Более высокий уровень долгосрочного выживания у лиц, реагирующих на бортезомиб, циклофосфамид, дексаметасоновую индукционную терапию в когорте, имеющей право на трансплантацию, большинство больных миеломой среднего возраста.

INTRODUCTION

Multiple myeloma (MM) is considered the second common hematologic malignancy (15%) and accounts for around 1-% of all malignancies. It is characterized by abnormal clonal proliferation of plasma cells in bone marrow with overproduction of monoclonal immunoglobulin in blood or urine or both. 1 – 5

Although MM is considered a chronic and incurable disease, advances in the last two decades in understanding the biology of the disease, the introduction of a plethora of novel therapies, and better supportive care have almost doubled the overall survival when compared with data from the era before. 6 – 9 The novel therapies, which include immunomodulatory drugs (IMiDs), monoclonal antibodies and proteasome inhibitors (PIs) are used for induction therapy for newly diagnosed MM patients. They are highly effective and are now considered to be the standard of care followed by autologous hematopoietic stem cell transplantation (ASCT) for eligible patients. 5 , 6

Popular induction regimens in transplant eligible MM patients include VCd (d: low dose dexamthasone) (bortezomib, cyclophosphamide and dexamethasone), VTd (bortezomib, thalidomide and dexamethasone) and VRd (bortezomib, lenalidomide and dexamethasone). These regimes produce a high response rate and improved overall survival (OS) when compared to doublets-containing regimens. 3 , 10 , 11

Published data on the VCd regimen shows this combination as an effective treatment with mild toxicity and an excellent overall response rate of around 90%. 12-16 Weekly subcutaneous administration of bortezomib instead of twice-weekly and intravenous protocol showed better tolerance with lesser toxicity and more convenience without impact on outcome and response rate. 17 – 19 Another advantage of the VCd protocol is its tolerability with renal impairment. Due to all of these factors, many centers in the United Kingdom, Europe and Australia adopted the induction with VCD followed by ASCT as a standard of care. 13 , 17

Multiple retrospective trials showed non-inferiority of VCd regimen as compared with VRD in terms of response rate, progression-free survival (PFS) and OS with better tolerability and fewer side effects. 20 , 21

A phase II randomized trial (IFM 2013–14) comparing VTD to VCd showed a better response rate with the VTD regimen; however, the VCd regimen in this study was given in a different schedule than the current way of administration. 22 In another phase II randomized trial (EVOLUTION), VRD was compared to VCd and showed similar response rates, PFS and OS. 16

The current literature does not give a definitive conclusion regarding the best choice of regimen in MM induction. Moreover, clinical trials may overestimate outcomes due to specific inclusion criteria. In contrast, real-world clinical practice allows exploring the therapy's outcome and effectiveness on a heterogeneous group of patients with all age groups and different comorbidities in all populations around the world. Also, there is a paucity of data on the outcome of the VCd protocol in the Middle East and countries with limited resources.

For all the above-mentioned reasons, we conducted our real-world retrospective study to report our experience with VCd regimen in patients with transplant eligible MM who responded to this combination and underwent autologous stem cell transplantation, with evaluation of the long-term SO.

PATIENTS AND METHODS

This retrospective study was conducted at a single tertiary care center between July 2007 and July 2020. The data was collected from the transplantation registry database of King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh. We screened 107 newly diagnosed MM patients who received at least one cycle of VCd induction and then underwent ASCT. We excluded 5 patients with amyloidosis or plasma cell leukemia, but 15 patients did not experience a partial response or more (the overall response rate was 85%). We then recruited only 87 patients who had responded to VCd alone in our analysis. The staging was done by using the International Staging System (ISS) and the Revised International Staging System (R-ISS) where high cytogenetic risk was defined as the presence of at least one of the following abnormalities: 17p deletion, t(4;14) and t(14;16). 23 The study was approved by the institutional review board at KFSHRC. All procedures were conducted in compliance with the ethical standards of the 1964 Helsinki declaration and its subsequent modifications and with the institutional and/or national research committee. Endpoints included the outcomes of newly diagnosed MM after VCd induction and ASCT in terms of OS, PFS, as well as identification of the prognostic factors and demographics in our area.

Protocol description

The VCd regimen comprises weekly subcutaneous bortezomib 1.3 mg/m 2 , weekly oral cyclophosphamide 300 mg/m 2 (maximum 500 mg) and weekly dexamethasone 40 mg oral, for 28 days per cycle and median number of 4 cycles. 15 , 17 All patients received prophylaxis acyclovir and sulfamethoxazole-trimethoprim. The mobilization protocol included the administration of cyclophosphamide at a dose of 1.5 g/m 2 and G-CSF at a dose of 5 μg/kg every 12 hours. G-CSF administration commenced 24 hours after cyclophosphamide, and CD34 cell count was monitored through peripheral blood tests until it exceeded 20×10 3 /mL. Once the CD34 count was above the threshold, we proceeded with stem cell apheresis aiming to collect around 5×10 6 CD34 cells/kg of the patient's weight. In cases where the target cell dose was not achieved, we employed plerixafor at a dosage of 240 mcg/kg on the night before apheresis to facilitate reaching the target cell count. Afterward, the stem cell product was frozen and stored, and on the day of the transplant, the patient received melphalan conditioning at a dosage of 100 mg/m 2 on day-1 and day-2 before the infusion of the cryopreserved stem cells. 24 , 25

Responses were assessed after the fourth cycle of the VCd induction and at 100 days post-transplant. BM biopsies were routinely performed before ASCT. The International Myeloma Working Group Uniform Response Criteria were utilized to assess treatment response. 26

Statistical methods

The characteristics of the patients were analyzed by counting the frequencies of categorical variables. The survival outcomes were determined using the Kaplan-Meier estimator. The survival curves were compared using the log-rank test. The endpoints of the study included the response rate at day 100 after stem cell transplantation that followed 1–4 cycles of induction, as well as OS and PFS. OS was defined as the time from diagnosis to either death or the last follow-up, while PFS was estimated from the time of transplantation to disease progression. To assess the relationship between variables, both univariate and multivariate analyses were conducted using the Cox regression hazard model with 95% confidence intervals. The statistical analysis was performed using IBM SPSS version 20 software (Armonk, NY, USA: IBM Corp).

RESULTS

The study included 87 patients with newly diagnosed MM who underwent autologous stem cell transplantation after receiving VCd induction ( Table 1 ). The minimum follow-up was 9 months. The median age was 52 years (range 21–69). The common immunoglobulin (Ig) subtype was IgG-Kappa (53 patients; 62.6%), while the light chain was the second most common subtype (15 patients; 17.2%). Twenty-six patients (29.9%) presented with renal impairment (defined as serum creatinine 120 μmol/L), 61 patients (70.9%) had anemia and 78 patients (89.7%) had bone involvement. Myeloma R-ISS could be calculated in 78 patients, 47 (60.3%) had Stage II. Cytogenetic data by fluorescence in situ hybridization (FISH) were available for 83 patients, of whom 73 (88%) had standard risk cytogenetic.

Based on IMWG 2006 criteria, the post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively.

There was no significant impact of R-ISS staging on the pre-transplantation response, although CR tended to have a higher stage I (50%) compared to stage III (25%) ( P =.79). Also, R-ISS staging did not impact post-transplantation response ( P =.82). Thirty patients (42.8%) achieved CR or better after induction in the standard risk cytogenetic group compared to 1 patient (10%) in the high-risk group ( P =.044).

No patient died in the first 100 days post-transplantation. Fifty-one patients (58.6%) received maintenance therapy, of which 29 patients received lenalidomide and 14 patients received bortezomib. The median PFS post-transplantation for the whole cohort was 49 months and 5 years OS was 84% ( Figures 1 and 2 ), while the median follow-up was 51 months.

PFS showed statistically significant improvement for stage 2 (R-ISS) compared to stage 3 (median PFS 56 vs 38 months, P =.035). Compared to the high-risk group (51 vs 38 months, respectively), PFS trended to toward a better PFS in the standard cytogenetic group.

Also, patients who achieved sCR in pre-transplant evaluation showed a higher median PFS (72 months) compared to patients with PR at 52 months. Regarding post-transplant response, there was a statistically significant improvement in median PFS for patients who achieved sCR vs PR (83 vs 35 months, P =.037) ( Figure 3 ). The median OS was worse with stage 3R-ISS (118 months) compared to stage 1 or 2 R-ISS (median OS: NR), which was obvious with high risk cytogenetic by FISH (78 months), although this difference was not statistically significant.

Patients who achieved sCR, CR or VGPR in pre-transplant showed higher median OS (NR) compared to patients with PR or SD (118 and 32 months, respectively P value .046). Also, the post-transplant response showed a statistically significant improvement in median OS in patients who achieved ≥VGPR compared to <VGPR ( P =.032) ( Figure 4 ).

Fifty-one patients (58.6%) received maintenance; 29 patients received lenalidomide and 14 patients received bortezomib while 8 patients were on thalidomide or dexamesathone. The use of maintenance showed a trend of better PFS of about 6 months but it was not statistically significant, mostly due to heterogeneous medications.

Univariate and multivariate associated variables and survival (PFS and OS) are shown in Tables 2 and 3 . Only R-ISS showed a statistically significant influence on PFS ( P =.04). The hazard ratio (HR) of those who had stage 2 (better survival) compared to those with stage 3 was 0.355 ( P =.028 by univariate analysis). Regarding OS, both LDH level and patients who achieved ≥VGPR post-transplant had a significantly better OS ( P =.003 and .042, respectively) by univariate analysis, while only LDH levels showed a significant difference in multivariate analysis.

DISCUSSION

Different induction regimens are being used in transplant-eligible MM aiming to achieve the best possible response before autologous stem cell transplant without compromising the stem cell collection and without major toxicity. Of such regimens, VCd protocol is considered a well-tolerated, convenient and affordable option. In this study, the VCd regimen showed improved long-term survival in patients who achieved response to VCd and underwent ASCT thereafter.

It is important to note that in our study, the median age of enrolled patients was 52, compared to the median of 60 or older in most international studies. 17 , 21 , 22 This is mostly due to the fact that the median age of the population in Saudi Arabia is young and much younger than the observed age in industrial countries. Twenty-six (29.9%) patients presented with a renal impairment which favored the use of VCd protocol, compared to 38% of patients with Kumar cohort. 27

Our pre-transplant responses, ≥CR and ≥VGPR rates were 40% and 79%, respectively. These results are comparable to published data from the phase 2 VCD study (46% and 71%, respectively) as well as study by Areethamsirikul et al. Also post-transplant response ≥CR and ≥VGPR rates were 51% and 83.9%, respectively, which is also comparable to clinical trial. 11 , 13 Our VGPR rate was higher than published results from other VCd studies which reported VGPR rates between 40% and 71%. This can be explained partially by the different schedules of VCd used in many of other trials (3 weeks cycled protocols), and also other trials had an older population. 12 , 14 , 15 , 21 , 22 , 27 – 29

Compared to trials that used VRd protocol as an induction regimen, the rate of post-transplant sCR in our study was 51.7% vs 46% on average from VRd trials. Of course, we need to keep in mind that patients with renal impairment don't need dose modifications with the use of VCd regimen as compared to VRd. 10 , 21 , 30 , 31 Kumar et al and others stated that the overall response rates were similar for VCd and VRd after induction therapy. 10 , 27 , 30 , 31 The original phase 2 EVOLUTION study which compared VCD to VRd regimen showed similar pre-transplant response rates, PFS and OS rates. Up to our knowledge, there are scarce prospective randomized trials comparing VRd vs VCd regimens directly. 32

Our median PFS was 49 months, which was comparable to results from other VCd studies like Figueiredo et al (44 months) and Ciftciler et al, while this result was higher than results from other several studies (33 months). Five-year OS (84%) was comparable to most of other studies (75–91.5%). 11 , 12 , 17 , 21 , 28

Several studies showed that achieving sCR post-transplant is associated with improved PFS and OS regardless of the induction regimen used. 21 , 33 Our study showed this clearly with a median PFS for patients who achieved sCR vs PR post-ASCT of 83 months vs 35 months, respectively, ( P =.037) ( Figure 3 ) and similarly for median OS for patients who achieved ≥VGPR compared to <VGPR ( P =.032) ( Figure 4 ).

The variability of results from different trials was mainly due to heterogeneities in patient characteristics as well as the differences in induction regimens dosing and schedules like the route of bortezomib administration and the schedule of the cycle (3-weekly or 4-weekly cycles) as well as the usage of maintenance. Some of the trials that used VCd induction protocol and their outcomes are summarized in Table 4 . 34

Fifty-one patients (58.6%) received maintenance therapy, of which 29 patients (56%) had lenalidomide and 14 patients had bortezomib, while 8 patients were on thalidomide or dexamesathone. The use of maintenance showed a trend of better PFS of about 6 months but the difference was not statistically significant. This was contrary to results from a recent meta-analysis, 35 which could have been because of the high CR rate post-ASCT and the heterogeneity of maintenance in our cohort.

Our study was one of the largest cohort studies in a single center that showed the efficacy of VCd protocol in real-world clinical practice, in a unique patient population not studied previously in other clinical trials (Middle Eastern population). This data represents our real-life experience in treating patients with comorbidities and renal impairment without any clinical trial constraints. We conclude that VCd induction is highly effective (even in high-risk disease), convenient, tolerable affordable. This regimen represents an excellent choice for MM patients, especially in low and middle-income countries with limited resources. Finally, the patients who responded to the induction VCd regimen had good long-term survival while those who did not respond successfully shifted to VRD or VTD.

Our study was limited by its retrospective design and the selection of responded patients, also, insufficient toxicity assessment. However, by reviewing the data, there was no dose modification of bortezomib indicating that it is a tolerable protocol without significant neurologic toxicity. Further, prospective randomized trials are needed to compare VCd with other novel agents which are developing rapidly. VCd recommended for previously untreated MM, including patients with poor-risk cytogenetic abnormalities.

Funding Statement

None.

Footnotes

CONFLICT OF INTEREST: None.

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