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July 2007, Volume 57, Issue 7

Original Article

Multiple myeloma: a ten year study of survival and therapy in a developing nation

Caroline Edijana Omotit  ( Department of Haematologyt University of Benin Teaching Hospital, P.M.B. 1111, Benin City, Nigeria. )
Casmir Edisma Omuemu   ( Department of Medicine , University of Benin Teaching Hospital, P.M.B. 1111, Benin City, Nigeria. )

Abstract

Objective:To analyze the survival related to the rapeutic modalities and haematological indices at presentation with outcome performed on records of all multiple myeloma (MM) patients' Methods:Aprospective study was conducted in the University of Benin Teaching Hospital, Nigeria from 1993 to2003. Thirty patients were identified with diagnosis confirmed on the basis of atypical plasmacytosis (=30% inthe bone marrow), monoclonal component in the serum or urine and radiological evidence of the typical skeletallytic lesions. Results:Males (n=20) out numbered the females (n=10), with a median age of 54 years. The mean duration of survival of all patients was 7months (median 3months; P<0.0001) with only 13.3% of the patients surviving at two years. The mean duration of survival of 10 patients on either therapy of vincristine, adriamycin,dexamethasone (VAD) or 8 patients on melphalan, prednisolone (MP) was 3 months, significantly shorter than21 months for the 5 patients on a combination of both forms of therapy at different times (COMB) (P=0.0067).The Kaplan-Meier estimates of survival showed survival probability was least in those without definitive therapy(NONE) as expected. Conclusion:Late presentation and inadequate treatment from poor compliance with therapy in a setting ofpoverty and ignorance are suggested as factors contributing to the poor survival of the patients studied (JPMA57:341:2007).

Introduction

Plasma cell dyscrasias are a group of disorders thatarise from clonal proliferation of neoplastic plasma cells orassociated B cells. Typically clinical manifestation varies asa result of the heterogenous biology spanning the entirespectrum from the early phase of indolent/smolderingmyeloma to highly aggressive overt and terminal multiplemyeloma (MM),1which is still incurable with the available treatment options.2,3 The occurrence of MM is worldwideand there is no doubt that the Negroid population and Afrocarribeans have a much larger share than the Caucasians, as also confirmed by the SEER dataprogram.4,5The decline in mortality and higher probabilityof survival for MM patients in the western world is due torecent advanced novel therapy protocol and wider use of thePCR-ASO (allele-specific oligonucleotide) designed todetect CDR3 sequence of the tumour/monitoring minimalresidual disease.6,7 This is also coupled with the purging efficacy of the autologous blood stem cell transplants inMM.8,9 However, these advanced management techniques are not readily available in most developing countries.Hence, the aim of this study was to analyze the rapeuticmodalities currently in use and determine the survivaloutcome of 30 patients managed for this condition in atertiary health institution in a developing nation.

Patients and Methods

Between 1993 and 2003, 30 cases of MM patients consecutively seen at UBTH, a major referral center serving the South-South geopolitical region of Nigeria were studied. Clinic oimmunologic and demographic information of the patients including referrals and autopsy findings were noted. Pretreatment evaluation included complete clinical,radiologic skeletal survey and laboratory workup carriedout at the center. Diagnostic criteria, as recommended were based onclinical information, the presence of at least 30% atypicalplasma cells on bone marrow examination (or biopsy of atissue with monoclonal plasma cells), monoclonal proteinsin the serum or urine with or without evidence of end-organ damage.10,11 During the monthly cycle of treatment,patients were followed up for physical examination, bloodcount, renal and liver function tests. Bone marrowaspiration and biopsy with serum and urine electrophoresiswere performed at intervals when patients' monoclonalcomponents (MC) had reached maximum reduction.Overall duration of survival was estimated in all patientsusing simple percentage from the time of diagnosis/start of treatment to the date of death or the last follow up visit.

Table 1. Age distribution of multiple myeloma patients on presentation.

Age (years)

Frequency (%)

30-40

4(13.3)

41-50

11 (36.7)

51-60

8(26.7)

>60

7(23.3)

Total

30(100)

Table 2. The mean haematological indices in multiple myeloma patients at presentation and outcome at 1 year of therapy.

 

Alive

Outcome

Dead

 

Parameters

   

P-value

 

(n=10)

(n=7)

 

Haemoglobin (g/dl)

10.3 (t2.7) 6.8 (t0.6)

0.0031

Total leucocyte count (x 10 9/L)

7.7 (t2.8) 8.1 (t3.9)

ns

Platelet count (x10 9/L)

241 (t98) 108 (t66)

0.0050

Erythrocyte sedimentation rate (mm/hr)

93.6 (t47) 147 (t8)

0.0065

ns: not significant.

[(1)]

Instat package system was used to analyze the data obtained. The haematological indices were estimated using the Mann-Whitney and one-way analysis of variance(ANOVA) for significant association. Survival probability was estimated using the Kaplan Meier method.  

Results

Atotal of 30 patients aged 34-75 years with an established diagnosis of MM, based on serumimmuno electrophoretic and clinical criteria over a ten-year period (1993-2003) were studied. The age-corrected male:female ratio of 2:1 indicated higher incidence of MM inmales. The overall median age at presentation was 54 years with 13.3% of the patients less than 40 years (Table 1). The haematological values at presentation were found to influence the outcome of survival after chemotherapy was started as shown in Table 2. We found astrong association between haemoglobin (Hb) and plateletcount at presentation and 1year survival in the myelomapatients (P=0.0031 and P=0.005 respectively). Also, the mean erythrocyte sedimentation rate (ESR) for the myeloma patients alive at 1year was significantly lower than those that died within 1 year (P=0.0065). A positive correlation between Hb and platelet count at presentation was also obtained (r =0.436; P= 0.016).The Kaplan Meier estimates of survival probability for the four groups of patients (according to therapy) aredisplayed in figure. The chemotherapeutic regimen utilized were the standard single alkylating agent of MP administered to 26.7% of the patients, VAD administered to33.3% of the patients and 5 cases (16.7%) who had initially MPand later switched to VAD after non-response of 3-4months with one regimen. There was a trend for longersurvival in the 5/23 patients given cycles of MPand laterreplaced with VAD when compared to the single regimensof either MPor VAD alone (median, 21months vs 3months;P=0.0067). Expectedly, the poorest survival recorded was in23.3% (7/30) patients who had no form of therapy (NONE)due to financial constraint and other limiting factors. The mean duration of survival in the whole series was 7 months(median 3 months; P<0.0001) with a range of 1-96 months.Response to chemotherapy is an independent factor associated with survival; and treatment results are analyzed on an intention to treat basis. Time to response was defined as the interval between treatment initiation and documentation of at least partial response (PR) i.e. >50%and >90% decrease of serum and urine MC level respectively. Complete response (CR) was defined as disappearance of the MC in serum and/or urineimmunfixation, less than 5% plasma cells in the bonemarrow and complete regression of extramedullary lesions if present. Patients who discontinued treatment for anyreason before response assessment were considered as non-responders. Twenty-three patients who received chemotherapy had various outcome of response: CR wasseen in 4 cases, PR in 12 cases and no response in 7 cases.

Discussion

There have been major advances in the treatment of MM in the past 20 years but for the individual patient the prognosis still remains uncertain. MM is seen in all racesbeing the most prevalent blood cancer after non-Hodgkin'slymphoma.12It is said to account for 1% of all human cancers and 10% of all haematological malignancies.13 The occurrence of MM is worldwide but there are considerable differences in the recorded incidence and survival indifferent geographic areas.The median age of 54 years at presentation revealed that our patients tend to present at much earlier age than elsewhere. For instance, the age of those referred to the Olmsted county and Mayo clinic, USAwas 74 and 62 yearsrespectively.14,15We also found in this study that the meanduration of survival in the whole series was significantly low (7 months; P<0.0001) in contrast to the longer duration experienced in the more developed economy.2,16,17 This survival outcome is poor when compared to the Westernworld as the 5 year survival could not even be estimated because most of the patients did not live up to this number of years or were lost to follow up. The survival in those with renal involvement in Northern India was reported to be only4 months while those on dialysis was 6 months.18 Limited resources, illiteracy and ignorance led tolate presentation and inability to begin and sustain treatment probably contributed to the short duration of survival.Patients resort to herbal and other unorthodox form oftreatment before presentation. Missed diagnosis by healthcare providers in the primary and secondary health carefacilities before referral also contributed to delay indiagnosis and onset of complications before presentation.These factors are similar to the studies in Senegal and other African literature19and in China.20 Our patients being on the younger side may probably have aggressive disease as shown with the various molecular biology of MM.Exposure to chemical substances and gas flares may beassociated with an increased risk of MM implicating environmental factors as important aetiologic/causalagent.21,22 This is because 83.3% of the patients reviewedwere from the Niger Delta region of the country noted forits petrochemical industries and gas flare sites coupled with pollution of water from oil spillage. Logistics for providing blood and blood components is very difficult for most of thepatients due to limited resources/financial constraint.Inspite of the advances recorded in thechemotherapeutic treatment of MM, the survival has onlyslightly improved. Reports from Western countries revealedthat age, presence of complications and aetiologic environmental factors were negative prognostic factors21,23that were also present in our study with a high percentage(13.3%) presenting at <40 years. Some of the complications presented were cord compression, protein deposition invisceral organ eg kidney and immunosuppression(infection). Presence of osteolytic bone destruction (pain), ahallmark of advanced myeloma was also reflected inclinical pathological fractures in 33.3% of the patients and93.3% of the patients with haemoglobin <10g/dl. The probability of occurrence of anaemia due to cytokineproduction has been reported to depend on a number of variables which include the type, stage (Durie andSalmon)/duration of the malignancy, intensity of treatmentprotocol and the occurrence of intercurrent infection.24 Environmental exposure to radiation or chemicals has been associated with increased myeloma.25 Though there was noexposure to atomic/bomb or radiation, majority of thepatients were from the Niger Delta Zone of Nigeria where there is exposure to chemical pollution. On the other hand,results of epidemiologic studies attempting to establish associations between myeloma and certain infections orautoimmune diseases are however inconclusive.26 Aconsiderable number of the patients presented with the expected haematological counts. Patients with a lower Hband platelet count had a significantly lower remission rate with a poor outcome. This was shown in the strong association between the indices at presentation and 1yearsurvival (P=0.0031; P=0.005 respectively). Also, the mean ESR for the myeloma patients alive at 1 year was significantly lower than those that died within 1 year(P=0.0065).The apparent longer duration of survival advantageof patients on MPand later VAD over either single regimenalone is not easily explained. However, it is possible that them yelosuppression due to MPmay have wiped out most ofthe malignant cells. VAD on the other hand possiblycontinued to suppress mainly the malignant cells without myelosuppression, hence the apparent improved outcome.We had observed empirically that our younger patients (<60years) on VAD tended to do better as time progressed thanthe older ones even though both groups occasionallypresented with similar clinical and laboratory initialcharacteristics. This was also informed by the apparentpharmacological advantages of VAD over MP whichinclude rapidity of response, lack of myelotoxicity andusefulness in patients with poor renal performance.27It has also been reported that VAD chemotherapy is a better initialoption.28Therefore, the group of patients referred orpreviously on MPwere switched to VAD including thosewith adverse effects/toxicity and those perceived to bedoing poorly clinically, who did not respond after 3-4months on MP. Those refractory to myelosuppressive dosesof standard alkylating MPagent, VAD produced rapid and marked cytoreduction of over 75% in the treated patients by improved response rate. This generally was associated with prolonged survival as has been previously reported.29Infact,it has been said that patients younger than 50 years seem tohave a better prognosis when the observed survival rates areconsidered, but they showed an increased risk of death when the model takes into account the expected mortality ofthe underlying population. In all, data exist both to supportand to refute the concept that patients who respond very quickly to induction therapy have a worse prognosis than those with a slower response.In conclusion, the short duration of survival identified in our study compared to the western world canprobably be best addressed by general measures targeted atreducing poverty, ignorance and health care reforms toreduce late presentation. Specific measure to ensure affordability and availability of drugs and laboratorysupport for monitoring these patients are needed. The high response rate with long lasting remission with VAD hasagain been confirmed to be a good combination therapy inMM patients when a more aggressive therapeutic approachthan oral MPis warranted.

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