High early mortality rate in elderly patients with multiple myeloma receiving a vincristine–doxorubicin–dexamethasone regimen

Treatment-related mortality (TRM) is not uncommon in patients after the first course of vincristine–doxorubicin–dexamethasone (VAD) chemotherapy, but quite rare after melphalan–prednisolone (MP). This motivated us to compare the rates of TRM after the first course of VAD with those after the first course of MP. We retrospectively assessed survival and TRM in 179 patients treated for multiple myeloma with either MP or VAD. Survival was similar in two groups (P = 0.463 in log-rank test). However, TRM was significantly higher in patients after the first course of VAD (11 in 100 patients, 11.0%) than that after the first course of MP (1 in 79, 1.3%; P = 0.010). Poor performance status (P = 0.004) and advanced age (P = 0.009) before treatment were independent significant factors associated with TRM after the first course of induction therapy. Pyogenic infection was the major cause of TRM after VAD (9 in 11, 81.8%). We concluded that VAD should be cautiously used as induction therapy in multiple myeloma patients, especially in elderly and/or those with poor performance status.

Multiple myeloma is a cancer of the plasma cells. It usually afflicts the elderly. Most patients have a median overall survival of about 3–4 years. For decades, the vincristine–doxorubicin–dexamethasone (VAD) and melphalan–prednisolone (MP) regimens have been the two main standard induction chemotherapies for this disease. Previous studies have shown a comparable response rate and survival benefit between MP and VAD or VAD-based regimens [1, 2]. In clinical practice, the VAD regimen is often prescribed as induction chemotherapy for newly diagnosed multiple myeloma patients to achieve a rapid and maximal response and then to bridge into stem cell transplantation. The rationale is that the responses to the VAD regimen are more rapid in onset compared with those of the MP regimen when used in induction chemotherapy, especially when a rapid control of the disease is necessary [1, 3]. However, very limited trials have compared VAD and MP in detail with regard to treatment-related mortality (TRM).

We performed a retrospective analysis enrolling 179 patients diagnosed with multiple myeloma between September 1998 and August 2006 in a single institute. These patients received induction chemotherapy with either VAD or MP at the discretion of the clinicians. The median follow-up period was 15.0 months (range, 0.3–91.8 months). Patient characteristics are listed in Table I. The VAD and MP groups comprised 100 and 79 patients, respectively. Patients in the VAD group had a significantly higher incidence of impaired renal function and more advanced International Staging System (ISS) stage before treatment. There were no statistically significant differences in age, performance status (PS), serum calcium level, and hemoglobin level between the groups. Eleven (11.0%) patients in VAD group died after their first course of therapy, whereas only one (1.3%) in the MP group died. This difference in the TRM was statistically significant (P = 0.010). However, the overall survival was not different between the VAD and MP groups (P = 0.463 in log-rank test). Median overall survival for patients receiving either VAD or MP as front-line chemotherapy was 29.3 and 28.8 months, respectively.

Table I. Characteristics of 179 Patients With Multiple Myeloma

Characteristics	MP (100%), n = 79	VAD (100%), n = 100	P-value
a Significant. MP, melphalan–prednisolone; VAD, vincristine–doxorubicin–dexamethasone; LCD, light-chain disease; Ig, immunoglobulin; ISS, international staging system; TRM, treatment related mortality.
Sex (male/female)	54/25 (68.3/31.7)	74/26 (74/26)	0.406
Age <75, ≥75 yr	51/28 (64.6/35.4)	76/24 (76.0/24.0)	0.094
Performance status 0/1/2/3/4	1/40/28/8/2	0/42/33/20/5	0.240
Myeloma subgroup			0.752
IgG	43 (54.4)	56 (56.0)
IgA	21 (26.6)	26 (26.0)
IgD		1 (1.0)
IgE	1 (1.3)
LCD	14 (17.7)	17 (17.0)
ISS stage			0.013a
I	16 (20.3)	11 (11.0)
II	28 (35.4)	23 (23.0)
III	35 (44.3)	66 (66.0)
Serum creatinine <2, ≥2 mg/dL	64/15 (81.0/19.0)	62/38 (62.0/38.0)	0.006a
Serum calcium <12, ≥12 mg/dL	72/7 (91.1/8.9)	85/15 (85.0/15.0)	0.214
Hemoglobin ≥8.5, <8.5 g/dL	49/30 (62.0/38.0)	53/47 (53.0/47.0)	0.226
TRM after first-course chemotherapy	1 (1.3)	11 (11.0)	0.010a

We investigated the characteristics of patients who died to first-course treatment-related complications. The median age of 11 patients with TRM after first-course VAD regimen was 75 years (range, 71–82). All of these 11 patients were men. The only patient in the MP group whose death was associated with TRM was aged 90 years. The median time to death among those died in the first cycle was 15 days (range, 6–44) for those patients treated with VAD and 26 days for the one patient treated with MP. Most patients had ISS stage III disease (10 of 11 in VAD group and one of one in MP group) and PS grade 3–4 (9 of 11 in VAD group and none in MP group). Pyogenic infection was the main cause (9 of 11, 81.8%) of TRM after the first course of VAD, whereas seven of nine patients died to infections in the absence of neutropenia. Bleeding diathesis was the other cause (2 of 11, 18.2%) of TRM after the first course of VAD. The only MP-related death resulted from proximal deep vein thrombosis, not infection. Multivariate logistic regression analysis was performed for factors leading to TRM. Age (odds ratio 9.540, 95% confidence interval 1.761–51.688; P = 0.009) and poor PS (odds ratio 12.943, 95% confidence interval 2.304–72.705; P = 0.004) were significant independent factors associated with TRM after the first course of chemotherapy (Table II). These two factors remained significant as factors associated with first-course TRM (P = 0.017 for age ≥75, P = 0.003 for PS ≥3) when only patients treated with VAD were included for multivariate analysis.

Table II. Univariate and Multivariate Logistic Regression Analyses for Factors Leading to Treatment-Related Mortality After First-Course Induction Chemotherapy

Factors	Univariate			Multivariate
	Odds ratio	95% CI	P-value	Odds ratio	95% CI	P-value
a Significant. PS, performance status; ISS, international staging system; Hb, hemoglobin; CI, confidence interval; MP, melphalan–prednisolone; VAD, vincristine–doxorubicin–dexamethasone.
Age (yr) <75, ≥75	5.591	1.604–19.488	0.007a	9.540	1.761–51.688	0.009a
PS 0–2, 3–4	16.269	4.126–64.152	<0.001a	12.943	2.304–72.705	0.004a
ISS I, II, III	7.102	1.026–49.173	0.047a	2.448	0.239–25.103	0.451
Hb (g/dL) ≥8.5, <8.5	4.261	1.113–16.312	0.034a	2.908	0.486–17.412	0.242
Calcium (mg/dL) <12, ≥12	9.437	2.722–32.723	<0.001a	3.444	0.609–19.485	0.162
Creatinine (mg/dL) <2, ≥2	8.386	2.171–32.390	0.002a	2.106	0.359–12.362	0.410
Regimen MP, VAD	9.640	1.217–76.366	0.032a	9.396	0.967–15.591	0.053

Overall survival in our study is comparable with that reported in previous clinical trials and meta-analyses [4–6]. Similar to these studies, overall survival was not significantly different between the VAD and MP groups. However, we further demonstrated that the incidence of TRM after first-course induction chemotherapy was statistically higher in the VAD than in the MP group (11.0% vs. 1.3%, P = 0.010; Table I). As indicated in Table II, age and PS were independent factors associated with first-course TRM. It is possible that patients with multiple myeloma who achieved better survival after VAD regimens were mostly younger and had better PS. In contrast, although the VAD regimen provides a high response rate and rapid disease control in elderly patients and patients with poor PS, these patients had to trade off a higher mortality risk of induction therapy, which offsets the benefit of the VAD regimen. Therefore, VAD regimen should be used with caution as an induction therapy for newly diagnosed multiple myeloma patients who are elderly and/or with poor PS.

In clinical practice, we often have the opportunity to prescribe the VAD regimen as front-line chemotherapy for patients with advanced stage and poor renal function. The rationale for this treatment strategy generally relies on more rapid cytoreduction with the VAD regimen compared with the MP regimen [1, 3]. The results in Table I reflect this trend: the VAD regimen was prescribed more often when patients were ISS stage III (66 in 101, 65%) or had poor renal function (38 in 53, 72%). Interestingly, although a higher proportion of patients receiving VAD had advanced ISS stage (stage III, 66.0% vs. 44.3%; P = 0.004) and poor renal function (creatinine ≥2 mg/dL, 38.0% vs. 19.0%; P = 0.006) than those receiving MP, ISS stage and renal function are not independent factors associated with early TRM (Table II). Furthermore, age and PS, which showed no differences in MP and VAD regimens between groups, were independent factors that influenced first-course TRM. Our findings raise serious concern with regard to implementing VAD as first-line treatment for multiple myeloma patients who are elderly and/or have poor PS.

Multiple myeloma is believed to be an incurable disease of old age, and TRM is certainly an important consideration when selecting the type of induction chemotherapy. However, the incidence of early TRM has rarely been mentioned in literature, particularly for patients who are elderly and/or have poor PS. This probably results from the selective nature of clinical trials: patients who are elderly and/or have poor PS are seldom included in trials as are patients who died early during the follow-up period (Table III). Our study was performed in a veterans' general hospital with a patient population mainly comprising of elderly veterans; thus, elderly patients accounted for a high proportion in this study: 52 (29.1%) of the 179 patients were aged ≥75 years. This fact is also reflected in the median age at diagnosis (69 and 72 years for our VAD and MP groups, respectively). The relatively older age of our patients provided us with an opportunity to observe the significant association of age and PS with the development of first-course TRM.

Table III. Early Treatment-Related Mortality of Selected Trials After the First Course of Vincristine–Doxorubicin–Dexamethasone Regimen

Author, publication date	Patient numbers	Median age, yr	TRM (%)	Remark
a For untreated patients. b For patients with relapsed and refractory multiple myeloma. VAD, vincristine–doxorubicin–dexamethasone; TRM, treatment-related mortality.
Segeren et al.,1999 [12]	139	53	4 (3)	TRM means early death in 1–2 courses of VAD. The regimen of VAD was bolus given. All patients used prophylactic antibiotics
Anderson et al.,1995 [11]	142	57,a 59b	9 (6)	TRM means death within 30 days after the first course of VAD. All patients used prophylactic antibiotics
Lokhorst et al.,1989 [7]	31	60	3 (10)	TRM means death within 6 weeks after initiating VAD. Patients with TRM were excluded from this study
Samson et al.,1989 [8]	32	53	3 (9)	Two patients with early death were excluded. One patient's death was treatment-related
Monconduit et al.,1992 [13]	25	65	3 (12)	Three patients who died soon after first-course VAD were excluded from the study. Karnosky index <3 in 12 cases, 4–6 in 8 cases, and >7 in 7 cases

Previous clinical trials have successfully investigated the association of treatment with VAD with considerable morbidity, particularly from infection [3, 7–14]. Anderson et al. [11] reported that 9 (6%) of 142 patients died within 30 days after the first course of VAD; three (33%) of these nine patients died because of infection. First-course VAD-related mortality in our study was 11.0%. Not surprisingly, these patients had poor PS (9 of 11 had PS grade 3–4), were elderly (median, 75 years; range, 71–82 years), and had advanced-stage multiple myeloma (10 of 11 were of ISS stage III). Similar to previous reports, pyogenic infection was a major cause of death. Furthermore, most patients (seven of nine, 78%) developed severe pyogenic infection before the onset of chemotherapy-induced neutropenia. This implies that immunosuppression because of high-dose dexamethasone was responsible for the early mortality. The relatively low dose of doxorubicin (36 mg/m² split over 4 days) and the nonmyelosuppressive agent vincristine were probably not the cause [3, 15]. The latest report of the IFM 95-01 trial strongly supports this observation and suggests that high-dose dexamethasone should not be used in elderly patients with poor PS [16]. Ludwig et al. [17] also indicated the correlation between non-myeloma-related mortality and high-dose dexamethasone, especially for those who were elderly and with poor PS. Strategies to curb pyogenic infection are necessary to be explored further.

The situation of first-course MP-related TRM was similar to those reported by Facon et al. [16]: 3 (2.7%) of 109 died in the first 3 months and the causes of death included pyogenic infection (one patient), cardiac event (one patient), and neurologic event (one patient). In our study, only one (1.3%) mortality occurred in the MP group, and this patient died of deep vein thrombosis (survival: 26 days). Thus, our result is consistent with their result.

In conclusion, VAD should be used with caution as an induction therapy in multiple myeloma patients who are elderly and/or have poor PS because it is not appropriate for initial therapy in these patients. Several new effective agents, such as thalidomide and bortezomib, have been introduced for treating multiple myeloma [18–20]. No simple “one-size-fits-all” treatment paradigm for multiple myeloma exists currently [21]. With the availability of so many treatment modalities, a regimen associated with high early TRM should not be used as first-line therapy for patient who are elderly and/or have poor PS.

Methods

The medical records of patients with multiple myeloma diagnosed in our hospital between September 1998 and August 2006 were reviewed. The data of those patients who received the first course of chemotherapy with either VAD or MP were collected for analysis. The diagnosis of plasma cell disorders was based on commonly accepted criteria [22–24]. The clinical stage of multiple myeloma was determined according to the ISS [25].

The VAD regimen comprised vincristine (0.4 mg/day, continuous infusion for 24 hr on days 1–4), doxorubicin (9 mg/m²/day, continuous infusion for 24 hr on days 1–4), and decadron (40 mg/day, intravenous bolus on days 1–4, 9–12, and 17–20). The MP regimen comprised 4-day oral administration of melphalan (8mg/m²/day) and prednisolone (60 mg/m²/day). Full drug doses were administered if granulocytes were >2 × 10⁹/L and platelets were >100 × 10⁹/L. A graded dose-reduction scheme was used for lower granulocyte and/or platelet counts according to the National Cancer Institute's proposed guidelines for anticancer drugs. Impaired renal function was defined as having serum creatinine level ≥2 mg/dL. Patients were placed in the VAD or MP group depending on the regimen used in the first course of chemotherapy.

Mortality related to the first course of treatment (first-course TRM) was ruled in if the patient died to any complication (e.g., pneumonia, septic shock, etc.) related to VAD or MP after first administration. Neutropenia was defined as absolute neutrophil count <0.5 × 10⁹/L. A patient's PS was graded using Eastern Cooperative Oncology Group Scale [26]. Overall survival was defined as the interval between the first day of first-course chemotherapy and death of the patient.

Statistical Package for the Social Sciences (version 13; SPSS, Inc., Chicago, IL) was used for analysis. Survival analysis with the Kaplan–Meier estimate was used with the log-rank test for comparing overall survival rates between groups. The χ² test was used to analyze the distribution of treatment groups. Clinical and laboratory data were analyzed using binary logistic regression, with TRM after the first-course chemotherapy. Parameters shown to be significant in univariate analysis were included in multivariate analysis. The level of statistical significance was set at 0.05 (P < 0.05) for all tests.

Hao-Wei Teng* †, Chung-Jen Teng* † ‡, Wei-Shu Wang† ‡, Po-Min Chen* †, Tzeon-Jye Chiou* †, Hui-Chi Hsu† §, Jin-Hwang Liu* †, Chueh-Chuan Yen* †, Liang-Tsai Hsiao* †, Muh-Hwa Yang* †, Ta-Chung Chao* †, Ya-Hsu Yang¶, Jyh-Pyng Gau* †, * Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China, † National Yang Ming University School of Medicine, Taipei, Taiwan, Republic of China, ‡ Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan, Republic of China, § Department of Hematology and Oncology, Yangming Branch, Taipei City Hospital, Taipei, Taiwan, Republic of China, ¶ Zhongxiao Branch, Taipei City Hospital, Taipei, Taiwan, Republic of China.