Clinical profiles and survival outcomes of adult patients with multiple myeloma at a tertiary hospital in the Philippines

INTRODUCTION

Multiple myeloma (MM) is a neoplastic disorder involving the clonal proliferation of plasma cells in the bone marrow. It is characterized by varying degrees and combinations of end-organ damage, which may include renal impairment, hypercalcemia, anemia, and bone destruction.^[1,2] It is one of the more common hematologic malignancies, with 159,985 incident cases and 106,105 deaths annually. It accounts for 0.9% of all malignancies and 1.1% of all cancer deaths worldwide.^[3] The incidence seems to vary by ethnicity, with lower incidence rates in Asians compared to people in Australasia, North America, and Western Europe. However, analysis of global data over the past few decades has shown that the largest increase in MM incidence was seen in Asian countries, particularly in China, Taiwan, and North Korea.^[4] In the Philippines, MM is the 23^rd most common cancer overall and the 2^nd most common hematologic malignancy after the leukemias. It accounts for around 708 new cases or 0.5% of new cancer cases annually.^[5]

Although the majority of the available literature on multiple myeloma is based on Western populations, the recent decades have seen the emergence of reports describing the characteristics of patients in different Asian countries.^[6–8] By 2014, the first multinational study to describe the clinical profiles of Asian patients with MM was published. It pooled data from major tertiary centers in China, Hong Kong, Japan, Korea, Singapore, Taiwan, and Thailand.^[9] All throughout the currently available literature, however, the Philippine population is still largely underrepresented. There is a paucity of published data regarding the clinical profiles and survival outcomes of patients with MM in the Philippines. In this study, we retrospectively reviewed data representing adult Filipino patients with multiple myeloma seen at a tertiary care hospital. We looked into the clinical profile, treatment, and outcomes of these patients.

MATERIAL AND METHODS

RESULTS

Survival outcomes and prognostic factors

In Figure 1, the survival curve for all included patients is presented. The median OS was 60 months. Among the different parameters evaluated by univariate analysis, only the hemoglobin level and the serum albumin level had an impact on the OS [Table 4]. The OS of patients with hemoglobin ≥100 g/L was significantly better than that of those with hemoglobin <100 g/L (median OS: not reached [NR] versus 28 months; p = 0.0158; [Figure 2]). Although the median OS was NR in both groups (patients with serum albumin levels ≥3.5 g/dL and patients with levels <3.5 g/dL), those with serum albumin levels ≥3.5 g/dL had better survival than those with lower albumin levels (p = 0.0402; [Figure 3]). Neither the choice of frontline regimen nor the response to induction treatment was found to be a significant prognostic variable.

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Figure 1:

Survival curve in 74 adult Filipino patients with multiple myeloma. The median overall survival was 60 months.

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Table 4: Univariate analysis for overall survival in patients with multiple myeloma.

Parameter		Patients, n (%)	Median overall survival, months	p-value
Age at diagnosis	<40 years	6 (8.1)	48	0.1633 NS
	40–65 years	64 (86.5)	97
	>65 years	4 (5.4)	4
Sex	Males	39 (52.7)	97	0.5450 NS
	Females	35 (47.3)	60
Extramedullary plasmacytoma	Present	17 (23.0)	48	0.3613 NS
	Absent	57 (77.0)	97
Hemoglobin	≥100 g/L	20 (35.7)	NR	0.0158
	<100 g/L	36 (64.3)	28
Platelet count	>100 × 109/L	45 (81.8)	NR	0.0985 NS
	50–100 × 109/L	7 (10.9)	NR
	<50 × 109/L	4 (7.3)	1
Serum creatinine level	≥177 umol/L (2.0 mg/dL)	18 (34.0)	NR	0.6196 NS
	<177 umol/L (2.0 mg/dL)	35 (66.0)	NR
Serum calcium level	≥2.75 mmol/L (11.0 mg/dL)	9 (20.0)	NR	0.0979 NS
	<2.75 mmol/L (11.0 mg/dL)	36 (80.0)	NR
Serum albumin level	≥35 g/L	29 (59.1)	NR	0.0402
	<35 g/L	20 (40.8)	NR
Bone lesions	Pathologic fracture	18 (46.2)	NR	0.5633 NS
	Lytic bone lesions without fracture	16 (41.0)	48
	Osteopenia or no bone lesion	5 (12.8)	NR
Frontline treatment	Bortezomib-based	39 (60.9)	NR	0.0875 NS
	IMiD-based	9 (14.0)	60
	Bortezomib and IMID combination	6 (9.4)	48
	No bortezomib or IMiD	10 (15.6)	97
Response to frontline treatment	CR or VGPR	13 (45.0)	NR	0.6416 NS
	PR	10 (25.0)	NR
	Minimal to no response	12 (30.0)	NR

Abbreviations: NS, not significant; NR, not reached; FLC, free light chain; IMiD, immunomodulatory drug; CR, complete response; VGPR, very good partial response; PR, partial response.

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Figure 2:

Comparison of survival curves by hemoglobin level. Patients with hemoglobin ≥100 g/L had better survival than those with hemoglobin <100 g/L.

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Figure 3:

Comparison of survival curves by serum albumin level. Median overall survival (OS) was not reached for both groups, but patients with albumin ≥35 g/L (3.5 g/dL) showed a more favorable survival than those with albumin <35 g/L (3.5 g/dL).

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DISCUSSION

In this study, we looked into the demographic profile of Filipino patients with MM. Herein, slightly more males (52.7%) than females were affected with the disease. This is consistent with the data on both Western and Asian populations showing MM’s slightly higher predisposition among males.^[9,11,12] The Western literature also reports MM to be a disease of the older population, with a median age of approximately 66–70 years at the time diagnosis, with only 37% of patients younger than 65 years of age.^[11] Asian countries seem to have a slightly younger MM population, with the median age ranging from 59 to 66 years at the time of diagnosis,^[6–9] and a higher proportion (58.5%) of patients below 65 years of age.^[9] In this study, the median age was even much lower at 54 years, and the proportion of patients who were 65 years old or younger was much higher (94.6%). Consistent with the observation in the Asian Myeloma Network study, the differences in median age at diagnosis could be related to the differences in the life expectancies among different populations. The multinational study reported the highest median age at diagnosis for Japan (66), followed by Hong Kong (65), Taiwan (63), Singapore (62), Korea (61), China (59), and Thailand (59).^[9] The life expectancies for these countries roughly follow the same decreasing order, with Japan having the highest life expectancy in the world at 84.2 years. The Philippines reports a much lower life expectancy (69.3 years) compared to all the aforementioned countries.^[13]

We also looked into the clinical and disease characteristics of MM in the Filipino population. MM is diagnosed in a patient with clonal bone marrow plasma cell proliferation or extramedullary plasmacytoma accompanied by either an evidence of end-organ damage or the presence of a myeloma-defining biomarker. The forms of end-organ damage attributable to the disease include renal impairment, hypercalcemia, anemia, and bone lesions.^[14] The myeloma-defining biomarkers include (1) a clonal bone marrow plasma cell percentage of 60% or more, (2) a ratio between the involved and uninvolved serum-free light chain of 100 or more, and (3) the presence of more than one focal bone lesion on magnetic resonance imaging studies.^[14] Renal impairment can be attributable to a variety of causes (e.g. hypercalcemia, dehydration, infections, and the use of nephrotoxic agents) and is reported in up to 50% of newly diagnosed patients.^[1,15,16] In this study, only 28.4% were reported to have manifestations of kidney involvement, and only 34.0% of the patients had significant azotemia. Anemia can be secondary to marrow infiltration by the proliferative plasma cells, the myelosuppression from anti-myeloma treatment, the accompanying renal damage, or a combination of these causes. It is present in nearly all patients throughout the disease course.^[1,12,17] In this study, hemoglobin <100 g/L was seen in 64.3% of patients at the time of diagnosis. This value is almost twice the proportion (35%) that was observed in the Western population by Kyle and colleagues^[12] but is almost similar to that (60.7%) observed by Kim and colleagues in the Asian Myeloma Network study.^[9] The osteolytic bone disease from dysfunctional bone remodeling in MM can cause bone pains, pathologic fractures, and hypercalcemia.^[17,18] In this study, bone abnormalities were seen in 92.3% of the patients for whom skeletal imaging was done. The proportion is higher than what was reported by Kyle and colleagues^[12] (79%) and by the Asian Myeloma Network study (60.2%).^[9] On the other hand, hypercalcemia was seen only in a minority of patients (20.0%), consistent with the data on both the Western and Asian populations.

Among the included patients in this study, several disease parameters were sparsely recorded. These include the serum beta-2 microglobulin levels, the myeloma isotype, and the cytogenetic profiles. Two major reasons for the paucity of these data are the cost and the availability of the laboratory tests for these parameters. Our institution is a tertiary referral and training center that caters to the financially challenged Filipinos. For these patients and their healthcare providers, the cost of diagnostics and treatment has always been an important consideration in disease management. Also, among these particular laboratory tests, only conventional cytogenetics has been readily available for years. The isotype determination by immunofixation electrophoresis was available only in the most recent years. Serum beta-2 microglobulin levels still have to be tested in other institutions. In this study, the levels were recorded in only three patients and were elevated in all of them. Isotype determination was reported in only four patients, with all of them having the IgG isotype. This does not come as a surprise since the IgG isotype is the most common, reported in around half (46.0–55.2%) of cases.^[6–9,12] Although the cytogenetic profile is an important component of risk stratification in cases of MM,^[19,20] it has not been consistently determined and reported in our institution. Only 12 patients in this study had a record of conventional cytogenetics result and no patient had a record of FISH testing.

The most common presenting symptom in this study was bone pain (64.7%), mostly associated with spine involvement (46.5%). This was followed by renal manifestations (28.4%) and fatigue (25.7%). Bone pain was also the most common presenting symptom among 3209 Koreans (48.4%) in a study by Kim and colleagues,^[6] and among 1027 patients at the Mayo Clinic (58%) in a study by Kyle and colleagues.^[12] On the contrary, Zhang and colleagues observed that fatigue was the most common presentation among 595 patients in northern China, followed only by bone pain and infection.^[7]

MM has classically been described as an incurable disease. None of the established treatment modalities, including stem cell transplantation, have provided a definite cure. An enduring remission status is rather rare even after intensive interventions; the majority of patients inevitably relapse.^[21,22] The survival estimates for this disease vary across different reports. In our study (year of diagnosis: 2008–2019), the median OS was 60 months, much longer than the earlier, published reports. The study on patients seen at the Mayo Clinic (year of diagnosis: 1995–1998) reported a median OS of 33 months.^[12] The Asian Myeloma Network study showed a median OS of 47 months. When the patients were divided by year of diagnosis, the median OS for the 2002–2011 group was significantly longer than that of the 1986–2001 group (49 vs. 35 months).^[9] Other studies from different Asian countries reported median OS ranging from 27 to 50 months.^[6–8] Regardless, survival outcomes have significantly improved over the past few decades, with the rollout of several drug classes for multiple myeloma.^{[11,20,22,23]} These include the immunomodulatory agents (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, all of which have been available locally in the Philippines in recent years. The last decade has also seen the approval of newer agents mostly for relapsed and refractory cases, the IMiD pomalidomide, proteasome inhibitors carfilzomib and ixazomib, and monoclonal antibodies elotuzumab, daratumumab, and isatuximab.^[20] None of these newer agents, however, are locally approved and readily available in the Philippines. In this study, bortezomib-based regimens were the most commonly used treatment (60.9%) for newly diagnosed MM. Of these, the VCD regimen, used in 46.9% of patients, was the most popular. Among the included patients in this study, the earliest year of diagnosis was 2008; the same year bortezomib was first approved for frontline anti-myeloma treatment.^[24] This can explain the popularity of bortezomib in this study. This practice is in contrast to that reported in earlier published studies. A study which included patients initially diagnosed with MM from 1985 to 1998 reported the use of melphalan-prednisone combination (MP regimen) in 56% of the population.^[12] Neither bortezomib nor any of the IMiDs were approved for frontline myeloma treatment during that period. Thalidomide and lenalidomide received such approval last 2006 and 2014, respectively.^[24] The Asian Myeloma Network study, which included patients diagnosed between 1986 and 2011, reported the use of the novel agents for frontline therapy in only 36% of 2970 patients. In this study, the novel agents were included in the induction treatment of 84.4% of the 64 patients. The rest of them were given conventional regimens (melphalan or cyclophosphamide without bortezomib or IMiD). Of these, the MP regimen was popular and second only to the VCD regimen as the most commonly used induction treatment. Despite the approval and availability of bortezomib and both IMiDs for frontline therapy, the affordability of these newer drugs was prohibitive. In the resource-limited setting of our institution, melphalan was the cheaper and more accessible alternative, especially since most of these patients were not eyeing stem cell transplantation as an eventual option.

In this study, none of the 74 patients underwent HSCT. Although autologous HSCT has been shown to increase the OS of patients and has remained a vital arm in myeloma therapy,^[20,22] its availability has been widely discrepant across countries.^[4] In the Philippines, centers for stem cell transplant have already been growing over the past several years but access to their services is still limited by costs and the lack of insurance coverage. In our resource-limited setting, the inaccessibility of HSCT as an eventual treatment option contributed to the popularity of frontline melphalan treatment even in supposedly transplant-eligible patients.

Across studies, factors like age, platelet count, serum albumin and creatinine levels, cytogenetic abnormalities, disease stage, and response to therapy have been shown to affect the survival of patients with multiple myeloma.^[12,20] In the univariate analysis done by the Asian Myeloma Network study, even hemoglobin, marrow plasma cell percentage, and serum calcium were found to be significant prognostic factors.^[9] In this current study, however, of all the parameters investigated, only the hemoglobin and the albumin levels proved be significant prognostic factors by univariate analysis. Not even the choice of frontline regimen or response to treatment affected the survival. This deviation from the widely consistent findings of much larger studies on prognostic factors in MM can be explained by the small sample size included in this study. Also, because of the sample size, only 56 patients with baseline hemoglobin levels and 49 patients with baseline albumin levels were included in the survival curves. The 18 patients with unknown hemoglobin levels and 25 patients with unknown serum albumin levels could have possibly altered the outcomes of univariate analysis if only they had a record of their laboratory results. Multivariate analysis for the prognostic factors through Cox regression was also not possible due to this limitation. A larger study in the future can verify the prognostic significance of these laboratory parameters and investigate further the impact of the other parameters on the survival outcomes of MM in the Filipino population.

CONCLUSION

In conclusion, aside from the trend of a younger age at diagnosis, there are no unique patterns in the clinical characteristics of MM in adult Filipinos when compared to that of the Western population and the rest of the Asian population. The longer median OS of 60 months may reflect the increased availability of novel anti-myeloma drugs in the recent decade. The difficult access by the majority of the Filipino population to specialized hematology tests and HSCT services is highlighted in this study. The serum albumin and hemoglobin levels remain as significant prognostic factors, but larger studies are needed to investigate the impact of other clinical and treatment parameters on the survival of adult Filipino patients with MM.