Weekly as Opposed to Bi-Weekly Bortezomib as Part of Induction Chemotherapy in Newly Diagnosed Multiple Myeloma is Better Tolerated and Equally Efficient in Terms of Initial Therapeutic Response: Real-World Data from a Retrospective Audit

Research Article

Ann Hematol Oncol. 2021; 8(11): 1376.

Weekly as Opposed to Bi-Weekly Bortezomib as Part of Induction Chemotherapy in Newly Diagnosed Multiple Myeloma is Better Tolerated and Equally Efficient in Terms of Initial Therapeutic Response: Real-World Data from a Retrospective Audit

Faulkner LG1,2, Suresh C3, Sachedina S4, Barton L4, Asagba G4 and Garg M4*

1Department of Oncology, University Hospitals Leicester, UK

2Leicester Cancer Research Centre, University of Leicester, Leicester, UK

3Leicester Medical School, University of Leicester, Leicester, UK

4Department of Haematology, University Hospitals Leicester, UK

*Corresponding author: Garg M, Department of Haematology, 2nd Floor, Sandringham Building, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK

Received: August 20, 2021; Accepted: September 24, 2021; Published: October 01, 2021


Bortezomib is a proteasome inhibitor that has shown efficacy in the treatment of newly diagnosed multiple myeloma. The VTD (Bortezomib, Thalidomide, Dexamethasone) triplet chemotherapy regime is frequently used as induction prior to autologous stem cell transplant, in line with national and international recommendations.

The manufacturer’s protocol for Bortezomib recommend a twice weekly dosing schedule. Adverse effects are common, most notably peripheral and autonomic neuropathy. These adverse effects can be disabling, even at lower grades and often limit drug tolerance.

We propose a once weekly Bortezomib treatment regime as an alternate modus operandi. Here we use real-world data to demonstrate that weekly compared to bi-weekly Bortezomib is better tolerated whilst achieving similar outcomes in terms of initial therapeutic response. We demonstrate a trend of lower incidence of neuropathy- both peripheral and autonomic- with the weekly regime. There was also a trend of fewer serious adverse events with the weekly regime with lower rates of hospital admissions due to infections. In addition, we show that this regime is associated with better Thalidomide tolerance. We believe that delivery of Bortezomib through a weekly regime facilitates patients being able to maintain on Bortezomib longer and receive higher cumulative doses.

Keywords: Multiple Myeloma, Plasmacytoma, Induction, Response, Bortezomib, Peripheral Neuropathy


CI: Confidence Intervals; CR: Complete Response; CTCAE: Common Terminology Criteria for Adverse Events; CyBorD: Cyclophosphamide Bortezomib Dexamthasone; IMWG: International Myeloma Working Group; ISS: International Staging System; LDH: Lactate Dehydrogenase; MR: Minor Response; NDMM: Newly Diagnosed Multiple Myeloma; OR: Odds Ratio; ORR: Overall Response Rate; OS: Overall Survival; PD: Progressive Disease; PFS: Progression Free Survivals; PR: Partial Response; RVD: Lenalidomide-Bortezomib-Dexamethasone; SAE: Serious Adverse Event; SD: Stable Disease; TD: Thalidomide-Dexamethasone; VCD: Bortezomib, Cyclophosphamide, Dexamethasone; VGPR: Very Good Partial Response; VMP: Velcade-Melphalan-Prednisolone; VMPT: Velcade-Melphalan-Prednisolone-Thalidomide; VTD: Bortezomib, Thalidomide, Dexamethasone; VTE: Venous Thromboembolism


Treatment for Newly Diagnosed Multiple Myeloma (NDMM) in transplant-eligible patients involves induction chemotherapy followed by high dose therapy with an Autologous Stem Cell Transplant (ASCT). This may be followed by consolidation or maintenance therapy depending upon funding and approval.

A number of first-line induction regimes exist. Bortezomib (Velcade®) based induction regimes have been found to achieve higher response rates with favourable long-term outcomes such as overall (OS) and Progression Free Survival (PFS) [1]. Of the Bortezomib based regimes, the VTD (Bortezomib, Thalidomide, Dexamethasone) triplet has gained much popularity, demonstrating higher response rates than Bortezomib combined with an alkylating agent such as Cyclophosphamide [2]. NICE currently recommend Bortezomib in combination with Dexamethasone or Dexamethasone and Thalidomide as induction therapy for NDMM prior to ASCT [3].

The current recommended dosing protocol according to the Summary of Product Characteristics entails administration of Bortezomib on a twice weekly basis [4]. However, multiple adverse effects are associated with its use, for example, neuropathy, haematological cytopenias and increased infection risk due to immunosuppression.

Peripheral neuropathy is the most notable side effect. It is estimated to affect approximately one third of patients with NDMM treated with Bortezomib [5], although estimates vary widely. In the GIEMMA trial comparing VTD to TD, peripheral neuropathy grade >3 developed in 10% of those on VTD after three cycles, significantly higher than the TD arm [6]. Similarly, in the PETHEMA trial, peripheral neuropathy grade >3 developed in 14% of participants follow six cycles of VTD, once again significantly higher than the TD arm [7].

Baseline characteristics associated with an increased risk include pre-existing peripheral neuropathy, diabetes mellitus and alcohol dependency. Incidence is associated with treatment regimen and cumulative dosing and is more common with intravenous than subcutaneous administration [8]. Incidence also varies with concomitant chemotherapy agents, with higher rates seen in VTD compared to VCD (Bortezomib, Cyclophosphamide, Dexamethasone) [2]. Symptoms are usually predominantly sensory with painful paraesthesia and may also have a motor component. Onset can have significant impacts on quality of life, even at lower grades, and has been demonstrated to be fatal in extreme cases [9]. It has been shown to be reversible on discontinuation of treatment in the majority of patients, however time to reverse can vary from months to years [5,10].

Moreover, autonomic neuropathy has been widely reported with Bortezomib use. This usually manifests as orthostatic hypotension resulting in dizziness and falls. Severe cases have been reported [11]. Management involves lifestyle advice and hydration and reducing other antihypertensive medication and mineralocorticoids or sympathomimetics can also be prescribed [4].

Management of Bortezomib induced neuropathy is limited to dose reduction or discontinuation following onset [12]. This may have important implications for future treatment regimes as intolerance or refractoriness to Bortezomib limits the ability to obtain Bortezomib in further treatment lines. An alternative approach that has been widely adopted involves a weekly as opposed to bi-weekly dosing interval. This is often employed in those who are older with predisposition to peripheral neuropathy as aforementioned. This dosing schedule has been widely implicated in transplant-ineligible myeloma, but to date, no clinical trials have been conducted to compare the efficacy of this dosing frequency in transplant-eligible myeloma.

Materials and Methods

In order to investigate current Bortezomib prescribing practice locally, we conducted a retrospective audit. Real-world data was collected consecutively from all patients in our trust treated with VTD as first-line chemotherapy in the intensive treatment arm for either multiple myeloma or secretory plasmacytoma, between January 2015 and November 2020. All patients were treated at University Hospitals Leicester (UHL) a Teaching Hospital trust and tertiary Haematology center located in the East Midlands, UK.

Data was collected from electronic patient notes and chemotherapy prescription records; we collected data on VTD dosing, depth of response, side effects and Serious Adverse Events (SAE) occurring whilst on treatment, and any subsequent first-line treatment such as ASCT or maintenance chemotherapy. SAE were defined as any infection requiring hospital admission or a Venous Thromboembolism (VTE) event during the course of therapy.

Primary outcomes were depth of response to induction therapy, and the development of neuropathy (peripheral or autonomic) or SAE occurring whilst on VTD. Overall Response Rate (ORR) was defined as the proportion of patients achieving Partial Response (PR) or above. Secondary outcomes included cumulative Bortezomib dose, number of Bortezomib cycles and Thalidomide tolerance.

The twice weekly VTD regime involved Bortezomib 1.3mg/ m² (maximum 2.75mg) delivered subcutaneously (SC) on days 1, 4, 8 and 11 of a 21-day cycle. In the once weekly regime, patients received the same dose of Bortezomib on days 1, 8, 15 and 22 of a 35- day cycle. Hence number of Bortezomib doses and total Bortezomib dose received in each cycle was equivalent in the two regimes. In addition, 20mg oral Dexamethasone was given the day of and day after Bortezomib doses along with 100mg oral Thalidomide each day. Patients received antimicrobial prophylaxis according to local guidelines as well as intravenous bisphosphonates as standard practice of care. Whilst on thalidomide patient were anticoagulated with Aspirin 75mg OD up to 2016, then changed to prophylactic low-molecular-weight heparin and later to DOACs in accordance to evolving local practice and guidelines.

Treatment response was assessed after completion of 4-6 chemotherapy cycles; at this point those who had achieved PR or above and who were <72 years old were assessed for ASCT. Patients were either initially commenced on weekly VTD or converted to the weekly regime when Bortezomib related side-effects became intolerable. Bortezomib prescription was at the discretion of the consultant haematologist.

Those deemed suitable underwent harvesting with 3000mg/m2 Cyclophosphamide followed by myeloablative chemotherapy with Melphalan 140mg/m² or 200mg/m² with ASCT. Transplant suitability and Melphalan dosing decisions were at the discretion of the transplant consultant. Those unsuitable for transplant were offered further VD (Bortezomib and Dexamethasone) up to a maximum of 13 cycles.

Treatment response was categorized according to response of serum paraprotein levels, or serum free light chains (SFLC) in those with light chain disease, according to the International Myeloma Working Group (IMWG) uniform response criteria [13]. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5 [14].

Statistical analysis was performed on SPSS Version 26. Comparisons of baseline characteristics of continuous variables was assessed by independent sample t-test where the variable was normally distributed, or Mann-Whitney-U test where distribution did not meet the assumption of normality. For categorial baseline characteristics chi-squared (Χ²) was used or Fisher’s exact test where the assumptions of Χ² were not met. Comparison of continuous outcomes between groups was performed using two-sample independent t-test. Categorical outcomes were assessed by univariate logistic regression. p-values <0.05 were considered significant.


74 patients underwent VTD chemotherapy between January 2015 and November 2020. 51 patients initially commenced bi-weekly Bortezomib, 34 (66.7%) of which were converted to the weekly regime during the course of their treatment. 23 patients were initially commenced on weekly Bortezomib, two of which were stepped up to bi-weekly regime, one of who was then stepped back down to weekly regime. The total number of VTD cycles received ranged between 3 and 14. The treatment course of the cohort are set out in the flow chart (Figure 1).