Множественная миелома в молодом возрасте из центра лечения рака третьей ступени в Индии.

Introduction

Multiple myeloma (MM) primarily is a disease of the elderly with a median age of diagnosis of 70 years. However, in India, patients are diagnosed nearly a decade younger [ 1 , 2 ]. The incidence of MM is 10% below the age of 50 years and 2% below the age of 40 years [ 3 , 4 ]. Primarily because of this reason, disease characteristics, prognostic factors, and outcomes are poorly described in young patients ≤ 40 years with MM. Available literature suggests heterogeneity in outcomes among young patients with MM as compared to elderly patients [ 5 , 6 , 7 , 8 , 9 ]. The primary objective of this study was to analyze the clinico‐hematological profile, disease characteristics, and treatment responses in young adults (≤ 40 years) with MM over a period of 9 years. Secondary objectives were (a) to determine progression free survival (PFS), (b) to determine overall survival (OS), and (c) to evaluate prognostic factors influencing PFS and OS.

Materials and Methods

The prospective plasma cell dyscrasia database at our institute was screened for newly diagnosed MM. This database has been maintained since January 2013, and we included patients diagnosed upto December 31, 2021. Patients diagnosed with solitary plasmacytoma, plasma cell leukemia, plasmablastic lymphoma, POEMS syndrome, and amyloidosis were excluded from this analysis. Data collected included demographic information, clinical characteristics, laboratory parameters, diagnostic workup, treatment details, response to treatment, details of autologous stem cell transplant (ASCT), treatment at relapse and dates of progression and death. The International Staging System (ISS) and Revised International Staging System (RISS) were used to stage the disease. The tumor responses were assessed using the International Myeloma Working Group Criteria guidelines. High risk (HR) cytogenetics were defined as per mSMART 3.0. [ 10 ]

Interphase Fluorescence In Situ Hybridization (FISH) was carried out on total of 200 CD138 +ve plasma cells isolated from bone marrow aspirate using miltenyi MS column‐based Immunomagnetic cell separation method for ≥ 10% plasma cells (detected by flow cytometry) with 98% purity. Probes used for MM FISH panel include; Metasystems (Germany) LSI dual color break apart IGH probe, Abbott Molecular (IL, USA) LSI dual color fusion probes IGH/CCND1, IGH/MAF, IGH/FGFR3 , Cytotest (Rockville, USA) LSI dual color fusion IGH/CCND3 probe, and IGH/MAFB probe, Zytovision (Bremerhaven/Germany) Centromeric CEN3, CEN7 probes, Metasystems XL triple color 5p15/9q22/15q22, Metasystems LSI dual color deletion XL CDKN2C/CKS1B probe and Zytovision LSI dual color RB1 /13q12 and TP53 /CEN17 probes.

Patients were counselled for ASCT after four to six cycles of induction chemotherapy, depending on response to therapy. If transplantation was not feasible, patients continued therapy for 8–12 cycles, followed by maintenance. Although maintenance therapy was introduced at our institute in 2013, most patients began receiving it only in later years.

PFS was defined as the period from the date of diagnosis to the date of IMWG defined progression or date of death. OS was defined as the time period from the date of diagnosis to the date of death. PFS and OS were calculated using the Kaplan–Meier method. Log‐rank test was used to measure the effect of various variables on the PFS and OS and multivariate analysis was performed with the multivariate Cox proportional hazards regression model. A p value less than 0.05 was considered significant. Analyses were performed using IBM SPSS version 29.0 (SPSS Inc., Chicago, IL) and R studio version 2023.06.02. The study was approved by the Institutional Ethics Committee (Approval no 4140).

Results

Of the 1980 patients with newly diagnosed plasma cell dyscrasias between 2013 and 2021, we identified 132 patients aged ≤ 40 years at diagnosis. Among them nine patients with solitary plasmacytoma, three with POEMS syndrome, six with plasma cell leukemia, three with amyloidosis and one with plasmablastic lymphoma were excluded from the analysis. Finally, 110 patients were included in the analysis (Figure 1 ).

The baseline characteristics of patients are summarized in Table 1 . The median age of the cohort was 36 years (range: 18–40) with a male‐to‐female ratio of 3:1. Bone pain, fatigue, and cord compression were present in 83.6%, 18.2%, and 11.8% of patients, respectively. Of the 13 patients with cord compression, 7 had neurological recovery, 4 did not, and 2 lacked follow‐up data. The median LDH and β2 microglobulin of the cohort were 184 U/L (upper limit of normal being 190 U/L) and 3.5 ng/mL (range: 1.5–104), respectively.

The prevalence of chromosomal abnormalities detected by FISH is summarized in Table 2 . HR cytogenetics were observed in 20.8% of patients. t (4,14), t (14,16) and 1q gain were seen in 9.5%, 2.8%, and 13.5% of patients, respectively. Hyperdiploidy and monosomy 13 were seen in 34.3% and 31.1% of patients, respectively. None of the patients had del17p.

Thirty one percent of patients met criteria for macrofocal multiple myeloma (MFMM), defined as < 20% BM clonal plasma cells with multiple lytic lesions and/or plasmacytomas but without anemia, renal insufficiency, or hypercalcemia.

Treatment Details and Response

The first line chemotherapeutic regimens administered are summarized in Table S1 . VCd (Bortezomib, Cyclophosphamide, and Dexamethasone) and VRd (Bortezomib, Lenalidomide, and Dexamethasone) were the most frequently administered regimens, given to 55% and 38.5% of patients, respectively. The median number of cycles administered was 8 (range: 3–17). Among the 64 patients (68.7%) who received maintenance therapy (Table S2 ), proteasome inhibitors were given to 20.3% and immunomodulatory drugs (IMiD) were given to 48.4% of patients. Among proteasome inhibitors, Bortezomib was most commonly used and among IMiDs, Lenalidomide was most common. Response of patients to first line regimens as per IMWG 2016 criteria are summarized in Table 3 . Twenty nine patients (26.8%) received ASCT.

Further lines of chemotherapy regimens received are summarized in Tables S3 and S4 .

Survival Analysis

After a median follow‐up of 44.2 months, 48 patients were alive, 15 had died, and 47 were lost to follow‐up. Among the 15 deaths, four were attributed to infections, while cause of death for the remaining patients could not be ascertained.

The median PFS was 45.9 months (95% CI: 37.8 to NA) (Figure 2A ) and median OS was not reached in our study cohort (Figure 2B ). 1 year, 3 year, and 6 year OS rates were 93.9% (95% CI: 89.3–98.8), 91.1% (95% CI: 85.4–97.3) and 81.2% (95% CI: 72.6–90.8) respectively.

The median PFS was not reached in patients who received VRD, whereas it was 36.3 months in those who received VCD ( p value: 0.00029) (Figure 3A ). The 3 year‐PFS of patients who received VRD was 82.3% (95% CI: 70.3–96.3) and for those who received VCD was 51.4% (95% CI: 39–67.8).

The 3‐year PFS rate of patients who received and did not receive maintenance were 80.2% (95% CI: 68.8–93.6) and 42.1% (95% CI: 29–61.2) respectively ( p < 0.0001) (Figure 3B ). The 3‐year OS rate of patients who received and did not receive maintenance were 97.4% (95% CI: 92.6–100) and 86.1% (95% CI: 76.2–97.3) respectively ( p 0.0052) (Figure 3C ). Among patients who received PI versus those who received IMiD maintenance, 3‐year PFS rates were 83.9% and 78.7% respectively ( p value 0.045).

The 5‐year PFS rates of patients who were consolidated with transplant versus without transplant were 58.5% (95% CI: 41.4–82.5) and 27.8% (95% CI: 16.7–46.2) ( p = 0.0043) respectively (Figure 3D ). The 5‐year OS of patients who underwent transplant versus without transplant were 94.4% (95% CI: 84.4–100) and 84.4% (95% CI: 75.2–94.7) ( p = 0.031) (Figure 3E ).

The median PFS of patients of ISS Stage 1 was not reached (NR) and for Stages 2 and 3 were 45.1 months (95% CI: 26.7 to NA) and 36.3 months (95% CI: 18.4 to NA) respectively ( p = 0.058) (Figure 4A ). The median PFS of patients of R‐ ISS Stages 1, 2, and 3 were 56 months (95% CI: 37.8% to NA), 43.2 months (95% CI: 34.9% to NA) and 44.5 months (95% CI: 15.3 to NA) respectively ( p = 0.17) (Figure 4B ).

The median PFS of patients diagnosed with light chain myeloma were 36.3 months (95% CI: 18.4 to NA) and intact Immunoglobulin secreting myeloma were 44.5 months (95% CI: 34.9 to NA) with a p value 0.26.

The median PFS of patients who achieved CR/VGPR were 50.6 months (95% CI: 43.2 to NA) and those who had partial response and stable disease were 20.5 months (95% CI: 15.3 to NA) respectively with a p value 0.0024 (Figure 4C ).

The median PFS was 49.2 months in the MFMM group and 44.5 months in the non‐MFMM group ( p = 0.56; Figure 4D ). The 3‐year OS rates were 93.1% (95% CI: 84.3–100) for MFMM and 89.9% (95% CI: 82.5–98) for non‐MFMM with a p value 0.53.

Prognostic Factors for PFS and OS

In univariate analysis (Table 4 ), presence of anemia (<10 g/dL) ( p = 0.028), renal failure (≥ 2 mg/dL) ( p = 0.019), poor performance status at baseline ECOG PS ≥ 3 compared to ECOG ≤ 2 ( p = 0.041), HR cytogenetics ( p value 0.00078) patients who received VCD compared to VRD ( p = 0.0002), those who attained only partial response or stable disease ( p = 0.002) compared to CR and VGPR, those who did not receive maintenance therapy ( p = 0.0001) and those who did not receive transplant ( p = 0.0043) had significantly shorter PFS.

In multivariate analysis (Table 4 ), renal failure (≥ 2 mg/dL) (HR 3.23, 95% CI: 1.27–8.2, p = 0.01), poor performance status ECOG 3 and 4 compared to ECOG 1 and 2 (HR 1.98, 95% CI: 1.02–3.86, p = 0.04), HR cytogenetics (HR 3.16, 95% CI: 1.53–6.52, p = 0.002), those who attained only partial response or stable disease (HR 3.57, 95% CI: 1.70–7.39, p = 0.001) compared to CR and VGPR and those who did not receive maintenance therapy (HR 5.66, 95% CI: 2.69–11.89, p < 0.001) had significantly shorter PFS.

In the OS analysis, univariate analysis indicated shorter OS in patients who did not receive maintenance therapy ( p = 0.0052) or transplantation ( p = 0.031) but in multivariate analysis none of the variables were found to be significant.

Discussion

Our study represents the largest cohort of young MM patients reported from India. Whether MM in the young represents a distinct disease subset remains unclear. Understanding the disease in this subset has been hampered by lack of formal definitions and paucity of data on detailed evaluation and long‐term outcomes. Today, a significant proportion of patients with MM live for a decade or longer with modern therapeutic strategies [ 11 ]. Despite marked improvement in outcomes, the number of life‐years lost by young patients is significantly higher than in older patients. Yet they remain underrepresented in studies and treatment guidelines.

The incidence of young MM ≤ 40 years in our cohort is 5.5%, higher than proportions reported in western studies [ 5 , 7 , 13 ]. Many large‐scale studies set a cut‐off age of 50 years for defining young MM [ 13 , 14 ]. The clinical characteristics of cohorts from previous studies compared with our cohort are summarized in Table 5 . The frequency of anemia and renal failure at baseline in our cohort was 42.7% and 17.3% respectively albeit lesser as compared to other studies reported from India [ 15 , 17 ] whereas it is similar to studies published by Ludwig and Caulier. Approximately one‐fifth of our patients have LCD (21.6%) while literature has reported incidence ranging from 19% to 45% in patients ≤ 50 years [ 4 , 8 , 13 , 16 , 18 , 19 ]. Plasma cell percentage ≥ 30 was seen in about 38% of patients whereas it was higher for young patients in a study done by Cheema et al. [ 7 ] In the west, young patients with myeloma present with an early stage of disease compared to our patients. In our cohort more than one‐third of patients presented with ISS Stage III. This might be because of the late presentation of patients to our clinics compared to western countries. Similarly the relatively high incidence of cord compression in our study (11.8%) may be related to delays in diagnosis and presentation, which is more common in developing countries due to limited access to primary care, advanced imaging, early referral systems.

In our cohort, 31 % of patients had MFMM. In a large real‐world analysis from Greece and Israel [ 22 ], Katodritou et al. reported an incidence of ∼3% of all MM cases. In their series, MFMM was associated with significantly improved PFS and OS compared with other MM patients. However in our study, we did not observe a survival advantage. Median PFS (49.2 vs. 44.5 months) and 3‐year OS (93.1% vs. 89.9%) were comparable between MFMM and non‐MFMM groups, and MFMM status did not retain independent prognostic value on multivariate analysis.

HR cytogenetics were seen in 20.8% of patients. In the study done by Caulier et al. [ 16 ] HR cytogenetics were seen in 18% of patients. A notable feature is that none of the patients in our study had del 17p. In the study by Shin et al. [ 4 ], del 17p was seen in one out of nine patients tested. Nakaya et al. [ 21 ] reported a significantly higher frequency of del 17p in patients younger than 40 years compared to the broader myeloma cohort (33% vs. 14% p = 0.008). It is not known whether young myeloma patients are more vulnerable to HR cytogenetics.

Our cohort demonstrated notably high median PFS and OS rates. Due to the younger age and fewer comorbidities treatment tolerance, and adherence will be better. While not all patients were able to receive maintenance therapy, those who did fared much better than those who did not as seen in our multivariate analysis. Even patients with standard‐risk cytogenetics can have prolonged remissions using conventional therapies. Better protocol adherence, close toxicity monitoring, continued supportive care, timely intervention and follow‐up at a high volume specialized center may account for the improved outcomes.

Since sustained complete response (CR) is the best indicator of OS, clinical research has focused on developing induction regimens that achieve deep and durable remission [ 23 , 24 , 25 ]. As a result, multiple drug combination therapies have gained favor. The majority of patients in our cohort received VCd and VRd as induction chemotherapy. Patients treated with VRd showed superior PFS and OS compared to VCd in our study. Our findings align with global trials such as GRIFFIN, PERSEUS, and IFM, which also report improved survival rates with VRd, especially when combined with ASCT [ 26 , 27 , 28 ].

Daratumumab, a monoclonal antibody with minimal long‐term side effects, is an advantageous treatment option for selected patients [ 26 , 27 ]. Bondili et al. discussed its impact on a patient with refractory anemia who had advanced on several lines, demonstrating its effectiveness [ 29 ]. However, in this cohort, none of the patients received Daratumumab in the first line setting. The development of CART cell therapies may offer additional therapeutic options to treat this population from early onset of the disease [ 30 , 31 ]. The use of novel agents in our setting was restricted mainly due to high cost, absence of universal health coverage, lack of generic alternatives, and limited access to clinical trials.

Most of the published data show superior survival for the younger cohort compared to elderly population [ 5 , 12 , 20 ]. Survival rates in India have also improved with the availability of novel agents. Unfortunately, the rate of ASCT in our country is very low compared to our western counterparts. The rate of ASCT in our study was about 27%. The low ASCT rate was due to a combination of factors. Financial limitations—despite institutional support programs, the high cost of ASCT including pre‐transplant conditioning and post‐transplant care is a limiting factor for many patients. Infrastructure limitations were also significant—our transplant unit initially had only six beds shared between autologous and allogenic transplants, often prioritizing urgent cases such as high‐risk leukemias. Although capacity was expanded in 2022, this limitation impacted the cohort under analysis. In addition, eligibility was influenced by disease response and patient fitness, which further reduced the number of patients proceeding to transplant. These observations are consistent with previously published data from our center [ 32 ] and other Indian cohorts [ 33 ]. Given that younger patients are generally fit, a second ASCT may be feasible and could further improve OS [ 34 , 35 ]. Whether emerging novel therapies might overcome the benefit of ASCT has yet to be evaluated.

It is important to monitor these patients for long‐term toxicities such as cardiovascular events and secondary malignancies, owing to their extended duration of survival, especially in the era of indefinite lenalidomide maintenance.

Despite the retrospective nature of our study and important limitations in the form of lack of data on long‐term side effects, we addressed a wide range of clinicopathological characteristics, outcomes and factors affecting survival for a large cohort of patients. Although our analysis focused only on young patients, comparisons with the older cohort could have provided additional context. Furthermore, as ours is a tertiary referral center, there is an inherent selection bias: patients who reach our institution are often those who survive long enough and are physically and financially able to seek specialized care. This group may have better performance status and support systems than the broader MM population, potentially affecting survival outcomes. In addition, the relatively small numbers in certain subgroups, such as those with high‐risk cytogenetics, may have limited statistical power, and these findings should be interpreted within this context.

Nonetheless, even with resource limitations and restricted access to novel therapies, young MM patients in our study exhibited promising survival outcomes.

Author Contributions

Conception and design: George John, Bhausaheb Bagal. Collection and assembly of data: George John, Bhausaheb Bagal, Lingaraj Nayak, Navin Khattry, Anant Gokarn, Sachin Bharat Punatar, Sumeet Mirgh, Manju Sengar, Hasmukh Jain, Nishant Jindal, Akanksha Chichra, Alok Shetty, Nikhil Patkar, Gaurav Chatterjee, Prashant Tembhare, Shweta Rajpal, Dhanlaxmi Shetty, P G Subramanian, Sumeet Gujral, Kinjalka Ghosh, Hemani Jain. Data analysis: George John, Bhausaheb Bagal, Akash Pawar, Sumeet Mirgh, Sachin Bharat Punatar. All the authors are responsible for writing of the manuscript, final approval of the manuscript, and are accountable for all aspects of the work.

Funding

The authors have nothing to report.

Ethics Statement

The study was approved by the Institutional Ethics Committee (Approval no – 4140).

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Table 1 : First line regimens.

Supporting Table 2 : Maintenance Therapy.

Supporting Table 3 : Second line Regimens.

Supporting Table 4 : Third line Regimens.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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