This study was presented at the 17th International Myeloma Workshop as a poster presentation (September 12–15, 2019).
A three-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CVD) shows significant efficacy and manageable toxicity as induction therapy in patients with multiple myeloma.
In this phase II study, we enrolled 45 patients who achieved a very good partial response (VGPR) or partial response (PR) after autologous stem cell transplantation (ASCT) and evaluated the efficacy and toxicity of CVD consolidation. CVD consolidation comprised three cycles of cyclophosphamide 300 mg/m2 orally on days 1, 8, and 15, and bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, and 22, along with dexamethasone 20 mg orally or intravenously on days 1 and 2, 8 and 9, 15 and 16, and 22 and 23.
At enrollment, 39 patients (86.7%) showed VGPR, and nine (13.3%) presented with PR. Nineteen patients (45.2%) achieved a complete response or better as their best response after the end of consolidation. Overall, 22 of 42 patients (52.4%) experienced an improved response status with CVD consolidation. Three-year overall survival and progression-free survival rates were 89.0% and 42.7%, respectively. The most common non-hematologic toxicities were peripheral neuropathy and infection (20.5%), with no grade ≥ 3 neuropathy observed.
These results showed that CVD consolidation therapy improved the response with reasonable toxicity in patients with residual disease after ASCT. This trial was registered with the Clinical Research Information Service, Republic of Korea (KCT0001327).
Multiple myeloma (MM) is a neoplastic disease characterized by monoclonal proliferation of plasma cells and accounts for ~1%–2% of malignancies [
Although ASCT is generally tolerable and associated with acceptable mortality, even in elderly patients, patients receiving ASCT frequently experience incomplete immunity, prolonged cytopenia, peripheral neuropathy, and organ dysfunctions [
Bortezomib is a potent first-in-class proteasome inhibitor showing remarkable efficacy in newly diagnosed and relapsed/refractory MM [
Patients aged ≥ 20 years diagnosed with symptomatic MM and treated with at least one induction chemotherapy, including a thalidomide- or bortezomib-based regimen, or VAD and ASCT, were included in this trial. All eligible patients were required to present a very good partial response (VGPR) or partial response (PR) on evaluation within 10–14 weeks after the infusion of autologous stem cells and no clinical evidence of disease progression until study enrollment. Other eligibility criteria included the following: appropriate bone marrow function, which was defined as absolute neutrophil count > 1,000/μL, hemoglobin > 9.0 g/dL, and platelet count > 70,000/μL; appropriate liver function, which was defined as serum transaminases and serum total bilirubin < 3-fold higher than the upper normal limit; no evidence of congestive heart failure with left ventricular ejection fraction (LVEF) of > 50%; Eastern Cooperative Oncology Group performance status between 0 and 2; negative pregnancy test result or menopausal period of > 1 year if of child-bearing age; life expectancy of > 6 months; willingness to provide written informed consent. Exclusion criteria were as follows: diagnosis of primary amyloidosis, smoldering MM, or monoclonal gammopathy of undetermined significance; plasma cell leukemia with peripheral plasma cells at > 20%; grade ≥ 2 peripheral neuropathy; grade ≥ 2 toxicity due to previous treatment, including ASCT; progressive disease (PD) after ASCT; having received other post-ASCT therapies, such as chemotherapy and/or radiation; positive for human immunodeficiency virus; active hepatitis B and/or hepatitis C infection; previous hypersensitivity to bortezomib, boron, or mannitol; presenting a severe acute infection requiring urgent treatment; currently pregnant or breast-feeding; symptomatic heart failure or LVEF < 50%; history of any other malignant disease, except basal cell carcinoma or
This multicenter, single-arm, open-label phase II study was conducted at 12 centers in Korea, with enrollment between July 2014 and January 2018. The trial comprised three periods: screening, treatment, and follow-up. During the screening period, patients who received ASCT and showed VGPR or PR within 10–14 weeks after the infusion of autologous stem cells were recruited, and baseline evaluations were performed for enrollment. All patients satisfying the inclusion criteria started treatment within 2 weeks. During the treatment period, three 4-week cycles of oral cyclophosphamide 300 mg/m2 on days 1, 8, and 15; subcutaneous bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22; and oral or intravenous dexamethasone 20 mg/day on days 1 and 2, 8 and 9, 15 and 16, and 22 and 23 were performed. Bone marrow examination was performed at the study enrollment and the end of treatment, and minimal residual disease (MRD) was assessed using clonoSEQ (v2.0, Adaptive Biotechnologies, Seattle, WA). To prevent infectious diseases, such as those associated with
Dose escalation was not allowed during the study period. Bortezomib dose reductions were stipulated for grade 4 thrombocytopenia (< 25,000/μL) or neutropenia (< 500/μL) that recurred or did not recover within two days and/or grade 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain (level-2, 1.0 mg/m2; or level-3, 0.7 mg/m2). Cyclophosphamide dose reductions were performed for grade 3 non-hematologic adverse events or grade 4 hematologic adverse events. In cases of grade 4 hematologic adverse events, dose modification of cyclophosphamide was performed preferentially before the dose of bortezomib was modified. Dexamethasone was administered if bortezomib was administered or if dexamethasone-related grade 3 adverse events were observed.
Categorical and continuous variables were assessed using Fisher exact test and the Mann-Whitney U test, respectively. Survival data and skeletal-related events were analyzed using Kaplan-Meier curve estimates. Overall survival (OS) was defined from the start of consolidation therapy to the date of death from any cause or the last follow-up date. Progression-free survival (PFS) was calculated from the start of consolidation therapy until the date of disease progression or death. Differences were considered statistically significant at a two-sided p < 0.05. All statistical analyses were performed using SPSS ver. 21.0 (IBM Corp., Armonk, NY).
Sixty patients with symptomatic MM who achieved PR or VGPR after ASCT were initially screened. Of these, 13 patients did not meet the eligibility criteria, and two refused to participate in the study. Subsequently, 45 patients were enrolled in this study (
All patients were available for response evaluation before and after consolidation therapy.
After completing consolidation therapy, 13 patients (30.9%) achieved complete response (CR) or better, of whom 12 presented with VGPR and one showed PR initially at the time of study enrollment. Among 22 patients (52.4%) who presented with VGPR at the end of consolidation therapy, four showed PR at enrollment. Overall, 18 of 42 patients (42.9%) experienced an improved response status immediately after completion of the consolidation therapy. Two patients had PD after completing consolidation therapy, and both presented high-risk cytogenetics at diagnosis and t(4;14) according to fluorescent
Additionally, we identified further improvement in response status during the follow-up visit after the end of the treatment in seven patients. Four patients who showed VGPR at the completion of consolidation therapy achieved CR or stringent CR during follow-up. One patient who showed PR revealed VGPR later, and two patients who presented with stable disease showed improved responses to VGPR and PR, respectively. The median time to best response from the start of CVD consolidation was 3.3 months (range, 1.9 to 27.5 months). Furthermore, 22 of the 42 patients (52.4%) experienced an upgraded response status with CVD consolidation therapy.
During the follow-up period (designated as 36 months after completion of consolidation therapy), clinical outcomes, including survival data, disease progression, and next treatment, were analyzed. Three-year OS and PFS were 89.0% and 42.7%, respectively (
During follow-up, 22 patients started the next treatment, with a median time to the next treatment of 34.9 months. Of these, 11 patients received carfilzomib-based therapy, and seven were treated with a bortezomib-based regimen.
Skeletal-related events, including new pathologic fracture, spinal cord compression, skeletal-related surgery, and radiation therapy of skeletal lesions, were observed during the study period among 41 available patients. The cumulative incidence of skeletal-related events was 16.3% within 3 years after completion of consolidation therapy (
Additionally, we compared bone density before and after consolidation therapy. According to World Health Organization criteria (osteoporosis: ≥ 2.5 standard deviations of bone density T-score below the mean of a young adult reference population; and osteopenia: 1–2.5 standard deviations below the mean of a young adult reference population), 11 of 29 available patients (37.9%) showed osteoporosis before consolidation therapy, whereas only four (20.0%) had osteoporosis after the completion of consolidation therapy (p=0.050) (
We assessed the degrees of neuropathy and pain response using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG/NTX) and the numeric rating scale (NRS) during and after consolidation therapy to evaluate the quality of life.
Thirty patients received the planned therapy sequence without dose modification or changes to the treatment schedule. Ten patients were required to skip the planned drug administration, with the most common reason being hematologic adverse events, such as neutropenia (n=5) and thrombocytopenia (n=2), whereas three patients skipped due to elevated transaminase levels and occurrences of rectal fistula and herpes zoster infection, respectively. Patients with rectal fistula stopped all planned administrations after the 3rd week of the 2nd cycle, at which point bortezomib had been administered seven times, whereas the other patients received at least 11 doses of bortezomib. Dose reduction was required in five patients, three of whom received a reduced dose of bortezomib due to grade 2 peripheral neuropathy (n=2) and elevated transaminase levels (n=1). Delayed administration occurred in seven patients, with neutropenia being the most common reason (n=3), and others included peripheral neuropathy, herpes zoster infection, and increased transaminase levels.
All treated patients were graded for toxicity, which was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v4.03). Overall, the most common adverse events were peripheral neuropathy and infection, which occurred in nine patients (20.5%) separately; however, most cases were grade 1 or 2, and no patient had grade ≥ 3 neuropathy (
In this study, 45 patients who achieved PR or VGPR after ASCT were treated with three cycles of consolidation therapy comprising CVD. The results showed that CVD consolidation immediately increased the quality of response status in almost 50% of enrolled patients at the end of treatment. Additionally, further improvement was observed during the follow-up period, with 45.2% of available patients achieving CR or better after completion of CVD consolidation therapy. Survival rates at 3 years were 89.0% (OS) and 42.7% (PFS), and the toxicity profile was acceptable, with most non-hematologic adverse events, including neuropathy, being grade 1 or 2.
MM is incurable, and disease relapse is usually inevitable in most patients, even with the development of diverse therapeutic strategies, such as the introduction of novel agents and ASCT. In this respect, emphasis should be placed on decreasing the disease burden in order to prolong survival outcomes and delay relapse in patients who have residual disease after ASCT following induction therapy, given the significant association between achieving optimal response status and survival outcomes [
As previously noted, the clinical benefits of bortezomib-based consolidation therapy remain unclear. Zhang et al. [
Bone lesions are an important hallmark of MM and usually persist even after achieving CR. This study revealed that bone density significantly improved with consolidation therapy, and that the rate of patients with osteoporosis receiving this therapy decreased by almost 50%. These results agree with a previous study reporting correlations between improved bone density and decreased tumor burden [
To the best of our knowledge, this study is the first to investigate the efficacy and toxicity of CVD consolidation therapy. The CVD regimen showed compatible efficacy along with a relatively tolerable toxicity profile. In particular, there was no grade ≥ 3 neurotoxicity in the study population, which might be due to the composition of the regimen and the relatively short duration of the consolidation treatment. Additionally, the results demonstrated tolerability in terms of the scale of neurotoxicity (FACT-GOG/NTX) and pain response (NRS). The strength of this study might be that we included patients with residual disease, even after ASCT. Moreover, this study has practical significance, as we suggest a post-ASCT treatment option for patients who are expected to have a relatively high risk of early progression after ASCT.
We also assessed the value of MRD status with CVD consolidation therapy. MRD-negativity, defined according to changes in dominant clones during consolidation therapy, showed meaningful results in the patients. Additionally, the results for MRD status were significant relative to the post-consolidation response status. Although there were limitations in defining clonal assessment owing to the lack of initial samples at diagnosis, the results showed that MRD assessment would be valuable with CVD consolidation. This study enrolled a considerable number of patients initially treated with a doublet regimen, currently largely substituted by a triplet or quadruple regimen. Although we found no meaningful difference according to the induction regimens in our patients, the role of CVD consolidation therapy with newly adapted induction regimens warrants further investigation.
In conclusion, three cycles of CVD consolidation therapy in patients presenting with VGPR or PR after ASCT showed an improved response status and comparable survival results with acceptable toxicity profiles.
Supplementary materials are available at Cancer Research and Treatment website (
The Institutional Ethics Committee approved this study (approval number: NCCCTS13679), which was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before enrollment.
Conceived and designed the analysis: Min CK, Eom HS.
Collected the data: Jung J, Kim K, Jung SH, Yoon SS, Lee JH, Kim JS, Shin HJ, Bang SM, Sohn SK, Suh C, Yoon DH, Min CK, Eom HS.
Contributed data or analysis tools: Jung J, Kim K, Jung SH, Yoon SS, Lee JH, Kim JS, Shin HJ, Bang SM, Sohn SK, Suh C, Yoon DH, Kong SY, Min CK, Eom HS.
Performed the analysis: Jung J, Kong SY, Eom HS.
Wrote the paper: Jung J, Min CK, Eom HS.
Conflict of interest relevant to this article was not reported.
We thank Dr. Jongkwang Kim (Research Core Center, National Cancer Center, Korea) and Dr. Namshik Han (University of Cambridge) for their bioinformatics support and valuable review of the manuscript.
CONSORT diagram of the study population. CVD, cyclophosphamide, bortezomib, and dexamethasone.
Kaplan-Meier curves after consolidation therapy. Kaplan-Meier curves of overall survival (A) and progression-free survival (B) in patients who received consolidation chemotherapy comprising cyclophosphamide, bortezomib, and dexamethasone after autologous stem cell transplantation for multiple myeloma.
Kaplan-Meier curves according to minimal residual disease (MRD) status after consolidation therapy. Kaplan-Meier curves of overall survival (A) and progression-free survival (B) according to MRD status after consolidation therapy.
Kaplan-Meier curves according to response status and minimal residual disease (MRD) after consolidation therapy. Kaplan-Meier curves of overall survival (A) and progression-free survival (B) according to response status and MRD after consolidation therapy. CR, complete response.
Baseline demographics and clinical characteristics
Characteristic | Value (n=45) |
---|---|
Male | 29 (64.4) |
Female | 16 (35.6) |
54 (35–62) | |
IgG | 29 (64.4) |
IgA | 9 (20.0) |
Light chain only | 7 (15.6) |
Kappa | 31 (68.9) |
Lambda | 14 (31.1) |
I | 13 (28.9) |
II | 21 (46.7) |
III | 11 (24.4) |
3.4 (2.2–5.5) | |
3.44 (1.97–19.5) | |
8 (17.8) | |
43.5 (2–99) | |
4.59 (0–27.3) | |
29.7 (0–6,789) | |
Normal | 35 (77.8) |
Abnormal | 10 (22.2) |
del13q | 4/23 (17.4) |
del17p | 1/22 (4.5) |
t (4;14) | 4/22 (18.2) |
t (14;16) | 0/19 (0) |
t (11;14) | 4/19 (8.9) |
Standard risk | 19/24 (79.2) |
High risk |
5/24 (20.8) |
TD | 23 (51.1) |
VTD | 19 (42.2) |
VMP | 1 (2.2) |
CTD | 1 (2.2) |
VCD | 1 (2.2) |
G-CSF only | 21 (46.7) |
G-CSF with chemotherapy | 24 (53.3) |
MEL200 | 35 (77.8) |
MEL140 | 1 (2.2) |
BUMEL | 1 (2.2) |
BUTHIO | 8 (17.8) |
Values are presented as number (%) or median (range). ASCT, autologous stem cell transplantation; BUMEL, busulfan and melphalan; BUTHIO, busulfan, and thiotepa; CTD, cyclophosphamide, thalidomide, dexamethasone; FISH, fluorescent
Defined as del17p or t(4;14) or t(14;16).
Summary of responses
Response | Post-induction | Post-ASCT | Before CVD (baseline) | End of treatment |
Best response |
---|---|---|---|---|---|
sCR | 0 | 0 | 0 | 3 (7.1) | 8 (19.0) |
CR | 1 (2.2) | 1 (2.2) | 0 | 10 (23.8) | 11 (26.2) |
VGPR | 24 (53.3) | 36 (80.0) | 39 (86.7) | 22 (52.4) | 18 (42.9) |
PR | 20 (44.4) | 7 (15.6) | 6 (13.3) | 1 (2.4) | 1 (2.4) |
SD | 0 | 1 (2.2) | 0 | 4 (9.5) | 2 (4.8) |
PD | 0 | 0 | 0 | 2 (4.8) | 2 (4.8) |
sCR plus CR | 1 (2.2) | 1 (2.2) | 0 | 13 (31.0) | 19 (45.2) |
High-quality response (≥ VGPR) | 25 (55.6) | 37 (82.2) | 39 (86.7) | 35 (83.3) | 35 (88.1) |
At least PR | 44 (97.8) | 44 (97.8) | 45 (100) | 36 (85.7) | 38 (90.5) |
ASCT, autologous stem cell transplantation; CR, complete remission; CVD, cyclophosphamide, bortezomib, and dexamethasone; PD, progressive disease; PR, partial response; sCR, stringent complete remission; SD, stable disease; VGPR, very good partial response.
Evaluated in 42 patients,
Thirty-three patients presented their best response at the end of treatment.
Multivariate Cox analyses according to MRD status for OS and PFS
OS | PFS | |||||
---|---|---|---|---|---|---|
|
| |||||
HR | 95% CI | p-value | HR | 95% CI | p-value | |
Pre-consolidation VGPR (vs. PR) | 2.213 | 0.179–27.357 | 0.536 | 0.084 | 0.008–0.916 | 0.042 |
| ||||||
Post-consolidation CR (vs. VGPR or less) | 0.616 | 0.044–8.658 | 0.720 | 0.242 | 0.058–1.008 | 0.051 |
| ||||||
MRD-positivity (vs. negative) | 1.158 | 0.082–16.251 | 0.914 | 5.999 | 1.420–25.349 | 0.015 |
CI, confidence interval; CR, complete response; HR, hazard ratio; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response.
The results of bone mineral density and bone-related markers before and after consolidation
Before consolidation | After consolidation | p-value | |
---|---|---|---|
Bone densitometry (t-score) | −1.8 (n=29) | −1.3 (n=20) | 0.044 |
Osteoporosis, n (%) | 11/29 (37.9) | 4/20 (20.0) | 0.050 |
Osteopenia, n (%) | 11/29 (37.9) | 11/20 (55.0) | - |
Normal, n (%) | 7/29 (24.1) | 5/20 (25.0) | - |
Bone-specific ALP ( μg/L) | 13.2 (n=41) | 9.56 (n=38) | < 0.001 |
Osteocalcin | 15.7 (n=28) | 13.1 (n=32) | 0.353 |
NTX (nM BCE/mM Cr) | 24.0 (n=37) | 15.3 (n=40) | 0.001 |
ALP, alkaline phosphatase; NTX, N-terminal cross-linking telopeptide of type I collagen.
Median values were compared by Wilcoxon signed rank test,
Compared by the McNemar test.
Evaluation of neuropathy and pain response during consolidation
No. of cycles | ||||
---|---|---|---|---|
| ||||
FACT-GOG/NTX | NRS | |||
|
| |||
Median (range) | No. | Median (range) | No. | |
Baseline | 50.5 (22–76) | 40 | 2.0 (0–5) | 38 |
| ||||
C2D1 | 46.0 (11–79) | 39 | 2.0 (0–7) | 38 |
| ||||
C3D1 | 49.0 (3–85) | 37 | 1.0 (0–8) | 34 |
| ||||
EOT | 52.0 (3–84) | 37 | 1.5 (0–8) | 36 |
| ||||
FU3 | 45.0 (18–79) | 27 | 1.5 (0–6) | 26 |
| ||||
FU6 | 49.0 (24–80) | 22 | 2.0 (0–5) | 22 |
| ||||
FU9 | 42.0 (25–65) | 16 | 1.0 (0–7) | 15 |
| ||||
FU12 | 41.0 (19–61) | 15 | 1.0 (0–5) | 13 |
| ||||
FU15 | 41.0 (23–70) | 13 | 0 (0–4) | 12 |
| ||||
FU18 | 49.0 (35–67) | 10 | 0 (0–3) | 10 |
C2D1, the first day of second cycle; C3D1, the first day of third cycle; EOT, end of treatment; FACT-GOG/NTX, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FU, follow-up; NRS, numeric rating scale.
Adverse events in the treated population
Adverse event | Grades 1 & 2 | Grade ≥ 3 | Total |
---|---|---|---|
Neutropenia | 1 (2.3) | 5 (11.4) | 6 (13.7) |
Thrombocytopenia | 2 (4.5) | 3 (6.8) | 5 (11.4) |
Anemia | 1 (2.3) | 0 | 1 (2.3) |
Nausea | 2 (4.5) | 0 | 2 (4.5) |
Vomiting | 1 (2.3) | 0 | 1 (2.3) |
Constipation | 3 (6.8) | 0 | 3 (6.8) |
Diarrhea | 2 (4.5) | 0 | 2 (4.5) |
Elevated transaminase levels | 1 (2.3) | 1 (2.3) | 2 (4.5) |
Neuropathy | 9 (20.5) | 0 | 9 (20.5) |
Infection | 8 (18.2) | 1 (2.3) | 9 (20.5) |
Rash | 5 (11.4) | 0 | 5 (11.4) |
Insomnia | 4 (9.1) | 0 | 4 (9.1) |
Fatigue | 6 (13.7) | 0 | 6 (13.7) |
Dizziness | 1 (2.3) | 0 | 1 (2.3) |
Values are presented as number (%).