VAD Chemotherapy versus Bortezomib Containing Regimens as Remission Induction For ASCT in Multiple Myeloma: A Single Center Experience.

Introduction

Multiple myeloma (MM) is a hematological neoplasm of origin from B cell in bone marrow. MM cases have a monoclonal protein (M-protein) in serum and urine as a results of an uncontrolled proliferation of plasma cells 1 . The most clinically findings of MM are characterized by hypercalcemia, renal failure, anemia and bone lesions. Approximately 1 to 2 percent of the all malignancy, and 15 percent of the hematologic neoplasms consist of MM cases 2 . İt’s known that MM is not curable disease, and so the aim of the MM treatment is to be increasing the patient quality of life and disease free survival of MM cases 3 .

According to patient’s chronological age and patient’s performance status, treatment approaches in MM is differently. The initial estimation for choosing to treatment of MM is depending on eligiblity for high dose therapy (HDT) and autologous stem cell transplantation (ASCT) based on patient’s age, performance status and comorbidities 4 . The complete response and very good partial response before ASCT are targeted by the induction chemotherapy protochols in the ASCT-candidates MM patients 5 . At the present time, the published data shows that tree-drug regimens including immunomodulatory drugs, proteasome inhibitors, alkylating agents and corticosteroids, are the mainstay of initial therapy for induction chemotherapy of pre-ASCT 3 . In recent years, the avaliable data showed that the overall survival time and patient’s quality of life in MM cases is improved by usage the novel agents 6 .

MM cases has been used as induction treatment by in VAD regimen (vincristine-doxorubicin-dexamethasone) in historically. Using the VAD regimen as induction chemotherapy in pre-ASCT period, it was compared with the older regimens including (Melphalan+ Prednison) and the data showed which VAD regimen was more potent and not disturbing the mobilization of stem cells 7 . A different report was showed that the the rate of complete response and overall survival were 27% and 84% by the induction chemotherapy as VAD regimen 8 . On the other hand, a published data showed that overall response rate by using bortezomibe containing regimens including bortezomibe with cyclophosphamide plus dexamethasone or lenalidomide plus dexamethasone was 63 % and 73% in pre ASCT period, respectively 9 . İn a nowadays, while the VAD regimen that it must be with hospitalization for administration, is not preferred, the bortezomibe containing regimen which are easier administration and improving response rates is preferred 9 .

When we look at the litarature, although the VAD ptotokol as pre-ASCT induction therapy is outdated, we couldn’t find enough the data that were compared with survival rate in post ASCT period of bortezomib-containing regimens and VAD protochol. Aim of this study is offering the data that it was compared with response rate and survival effect of VAD regimen and bortezomibe containing regimens as pre-ASCT induction chemotherapy, retrospectively.

MATERIALS AND METHODS

Patients

The data of ninety six by ASCT eligible-MM cases who were followed-up in the Hematology Department of Ataturk Training and Research Hospital between 2008-2018 were retrospectively analyzed. Our study is a retrospective study, approval of local ethics committee and retrospective data screening was performed.All of cases was diagnosed by The İnternational Myeloma Working Group criteria for MM 1 . ASCT eligilibity in MM cases was determined by presence of age ≤70 years, ECOG (Eastern Cooperative Oncology Group) performans status ≤2, and New York Heart Association functional status ≤ 2, absent of cirrhosis of the liver. All of MM patient's biochemical parameters, beta 2 microglobulin, hemoglobin value, white blood cell count, platelet count, sedimentation, ISS stage, precense of extramedullary mass, presence of lytic bone lesions, presence of pathological fracture, range of plasma cell in bone marrow was recorded at the initial diagnosis time, at the second – fourth –sixth cycles of induction chemotherapy. Complete response, partial response, very good partial response and progressive disease, and relapse disease states were recorded in the pre-ASCT induction period. The time of overall survival, progression free survival were recorded in post-ASCT period and during the follow-up period in cases without ASCT treatment. This study has been designed in accordance with 2013 Brazil version of Helsinki Declaration and was approved by the local Ethics Committee.

Treatment Regimens

The bortezomibe containing regimens administrated as that it was used to every 21 days as 1,8,15,21 days by using 1,3 mg/m 2 bortezomibe, 1,8,15 days by using 300 mg/m 2 cyclophosphamide, and 1,8,15,21 days by using 40 mg dexamethasone. İn the first cycle, dexamethasone was administrated four days as 40 mg in 1,8 days. According to treatment response, bortezomib contained regimens was given 4 or 6 cycles as pre-ASCT induction chemotherapy.

The use of infusional VAD protochols was administered as usage of protochols that 0,4 mg vincristine and 9 mg/m 2 doxorubicin was given each day by continuous infusions four days, and 40 mg dexamethasone was given on days 1 to 4, 9 to 12, and 17 to 20 of each of every 28 days.

MM patients without ASCT treatment was administrated 6-8 cycle bortezomibe containing regimens or four cycle VAD protochols as first line therapy.

Stem Cell Harvest Procedure and ASCT

ASCT was performed by achieving after at least partial response. Treatment response was evaluated by determining plasma cell in bone marrow and monoclonal M protein in serum or urine and absence of plasmocytoma.

MM cases were prepared for ASCT with melphalan 200mg/m 2 .

Evaluation response criteria to treatment

According to the IMWG response criteria, we determined the situation of complete response (CR), very good partial response (VGPR), partial response (PR), progressive disease (PD).

CR criteria is described by disappeared monoclonal M protein in serum and urine by immunofixation, and soft tissue plasmocytoma, <5% clonal plasma cells in bone marrow.

VGPR criteria is described by at least a 90% decreased of monoclonal M protein in urine and serum with or without presence monoclonal M protein in 24 hours urine and serum by immunofixation.

PR criteria is defined by ≥50% reduction of monoclonal M protein in serum and ≥90% reduction of monoclonal M protein in 24-hour urinary or to <200 mg/24 hour urinary monoclonal protein. In addition, soft tissue plasmocytoma at initial diagnosis have 50% reduction rate.

PD criteria was descirabed by >25% increase from lowest response value in the follow-up time:

Monoclonal M protein in serum ( ≥0.5 g/dL absolute increasing).

Monoclonal M protein in urine (≥200 mg/24 hours absolute increasing).

Plasma cell percentage in the bone marrow ( ≥10% absolute increasing).

And , ≥50 percent increase in the size or development of new bone lesions or soft tissue plasmacytomas.

Relapse was defined by the determining any clinical findings of MM including arising of serum creatinin ≥2 mg/dL, increasing serum calcium (>11.5 mg/dL), decreasing value of hemoglobin (≥2 g/dL), improving hyperviscosity by paraproteinemia in the serum.

Statistical analysis

Normality distributions of study groups were evaluated by the Kolmogorov-Smirnov test. The parametric values were given as mean ± SD, non-parametric values were given as median (Inter Quartile Range). Comparisons were done with Student’s t-test in cases of normal distribution and with Mann-Whitney U test in cases of asymmetrical distribution. The Spearman and polyserial correlation coefficients were calculated to evaluate the relationship between the measurements. Kaplan-Meier's curves were used for overall survival analysis. P < 0.05 was considered statistically significant.

Results

When the data of 96 cases who was candidate for autologous stem cell transplantation under the age of 70 years old were examined, it was observed that 66 cases received an induction regimen with bortezomib and 30 patients received an induction regimen with VAD ( Table 1 ). İt was observed that autologous stem cell transplantation was performed in 74 cases, autologous stem cell transplantation was not performed in 22 cases. It was compared patients treated by ASCT after induction chemotherapy and treated by only chemotherapy, we found that stage of ISS III (p=0.048), presence of high B 2 –microglobulin (≥ 5.5 mg/L) (p=0.028) was more frequently in patients with non undergoing ASCT, but at least VGPR before ASCT was more frequently in patients with undergoing ASCT (p=0.031).

Ten (45 %) of the 22 patients without autologous stem cell transplantation were lost during the induction regimen.We questioned the reasons for the non undergoing ASCT treatment in the remaining 12 patients, 6 (27.7 %) patients had comorbidity and 6 (27.7 %) patients did not accept with treated by ASCT. In these 12 cases non undergoing ASCT, 8 (66.6 %) cases had treated with VAD and 4 (33.3 %) had treated with bortezomib (p >0.05). The cases who did not undergo ASCT because of comorbidity were 3 of 4 cases using bortezomib in induction and 3 of 8 cases using VAD (p = 0.245).

The patients who was administered induction chemotherapy by bortezomibe containing regimens and by VAD protocol was compared with each other, according to the presence of achieving at least PR in the second month during the pre-ASCT period, the presence of achieving PR / CR and VGPR rates before the pre-transplant period, No statistically significant difference was found between the two groups of patient and it was showed at Table 2 . When 22 patients of non undergoing ASCT were excluded from statistically analyze, the response rates (at least PR, CR, VGPR in pre ASCT period and relapses in post ASCT period) were compared to treatment with Bortezomibe containing regimens and VAD protocols in induction cycle for patients undergoing ASCT. The response and relaps rates of Bortezomib containing regimens and VAD protocol were not different for undergoing ASCT patients, and it was showed in Table 3 .

When we performed survival analysis of our cases, the overall survival was 91.3 (±6 months) months in undergoing ASCT patients and 43 (±9 months) months in non undergoing ASCT patients, OS of undergoing ASCT patients was more longer and it was statistically significantly (p=0.001). İt was shown in Figure 1 .

In cases who VAD protocol was applied as induction regimen, patients who received bortezomib-containing chemotherapy as induction regimen were compared according to their OS, and, the mean OS of the cases receiving VAD protocol was found to be 87.4 (± 6.5) months and the mean OS of the cases receiving bortezomib-containing chemotherapy was 81.5 (± 9.3) months (p = 0.854). Figure 2 shows that the comparisions of overall survival according to induction therapy including bortezomib containin regimens and VAD therapy.

The OS analysis of 74 cases with autologous transplantation was evaluated 59.4 (± 14.8 ) months for bortezomibe containing regimen patients and 77.3 (± 5.4) months for VAD protocol patients respectively (p = 0.126). İt was shown in the Figure 3 . The progression free survival for 74 patients by ASCT treatment, it was 82.5 (±15) months for patients with bortezomib containing regimens as induction treatment and it was 79.8 (±7.3) months for patients with VAD protochols as induction treatment (p=0.717). The total survival of patients who underwent ASCT after reaching at least VGPR was longer than that of stem cell transplantation without reaching VGPR (p=0.019). İt was showed in Figure 4 . The OS of patients who underwent ASCT after reaching at least VGPR was 87.6 ± 7.9 months and, the OS of patients who underwent ASCT after without reaching at least VGPR was 49.5 ± 9.45 months.

Results

The standart treatment approach for MM cases who are younger than 65 years old, is high-dose therapy with ASCT after induction chemotherapy (10). İn our study, we compared with the treatment by VAD protocol and the bortezomib containing regimens as induction chemotherapy for ASCT eligible multiple myeloma patients. When we observed the status of the achieving of response to the treatment (PR, CR, VGPR, PD, relapses disease) in pre-ASCT or post-ASCT period, and the survival time (OS, PFS) on the follow-up period, we could not find a difference. İt was shown in our work in accordance with the literature that the total survival of the patients who had ASCT longer than the patients who did not 11 .

In 1990’s, VAD protocol were usually applied for pre-ASCT induction chemotherapy. But later in 2005, the first step therapy for multiple myeloma has been shifted to novel agent including proteosome inhibitors such as bortezomib and carfilzomib, immunomodulatory drug such as lenalidomide, monoclonal antibody targeted agent such as daratumomab 12 , 13 .

The response ratio of VAD protocol in our data was approxiametely similar in previously published data 14 , 15 . In the past study was showed to that the response rate of VAD protocol for induction treatment is approxiametely 10% for the rate of CR 16 . In our study determined too that the rate of CR for VAD induction treatment was 16.7 percent. İn the different study, it was showed that the rate of CR or VGPR was 13% by using VAD protocol in pre-ASCT period, respectively. Again, in this study, the rate of relapse after single ASCT in the first 2 years was found to be 17% 14 . İn the other study evaluated that the rate of CR, VGPR and PR by VAD protocol for pre-ASCT induction chemotherapy was 5 percent, 12 percent and 61 percent, respectively 17 . İn the newly diagnosed MM cases that prepared by 200 mg melphalan as conditioning regimens for ASCT and VAD inductiopn chemotherapy was found 6 percent as relaps rate for post-ASCT period in first 2 years 17 . In our study, the relapse rate of MM patients in post ASCT 2 years was 13.3 percent with VAD induction chemotherapy and 7.6 percent by bortezomib conditioning regimens and there was not statistically significant difference. In a previously study, pre-ASCT induction regimens by bortezomib containing regimens with VAD protocol were compared to each other, as a result, CR and VGPR ratios were higher in the bortezomib group in the pre-ASCT period, but similar to our findings, the survival in post-ASCT period did not differ according to the induction regimen 18 .

Although the response rates and total survival times in our study were not different in treatment by VAD protocol and bortezomib containing regimens, it was clear that there were different results when we look at the literature. İn a study was showed that bortezomibe containing treatment in only initial diagnosed patients had a significantly increase in the CR and VGPR rates but post-ASCT survival and at least PR rates before ASCT were similar by the treatment with bortezomibe containing regimens or VAD protocol for induction 18 . In HOVON-65 / GMMG-HD4 Randomized Phase III Trial, overall survival rates were similar when VAD and PAD (bortezomib-adriamycin and dexamethasone) treatments were compared in the group with normal creatinine value, however, PAD was superior in the group with impaired renal function 19 . İn recent years, bortezomib-containing induction regimens and bortezomib-free induction regimens were compared in the published meta-analysis, it was suggested that CR/VGPR ratio in post-ASCT and OS / PFS was concluded to be superior by the bortezomib containing chemotherapy 20 . According to the IFM 2005-01 Phase III Trial, it was described that CR, at least VGPR and overall response rates were significantly higher with bortezomib plus dexamethasone versus VAD. İn addition, in the same study was showed that CR, at least VGPR rates were significantly higher with bortezomib plus dexamethasone after first transplantation 21 . In our results were showed that pre-ASCT at least PR rates were 83.3% and 100% for bortezomibe containig regimens and VAD protocol, respectively. Our data was determined that at least the PR ratios for the VAD protocol before the ASCT, were higher than the previous publications reporting that the response rates were up to 84% 22 , 23 .We think that patients should take into consideration basal clinical and laboratory findings, treatment modalities (such as, bolus or continuous infusion and doxorubicin, and dexamethasone dosage) in order to explain the different results published in previous years about the response rates of the VAD protocols.

Induction therapy prior to ASCT is important to improve the stabilization of organ functions and the patient's performance status. Pre-transplant induction therapy must be at the convenience and low toxicity for stem cell collection process. İt was shown that using VAD protocol or bortezomib containing induction regimens were not different in stem cell mobilization 24 , 25 . İt is known the VAD chemotherapy is not dangerous normal bone marrow progenitors and provides quick responses 16 , 26 . In additionally, it should also be noted that VAD protocol has difficulty in administration according to agents containing bortezomib, because hospitalization is required and can be administered by continuous infusion, which can be exhausting for the patient and the physician.

One of the limitations of our study was the lack of genetic risk classification of our patients. In addition, in the group receiving VAD for induction chemotherapy, it is also important to consider which agents are used in second line treatment.

The result of this retrospective comparison showed that respone rates and assessment of survival data were similar in treatment by VAD protocol and bortezomibe containing regimens. We know that ASCT treatment also can be benefit patients with primary refractory disease, because the survey may be due to the total response after ASCT, regardless of the response to induction therapy.

CONLUSION

In our study, it was demonstrated that the OS was similar for bortezomib-containing chemotherapy and VAD as pre-ASCT induction chemotherapy. Both treatments are effective and their toxicity is predetermined and manageable treatment options.Although the applicability of VAD chemotherapy requires hospitalization, we can say that it is still an option in induction due to similar OS rates. However, we think it is appropriate to support our results with more comprehensive studies on this subject.

Acknowledgment

All authors have contributed appropriately to be listed and have agreed to the publication of the study results.

CONFLICT OF INTEREST

Authors have no conflicts of interest to declare.

Statement of Ethics

The study protocol was approved by an appropriate ethics committee.

Funding Sources

The authors declared that this study has received no financial support.

References

1 Rajkumar SV Dimopoulos MA Palumbo A International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014 15 12 e538 48 25439696 10.1016/S1470-2045(14)70442-5

2 Siegel RL Miller KD Jemal A Cancer statistics, 2018 CA Cancer J Clin 2018 68 1 7 30 29313949 10.3322/caac.21442

3 Palumbo A Cavallo F Gay F Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 371 10 895 905 25184862 10.1056/NEJMoa1402888

4 Macro M Divine M Uzunhan Y Dexamethasone+Thalidomide (Dex/Thal) Compared to VAD as a Pre-Transplant Treatment in Newly Diagnosed Multiple Myeloma (MM): A Randomized Trial Blood 2006 108 57

5 Harousseau JL Attal M Leleu X Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study Haematologica 2006 91 11 1498 505 17043025

6 Bray F Ren JS Masuyer E Global Estimates of cancer prevalence for 27 sites in the adult population in 2008 Int J Cancer 2013 132 5 1133 1145 22752881 10.1002/ijc.27711

7 Zhao Y [The efficacy and safety of PAD and VAD regimens for untreated multiple myeloma] Zhonghua Nei Ke Za Zhi 2010 49 9 762 4 21092447

8 Anderson H Scarffe JH Ranson M VAD chemotherapy as remission induction for multiple myeloma Br J Cancer 1995 71 2 326 30 7841049 10.1038/bjc.1995.65 PMC2033610

9 Kumar S Flinn I Richardson PG Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma Blood 2012 119 19 4375 82 22422823 10.1182/blood-2011-11-395749

10 Child JA Morgan GJ Davies FE High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma N Engl J Med 2003 348 19 1875 83 12736280 10.1056/NEJMoa022340

11 Gay F Oliva S Petrucci MT Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial Lancet Oncol 2015 16 16 1617 29 26596670 10.1016/S1470-2045(15)00389-7

12 Roussel M Lauwers-Cances V Robillard N Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome J Clin Oncol 2014 32 25 2712 7 25024076 10.1200/JCO.2013.54.8164

13 Mateos MV Dimopoulos MA Cavo M Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma N Engl J Med 2018 2 8 378 6 518 528 29231133 10.1056/NEJMoa1714678

14 Attal M Harousseau JL Facon T Single versus double autologous stem-cell transplantation for multiple myeloma N Engl J Med 2003 349 26 2495 502 14695409 10.1056/NEJMoa032290

15 Lokhorst HM Schmidt-Wolf I Sonneveld P Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma Haematologica 2008 93 1 124 7 18166796 10.3324/haematol.11644

16 Raje N Powles R Kulkarni S A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma Br J Haematol 1997 97 1 153 60 9136958 10.1046/j.1365-2141.1997.d01-2122.x

17 Moreau P Facon T Attal M Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial Blood 2002 99 3 731 5 11806971 10.1182/blood.v99.3.731

18 Eom HS Min CK Cho BS Retrospective comparison of bortezomib-containing regimens with vincristine-doxorubicin-dexamethasone (VAD) as induction treatment prior to autologous stem cell transplantation for multiple myeloma Jpn J Clin Oncol 2009 39 7 449 55 19487425 10.1093/jjco/hyp046

19 Sonneveld P Schmidt-Wolf IG van der Holt B Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial J Clin Oncol 2012 30 24 2946 55 22802322 10.1200/JCO.2011.39.6820

20 Sonneveld P Goldschmidt H Rosiñol L Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials J Clin Oncol 2013 31 26 3279 87 23897961 10.1200/JCO.2012.48.4626

21 Harousseau JL Attal M Avet-Loiseau H Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial J Clin Oncol 2010 28 30 4621 9 20823406 10.1200/JCO.2009.27.9158

22 Anderson H Scarffe JH Ranson M VAD chemotherapy as remission induction for multiple myeloma Br J Cancer 1995 71 2 326 30 7841049 10.1038/bjc.1995.65 PMC2033610

23 Segeren CM Sonneveld P van der Holt B Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma Br J Haematol 1999 105 1 127 30 10233375

24 Jagannath S Durie BG Wolf J Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma Br J Haematol 2005 129 776 83 15953004 10.1111/j.1365-2141.2005.05540.x

25 Oakervee HE Popat R Curry N PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma Br J Haematol 2005 129 755 62 15953001 10.1111/j.1365-2141.2005.05519.x

26 26-Kyle RA Rajkumar SV Multiple myeloma N Engl J Med 2004 351 1860 73 15509819 10.1056/NEJMra041875