Background: Multiple myeloma (MM) is a genetically heterogeneous malignancy in which cytogenetic abnormalities play a crucial role in determining patient survival. The Revised International Staging System (R-ISS), incorporating ISS stage, LDH, and high-risk cytogenetic abnormalities, provides improved prognostication. The Second Revision (R2-ISS) utilizes weighted scores for ISS stage, LDH, del(17p), t(4;14), and 1q21 gain to enhance risk stratification. Bortezomib-based triplet regimens, including VRd (bortezomib, lenalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), remain the preferred choices for induction therapy in India. The use of Novel regimens, such as DVrd (daratumumab-based), is not feasible in over 90% of cases due to their prohibitive cost.

Methods: We retrospectively analyzed 70 newly diagnosed MM patients treated at AIIMS Rishikesh between July 2021 and January 2025. All patients received one of four triplet regimens: VRd (n=52), VCD (n=13), KRd (n=3), or DVrd (n=2). High-risk cytogenetics were defined by FISH-detected del(17p), t(4;14), t(14;16), t(14;20), or gain(1q21). Patients were staged using both R-ISS and R2-ISS systems. Survival analyses were performed using Kaplan–Meier methods. Cox regression was conducted to identify predictors of progression-free survival (PFS) and overall survival (OS).

Results: The cohort comprised 46 males and 24 females, with a median age of 54 years (range 31–71). High-risk cytogenetics were present in 20 patients (28.6%), including del(17p) in five, t(4;14) in four, gain(1q21) in seven, and t(14;16) in two. Some patients harbored multiple lesions. Of 70 patients with complete R2-ISS data, 9 (12.9%) were stage I, 17 (24.3%) stage II, 40 (57.1%) stage III, and 4 (5.7%) stage IV.

After a median follow-up of 16 months, the median PFS for the cohort was 12.0 months, and the median OS was 14.1 months. Among standard-risk patients, PFS and OS were 13.3 and 14.1 months, respectively. In contrast, high-risk patients had a median PFS of 8.8 months and OS of 14.5 months. Based on R2-ISS, PFS was 13.8 months in stage I, 15.7 months in stage II, 11.4 months in stage III, and 6.9 months in stage IV. Median OS was 13.8 months in stage I, 23.7 months in stage II, 13.4 months in stage III, and 21.3 months in stage IV. The high OS in stage IV is likely an artifact of small numbers.

Regimen-wise, VRd and VCD demonstrated comparable efficacy. VRd patients had a median PFS of 12.5 months and OS of 13.9 months, while VCD patients had PFS and OS of 12.0 and 15.7 months, respectively. KRd recipients (n=3) remained progression-free with PFS and OS of 25.9 months. Both DVrd patients progressed early, with PFS and OS of 7.1 months, likely due to double-hit cytogenetics.

Multivariate Cox regression analysis showed that high-risk cytogenetics independently predicted worse outcomes, with a hazard ratio (HR) of 2.03 for progression (p = 0.031) and 2.28 for death (p = 0.027). Each unit increase in R2-ISS stage was associated with a 1.48-fold increased risk of progression (p = 0.045) and a 1.56-fold increased risk of death (p = 0.038). The induction regimen (VRd vs VCD) was not an independent predictor of survival after adjustment.

Conclusion: In this Indian cohort, high-risk cytogenetics and advanced RAISS stages independently predicted poorer survival. R2-ISS offered superior prognostic value over R-ISS. Standard-risk patients had similar outcomes with VRd and VCD, while KRd showed promise in a limited group. Early progression in DVrd-treated cases was linked to double-hit cytogenetics. Financial constraints in the indian setting restrict access to novel agents like daratumumab, influencing therapy choices. These findings underscore the need for detailed cytogenetic profiling and risk-adapted strategies. In resource-limited settings, maximizing available therapies and early transplant referrals may improve outcomes. Larger multicentric studies are warranted to validate these results and to assess the real-world impact.

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2025
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