Introduction

Multiple myeloma is a neoplasm characterized by the presence of plasma cell clones that produce an abnormal immunoglobulin (component M), which leads to osseous destruction, anemia, renal function deterioration, and hypercalcemia¹. It represents around 10% of the hematological neoplasms and mainly affects individuals over 60 years old². Its treatment has experienced a rapid evolution; chemotherapy has been displaced by drugs that activate the immune system, redirecting it in a specific manner to identify and eliminate malignant plasma cells³,⁴. At present, the most effective treatment consists of a combination of drugs (double, triple, or quadruple), which include immunomodulatory agents (lenalidomide and thalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and monoclonal antibodies (daratumumab and isatuximab), followed by high doses of chemotherapy and hematopoietic stem cell transplantation⁵,⁶.

In the Latin American context, and despite the clinical and biological characteristics of the diagnosis which are similar to those in other regions of the world⁷, there are great differences, due to, mainly, the limited access to specialized centers and a considerably late diagnosis⁸,⁹. The Hispanic population faces additional vulnerabilities, such as the low level of participation in clinical trials, and the limited access to new specific therapeutic strategies, such as CAR-T cells, compared to the Anglo population¹⁰.

This has led most of the patients to be treated with drugs which are more readily available at a more affordable cost. Among the drugs used in the region, thalidomide and lenalidomide are used as immunomodulators, bortezomib is used as a proteasome inhibitor, combined as a triplet and, in some cases, as a quadruple, along with the monoclonal antibodies anti-CD38¹¹.

A rarely discussed aspect that is present in every health-care system is financial toxicity, which affects individuals with a lower educational level mainly, having a significant impact on the quality of life¹².

Finally, a late diagnosis leads to more patients presenting complications, some irreversible, such as kidney failure or the presence of acute extramedullary disease. In addition, more patients are diagnosed at very advanced stages in the region (International Staging System [ISS] 3), which makes the comparison of results of various clinical studies difficult.

In Mexico, multiple myeloma is still considered an uncommon disease with significant underreporting, since very few centers have the necessary tools for the diagnosis, as well as the required drugs to complete first-line treatment¹³.

The main purpose of this real-life study was to describe the characteristics of patients with multiple myeloma treated at the reference center in Mexico City, identifying the severity and the rate of favorable responses to both treatments available.

Materials and methods

This retrospective study involves research on the clinical records of patients diagnosed with multiple myeloma treated at Hospital General de México between 2020 and 2023. We included the clinical records of patients who were considered eligible for transplant due to their functional status and who were given some treatment strategy comprising a combination of drugs (double or triple). The excluded criteria included: 1. Incomplete clinical records, 2. Clinical records of patients who abandoned treatment or could not continue with the treatment due to economic or distance issues; 3. Clinical records of patients who presented severe sepsis before the beginning of either treatment (Fig. 1).

Figure 1 Clinical records selected. 

Two treatment schemes were analyzed – thalidomide 100 mg-200 mg PO daily alone or in combination with dexamethasone 40 mg PO every 24 h on days 1-4, 8-11 of each cycle, and treatment based on bortezomib 1.3 mg/m² SC on days 1, 4, 8, 11 to the thalidomide and dexamethasone (TD) scheme for a total of six treatment cycles¹⁴,¹⁵ bortezomib, thalidomide, and dexamethasone (VTD).

The response criteria were established in accordance with the International Multiple Myeloma Working Group criteria. Patients with a greater than partial response (very good partial response and response complete) were considered responders.

The combination of albumin and beta2 microglobulin (ISS score) was used for risk stratification. Renal function deterioration was considered with a creatinine > 2 mg/dL at diagnosis¹⁶. In cases where cytogenetic results were available, they were described within the general characteristics.

Results

Response to the treatment

When analyzing the overall responses, 45.7% (n = 38) presented a favorable response (full remission or very good partial response), whereas 54.3% (n = 45) presented a non-optimal response (partial response, progression, or stable disease). Of the total cases, 33.7% were considered to have progression criteria. When analyzing the responses to each of the treatments, patients treated through the triplet (VTD) presented a higher rate of favorable responses compared to the patients who received a scheme based exclusively on thalidomide (59.6% vs. 22.5%, p = 0.001, 95% IC). Similarly, the cases treated with the TD scheme presented progression with a higher frequency than the VTD scheme (54.8% vs. 21.1%, p = 0.011, 95% IC). When comparing the effectiveness of both treatments, the time until the next treatment, the patients treated with the TD scheme presented a prolonged time until the following treatment compared to the VTD scheme (536 vs. 479 days, p = 0.38 95% IC) despite the fact that the cases treated with the TD scheme included a higher range of cases with progression. In Fig. 2A and B, the general comparison and detailed range of the responses between both treatments are presented.

Figure 2 A: the overall ratio of favorable and unfavorable responses and B: detailed classified responses between groups. 

Overall survival and associated risk factors

The average survival time was 662 days, with a survival of 3 years in 41% of cases. When comparing the survival according to the type of treatment, no difference between TD or VTD (Log Rank 0.076) was registered, and, despite patients with TD presenting a higher risk of progression, this difference was not reflected in the time until the next treatment (Log Rank 0.288). The overall survival and time until the following treatment are presented in Fig. 3A and B. Fig. 4A and B could include a forest plot on the main variables and the need to initiate the next line of treatment; however, only the triplet (VTD) had an impact on the ratio of favorable responses OR: 0.19 (IC 95% 0.075-0.523; p < 0.001).

Figure 3 A: overall survival using Kaplan-Meier and B: time to next treatment using Kaplan-Meier. 

Figure 4 A: forest plot on treatment response and B: need for next treatment. 

Discussion

This real-life study presents the experience of both main combinations used for the treatment of patients with multiple myeloma considered eligible for a transplant. After the introduction of the generic formulation of bortezomib, the inclusion of bortezomib in the TD scheme became more attainable, allowing to treat the majority of patients with triplets (VTD). Other treatments, such as the usage of monoclonal antibodies or stronger drugs such as lenalidomide or carfilzomib, were more limited and destined for patients with social health insurance, used mainly in subsequent lines of treatment¹⁷,¹⁸.

Thalidomide is one of the first drugs considered an immunomodulator (IMiD), used at first as a sedative to prevent nausea in pregnant women, it is now one of the most popular drugs for the treatment of MM due to its anti-inflammatory effect in the microenvironment as a stimulant for various lymphocyte subpopulations (CD4+ and CD8+), increasing the levels of IL-2 and interferon γ¹⁹,²⁰. At present, new and stronger drugs have emerged such as lenalidomide or pomalidomide which, combined with proteasome inhibitors (VRd or KRd) or monoclonal antibodies (elotuzumab-Rd, daratumumab-Rd, isatuximab-pomalidomide-dexamethasone), have become a better option in those patients in relapse or resistant to the first treatment or who are not eligible for a transplant²¹,²².

Due to the accessibility and cost, both thalidomide and bortezomib are the drugs used with more frequency, be it as a triplet (VTD) or as a double (TD). Despite these combinations having been displaced by more effective combinations, it is important to understand the ratio of favorable responses and their duration, especially since the drugs used are generic. In Turkey, Mersin et al. evaluated the responses to generic bortezomib when compared to the original without finding a difference in the responses or adverse events²³.

In this study, the greater ratio of favorable responses was found in the group treated with bortezomib (67.3%), although the percentage of complete responses remained low (3.8%). These data are consistent with the available evidence on combinations based on bortezomib in various clinical trials (APEX, GIMEMA-MM-03-05, and HOVON-65)²⁴,²⁵.

Since its introduction, bortezomib has presented a synergy with both immunomodulatory agents as well as with chemotherapy (cyclophosphamide and melafan) in various trials, improving the survival and the response to an autologous transplant²⁶,²⁷. Another aspect of the combination of an IP with an immunomodulator is its safety profile since the combination of drugs such as anthracyclines (doxorubicin and idarubicin) were more toxic and never better than the double²⁸.

One of the important aspects of our series is that a significant difference in the overall survival between the treatment regimens (TD vs. VTD) was not found; this had already been described in the first series that compared these combinations before an autologous transplant, where the main benefit was found in the favorable response ratio²⁹.

When analyzing the group of patients treated with VTD and comparing it to the response ratio in studies where a monoclonal antibody was included (CASSIOPEIA study; VTD vs. daratumumab-VTD), the ratio of favorable responses (RC+VGPR) of the VTD scheme was similar to our series (56.1% vs. 67.3%), but the percentage of full remissions registered for the clinical trial was slightly greater (8.9% vs. 3.8%)³⁰.

When trying to select the first-line treatment that is more effective without combining it with monoclonal antibodies, Rosiñol et al. analyzed the data from several patient databases treated with VRd (PETHEMA, GEM2012 and IFM2009) or VTD (PETHEMA, GEM2005 and IFM2013-04), who presented a greater benefit with the use of VRd, in particular when reaching a negative measurable residual disease³¹. Similar to the Cassiopeia study (VTD vs. D-VTD), the VRd combination was also challenged with the combination of the monoclonal antibodies anti-CD38. In the GRIFFIN study, Voorhees et al. studied the effect of VRd versus D-VRD; in patients eligible for transplant, they proved an advantage both in the ratio of complete responses (CR/CRs) at the end of the induction (19.2% for D-VRd vs. 13.3% with VRd), with measurable residual disease (21.2% vs. 5.8%), and survival free of progression³². When analyzing the results of the different first-line combinations (VTD, VRd, and CyBorD), no significant differences were identified between the ratio of favorable responses (above the partial response), which suggests that VTD remains an effective triplet as a first-line scheme in patients who are eligible for a transplant.

Finally, the greatest benefit at the first line is achieved with the inclusion of the monoclonal antibody anti-CD38 (daratumumab), which allows a greater ratio of complete responses, as well as a greater ratio of negative measurable residual disease as opposed to the schemes based exclusively on IP or immunomodulators³³.

Conclusion

With this real-life data, we conclude that the combination of VTD presents similar evidence in terms of the response to other series around the world, including the results from clinical trials (Cassiopeia study); even when most of the drugs were generic, the responses were superior to the TD combination, without having an influence on survival. When the combination with daratumumab is not available, VTD is a useful first-line option for patients eligible for a transplant.