================================

 Diagnostic criteria for symptomatic multiple myeloma (International Myeloma Working Group,2003)  

 *M paraprotein in serum and/or urine.

**Bone marrow (clonal) plasma cells or plasmacytoma.

 Related organ or tissue impairment (ROTI)(end organ damage) which is       manifested by  

 a) Increased calcium levels

 b) Renal insufficiency

 c) Anemia

 d) Bone lesions

 e) Others: symptomatic hyperviscosity,amylodosis and recurrent bacterial  infections  

*No specific level of serum or urine M protein is included in this diagnostic criteria.   

**Similarly no minimal level of bone marrow plasma cells was designated.

==================================================

Prospective evaluation included collection of demographic, clinical, laboratory,radiographic, treatment and follow up data.Various clinical presentations were noticed and recorded.  Investigations included routine blood examination, platelet count, peripheral smear, C reactive protein (CRP), lactate dehydrogenase (LDH), serum albumin, globulin, urea, creatinine, serum calcium, serum β2 microglobulin, uric acid, Bence Jones Proteins (BJP), serum and urine electrophoresis and bone marrow aspiration.              

Electrophoresis of serum and concentrated urine was performed in all cases.We used agarose gel electrophoresis to screen for the presence of M proteins.Quantification of M component was performed by densitometry of the monoclonal peak on electrophoresis.Immunofixation was performed when multiple myeloma or related disorders were suspected despite a normal serum electrophoretic pattern 6.It was also used to confirm a complete response following chemotherapy.              

Radiological evaluation included radiographs of the specific areas where the patient complained of bone pain, swellings or pathological fractures.When multiple myeloma was suspected  skeletal imaging survey was done.Computerized tomography and magnetic resonance imaging were done in selected cases.   

All the 35 patients in this study were categorized into three stages based on International Staging System(ISS) 3 and British Medical Research Council (BMRC) staging 7.Durie Salmon staging requires M component production rates to categorize the patients 2.This staging was not done because of incomplete data.  

The new ISS put forward by Greipp et al in 2003 is based on two easily measurable parameters, serum albumin and β2 microglobulin (β2 M) (Table 2).

Table 2       International Staging System (Greipp et al, 2003)

Stage

Findings

        Prognosis

   I

β2 M < 3.5

Albumin ≥ 3.5

         Good

  II

Neither stage I nor stage III

β2 M < 3.5 or  β2 M-3.5 to 5.5

Albumin ≥ 3.5

     Intermediate

  III

β2 M ≥ 5.5

 

          Poor

Patients with impaired renal function carries a bad prognosis irrespective of the stage.

The BMRC staging is based on haemoglobin, blood urea and the level of activity which is determined by Karnofskys performance status scale (Table 3).                   

Table 3   British Medical Research Council Staging

Stage

                    Findings

Prognosis

A

Hb >10 gm%

Blood urea <22mg%(8 mmol/L)

Minimal symptoms (karnofsky 100)

Good

B

Neither A nor C

Intermediate

C

Hb < 7.5 gm%

Blood urea > 28mg%

Restricted activity (karnofsky < 70)

Poor

 

Treatment :

General supportive measures undertaken included correction of anemia and metabolic abnormalities ,maintanance of renal function and adequate hydration, appropriate antibiotics to treat infections and paracetamol and weak opioids like codeine for pain relief.Allopurinol was given in 12 cases where serum uric acid levels were elevated.Bisphosphonate therapy was administered in all cases.Zoledronic acid 4 mg i.v was given monthly for minimum 12 months or death whichever is earlier.Creatinine levels were checked before each zoledronic acid infusion.Pamidronate was used at a slower infusion rate in two patients with borderline renal function. Appropriate spinal braces were used for stable compression fractures.  

 Twentyfive patients were treated with chemotherapy alone, five patients with surgery ,chemotherapy and radiotherapy and five patients with chemotherapy and radiotherapy.Chemotherapy consisted of oral melphalan (8 mg/m2 ) on days 1-4 and     oral  prednisolone (60 mg/m2 ) on days 1-4.The cycles were repeated every 28 days.We usually give 12 cycles or until intolerance or disease progression was observed.

 Respose assessment  

We assessed the therapeutic response before starting the fourth cycle of chemotherapy using EBMT  response criteria 4 which is given below:  

      * EBMT-European group for blood and marrow transplantation

      IBMTR-International bone marrow transplant registry

      ABMTR-Autologous blood and marrow transplant registry  

         Types of responses:  

  1. Complete response (CR)--No M protein is detected in serum or urine by    immunofixation for a minimum of 6 weeks and less than 5% plasma cells in   bone marrow.  
  2. Partial response--more than 50% reduction in serum M protein and/or         90% reduction in urine free light chain excretion.  
  3. Minimal response—25-49% reduction in serum M protein level and/or         50-89%   reduction in urine free light chain excretion.  
  4. Plateau—No evidence of continuing myeloma related organ or tissue damage, less than 25% change in M protein levels and light chain excretion for 3 months.  
  5. Progresive disease—Myeloma related organ or tissue damage continuing despite therapy.  
  6. Relapse—Reappearance of disease in patients previously in CR.  

Responders and nonresponders were statistically analysed to assess the significance of various parameters in predicting response to therapy.The factors that were analyzed included age, gender, haemoglobin level, ESR, platelet count, blood urea,  serum creatinine, serum albumin, calcium, b2 microglobin, LDH, CRP, Bence Jones proteins and percentage of bone marrow plasma cells .Statistical  analysis was done using version 14 of SPSS data editor software.Different categories of each parameter were compared using p-value and the level of significance was set at p < 0.05.

Results :

The patients included 18 males and 17 females with a mean age of 58.8 years at the time of presentation.There were 2 cases with age less than 40 years.  

Clinical spectrum  

The various clinical presentations in our study are depicted in the bar chart (Fig 1).    Bone pain was the commonest presenting symptom in our study( 83%).The commonest site of bone pain was over spine(60%) followed by pelvis and ribs.Pathological fractures were present in 21 patients.Out of this 21 patients ,vertebral compression fractures were present in 18 ,fracture shaft of humerus in 1 patient,fracture shaft of femur in 1 and intertrochanteric fracture in 1 patient.Of the 7 patients presented with infections, 3 had pnuemonia, 2 had urinary tract infection, one  had cellulitis, and one had maxillary sinusitis.Two patients presented with paraparesis and one patient presented with sensory deficits. One patient presented with generalized tonic clonic seizures which on work up turned out to be multiple myeloma. CT images of this patient are shown in fig 2. Of special interest  is a patient who presented with sensory deficits in both lowerlimbs, hyperpigmentation of tongue and skin and bone pains.On furthur evaluation, prostatomegaly and diabetes mellitus were detected and POEMS syndrome8 was diagnosed.

Fig 1

Fig 2

Investigations

 The results of various investigations are listed below:

          77% of patients were anaemic at presentation.Anaemia was normocytic normochromic variety in majority of cases.One interesting observation was that the number of patients who were hypocalcemic outnumbered those who were hypercalcemic.Elevated alkaline phosphatase seen in 4 patients may be attributed to pathological fractures.    

              Radiological evaluation revealed that 4 patients had solitary plasmacytomas,29 had multiple osteolytic lesions,1 had osteosclerotic lesion and 1 had osteoporosis only.The osteosclerotic lesion of the vertebra was seen in the patient  with POEMS syndrome.  

Staging  

When ISS was applied, 17 patients come under stage І,  12  patients in stage ІІ  and 6 in stage ІІІ.This implies good prognosis in 17 patients, intermediate  prognosis in 12 and poor prognosis in 6. When BMRC staging was applied, 5 patients come under stage A, 22 patients in stage B and 8 in stage C.  

         Treatment  

None of the patients developed serious complications following chemotherapy. Eight patients on melphalan developed alopecia, three developed diarrhea and gastro intestinal upsets, two had febrile reaction and one had hyperpigmentation of skin. Haematological toxicity was limited to grades 1 and 2.  

Surgery: One patient had fracture shaft of femur, one had intertrochanteric fracture and one had fracture shaft of humerus.Open reduction and internal fixation was done in these 3 cases.The patient operated for intertrochanteric fracture developed addisonian crisis following surgery,but survived. Two patients had motor weakness from spinal cord compression ( one by plasmacytoma and other one by pathological compression fracture ) and they were treated by spinal decompression followed by radiotherapy and chemotherapy. Radiographs of a case where internal fixation was done for pathological  fracture is shown in fig.3.

Radiotherapy: Radiotherapy was given post operatively in 5 cases and in 5 cases of solitary plasmacytomas.In all these cases chemotherapy was started prior to radiotherapy.

Response assessment

According to CLMTF criteria9 there are three types of responses—objective response, partial response and treatment failure.Here complete remission was considered as a subset of objective response.We considered complete response and partial response in EBMT criteria as an objective response.Plateau phase and progressive disease are grouped as treatment failure. Response assessment using EBMT criteria showed that 3 patients had complete response,15  had partial response, 9 had minimal response, 5 were in plateau phase and one had progressive disease.(Two patients defaulted after two cycles of chemotherapy).Altogether there are 18 objective responses,9 minimal responses and 6 treatment failure.This shows remarkable correlation with ISS.( stage I-17,stage II-12 and stage III-6). BMRC staging doesnot show such correlation.  

Of the five patients who expired during the course of our study,three were defaulters during various stages of chemotherapy and two were getting chemotherapy at the time of death. Two patients were lost on follow up after six cycles of chemotherapy.

     Fig.3a                                        Fig.3b

Analysis of p values showed that serum albumin (p=0.001), β2 microglobin (p=0.001), LDH (p=0.001), CRP(p=0.001), urea (p=0.002), creatitine (p=0.001), platelet count (p=0.014) and bonemarrow plasma cells (p=0.014) are statistically significant parameters.

Discussion:

Lack of a uniform criteria for diagnosis and response assessment posed problems in interpreting results of various myeloma study groups. A wide range of diagnostic criteria have been used by various investigators like Medical Research Council (MRC) of the United Kingdom, Nordic Myeloma Study Group,Chronic Leukemia-Myeloma Task Force (CLMTF) of the National Cancer Institute, Eastern Cooperative Oncology Group (ECOG) and  South West Oncology Group ( SWOG) .In 2003 the International myeloma working group has proposed a uniform diagnostic criteria which helps to standardize the results of various study groups.  

Several criteria for evaluation of therapeutic response are currently in use. CLMTF criteria, SWOG criteria and the widely used * EBMT/ IBMTR/ ABMTR response criteria (commonly referred to as EBMT criteria) are some of them. Recently in 2006 Durie and his associates modified the EBMT criteria and proposed an international uniform response criteria for multiple myeloma 10.Response to chemotherapy was assessed before starting the fourth cycle of chemotherapy since investigators like Belch et al reported that a minimum period of 3 months is required to get an effect out of chemotherapy.11

Studies done to assess the relationship between  a positive therapeutic response and survival yielded contrasting results in the past due to various reasons.Majority of such studies were retrospective,different response criteria were used,time to response were different and dosing schedules varied.Schaar et al 12  (2004) prospectively assessed the relationship between survival and the rate of monoclonal protein (M-protein) decrement during the first cycles of chemotherapy  in 262 patients with newly diagnosed MM and concluded that early response to chemotherapy predicts for survival in MM.In  another prospective study Powels et al showed that therapeutic response predicts for survival.Retrospective studies by Tsuchiya et al (1994) 13 and Blade J et al (1998)9 showed that a good response to therapy is associated with a longer survival.Recently Pineda Roman et al (2007) observed that complete response in myeloma extends survival in patients with no history of MGUS or smouldering myeloma 14.Hence therapeutic response can be taken as a surrogate marker of survival.It needs to be furthur observed whether patients showing objective response to chemotherapy in this study survives longer.  

 That forms the future perspective of this study.  

High dose chemotherapy followed by stem cell rescue has become a standard therapy for patients younger than 65 years.But advanced age, comorbidities and financial constraints often preclude the use of this approach and conservative regimens become the cornerstone of therapy for such patients.Melphalan-prednisolone regimen (MP) has been the gold standard therapy for multiple myeloma for many years.Although VAD  regimen (Vincristine, Adriamycin and Dexamethasone) has a rapid and superior objective response owing to the increased magnitude of tumour cytoreduction, it has not shown to prolong overall survival15,16.The administration of VAD regimen requires a central venous catheter, which leads to an appreciable incidence of sepsis and thrombosis4.However VAD regimen do not require dose adjustment in renal failure.A meta-analysis by myeloma trialists’ collaborative group(1998) confirmed that MP was as effective as combination chemothearapy ,and was more conveinient because of its oral route of administration and lower cost16.Only patients treated with MP were included in our study due to the variation in the magnitude of response with MP and VAD regimen.. There are reports confirming the efficacy of thalidomide and dexamethasone as first line therapy for newly diagnosed myeloma17.We used  thalidomide only for refractory and relapse cases. Thalidomide can be used in newly diagnosed myeloma patients only in the context of a clinical trial.4.Lenalidomide and bortezomib were not used in any of our patients.    

Bone pain was the commonest symptom in our series.This coincides with the studies of Kyle RA (2003) 18 and Advani et al (1978) 19.The next common presentation in our study is pathological fractures(60%). 20% of our patients presented with infections.Kyle RA reported similar figures in his series .Bone swellings were noticed in 11% of patients in our series,whereas Advani et al reported an incidence of 23%. No extramedullary plasmacytomas were noted in our study.                 

 Patients with compromised renal function showed poor response to chemotherapy.This was confirmed in many previous studies 9,13,18,19 .Patients with elevated serum LDH and positive CRP had a poor therapeutic response.This correlates with the current body of literature 20,21.CRP assay is proposed as a surrogate for measurement of IL-6 levels21,22. Thrombocytopenia also predicts a poor therapeutic response(p=0.014)18.Bence Jones Proteins were detected in urine in 17% of our patients.The reported figures in literature ranges from 9% to 77%.Several studies have shown that presence of BJP is associated with poor survival.The observations in our study shows that presence of BJP does not have any significance in predicting therapeutic response.This coincides with the findings of Advani et al19.

Normal β2 microglobin is 1.6 ± 0.4 mg/L.There is an excellent correlation between serum β2 M levels and myeloma tumor burden.Twenty eight percentage of our patients had β2 microglobin more than 4 mg/L.High levels of serum β2 microglobin and low albumin were associated with poor therapeutic response (p= 0.001).This correlates with the observations of several myeloma working groups3. However Advani’s study doesnot show any difference in survival with respect to albumin level.

A large number of bonemarrow plasma cells (>50%) is representative of high tumor load and is associated with a poor therapeutic response. (p-0.014). Studies by Tsuchiya et al 13 and Advani et al 19 showed that a low plasma cell percentage in bonemarrow is associated with longer survival.The significance of plasmablastic morphology was not analyzed in the current study.

Staging  

A good staging system enables the physician to categorize the patients according to risks and plan the management. It helps in predicting therapeutic outcome and survival.It also facilitates comparison between clinical trials.Durie Salmon staging is the most widely used staging system for multiple myeloma since its introduction in 1975. It classifies myeloma into 3 stages based on haemoglobin, serum calcium levels, bone lesions on X rays, M component  production rate  and serum creatinine.This staging has several disadvantages.                           

  1. Evaluation of bone lesions by X rays carries an element of interobserver variation.

  2. Determination of M component production rate requires identification of immunoglobin types by immunofixation .

  3. When Durie Salmon staging was used majority of patients come under stage 3.This causes problems in predicting therapeutic response and survival in low risk and intermediate risk patients.

  4. The criteriae are complex and many laboratory parameters are required.  

The disadvantage noticed with BMRC staging in our study is that a large subset of patients come under intermediate stage.The new ISS is simpler and it requires only two parameters, serum β2 microglobin and albumin.Both parameters are quantitative in nature.Moreover this staging system incorporates serum β2 microglobin which is probably the best independent prognostic indicator for multiple myeloma identified so far.

Conclusions:  

The new International Staging System shows good correlation with therapeutic response and it is simpler than conventional staging systems.Low serum albumin, high β2 microglobin, high urea, high creatinine, low platelet  count, large number of bonemarrow plasma cells , positive CRP and high serum LDH  are associated with poor therapeutic response. 

Acknowledgements:  

We are grateful to Kotian MS for compiling the data and statistics. We thank Dr.Sijeesh and Dr.Vishesh Kothari, Dept of internal medicine for their valuable  advice, discussion  and input.

Reference :

  1. Kyle RA. Multiple myeloma: An odyssey of discovery.Br J Haematol 2000;111:1035-44.  
  2. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma:correlation of measured myeloma cell mass with presenting clinical features,response to treatment,and survival.Cancer 1975;36:842-854.  
  3. Griepp PR, Miguel JS,Durie BGM,CrowleyJ.International Staging System for multiple myeloma. J Clin Onco 2005;23:3412-3420.
  4. Smith A, Wisloff F, Samson D.Guidelines on the diagnosis and management of multiple myeloma. Br J Haematol 2005;132:410-451.
  5. Kyle RA. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group British Journal of Haematology 2003;121:749–757.
  6. Kyle RA. Sequence of Testing for Monoclonal Gammopathies,Serum and Urine    Assays. Archives of Pathology and Laboratory Medicine 1999;123:114–118.
  7. Gassmann W, Pralle H. Staging systems for multiple myeloma: a   comparison. Br J Haematol 1985;59:703-711.
  8. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR.  POEMS syndrome: definitions and long-term outcome.Blood 2003;101:2496-2506. 
  9. Blade J, Fernandex-Llama P, et al. Renal failure in multiple myeloma. Presenting    features and predictors of outcome in 94 patients from a single institution. Arch   Intern Med 1998;158:1889-1893
  10. Durie BGM, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson A  International uniform response criteria for multiple myeloma.Leukemia 2006;20:1467–1473.
  11. Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P,White D, Willan A.    A randomized trial of maintenance versus no maintenance melphalan and prednisolone in responding multiple myeloma patients.British Journal of Cancer 1988;57: 94-99.
  12. Schaar CG, Kluin-Nelemans JC, Cessie S.Early response to therapy and survival in multiple myeloma.Br J Haematol 2004;125:162-166.
  13. Tsuchiya J, Murakami H, Kanoh T :Ten year survival and prognostic  factors inMultiple myeloma.Br J Haematol 1994;87:832-834.  
  14. Pineda Roman M,Bolejack V,Arzoumanian V,Frits van Rhee,Zangari M,Walker R. Complete response in myeloma extends survival without, but not with, history of prior monoclonal gammopathy of undetermined significance or smouldering disease. Br J Haematol 2007;136:393-399.
  15. Hjorth M, Hellquist L, Holmberg E, Magnusson B,Rodjer S, Westin J.Initial treatment in multiple myeloma: No advantage of multidrug chemotherapy over melphalan-prednisone.The Myeloma Group of Western Sweden.Br J Haematol 1990;74:185-91.
  16. Myeloma Trialists’ Collaborative Group.Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6633 patients from 27 randomized trials.J Clin Oncol 1998;16:3832-42.
  17. Rajkumar SV, Hayman S, Gertz MA,Dispenzieri A, Lacy MQ, Greipp PR et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20:4319-23.
  18. Kyle RA.Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proceedings 2003;78:21-23.
  19. Advani SH, Soman CS, Talwalkar GV, Iyer YS, Bhatia HM.Multiple myeloma: Review of 231 cases. Indian Journal of  Cancer 1978; 15:55 -61  
  20. Dimopoulos MA. High serum lactic dehydrogenase level as a marker for drug       resistance and short survival in multiple myeloma. Ann Intern Med 1991;115:931-35.  
  21. Bataille R, Boccadoro M, Durie BGM. C-reactive protein and  beta-2-­microglobulin  produce a simple  and  powerful myeloma staging system. Blood 1992;80:733-737.
  22. Rajkumar SV, Greipp PR.Prognostic factors in multiple myeloma.  Hematol Oncol Clin  North Am 1999;13:1295-1314.

 

This is a peer reviewed paper 

Please cite as : Binu sasidharan : Study Of Factors Predicting Therapeutic    Response In Multiple Myeloma  

J.Orthopaedics 2008;5(1)e19
URL: http://www.jortho.org/2008/5/1/e19

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