Editor's Note: Despite significant advancements in the treatment of multiple myeloma (MM) in recent years, particularly with the advent of innovative therapies, the prognosis for certain high-risk patient groups remains suboptimal. This is especially true for newly diagnosed multiple myeloma (NDMM) patients with renal impairment. At the 2024 American Society of Hematology (ASH) Annual Meeting held from December 7–10, Wen Gao, Professor of Hematology at Beijing Chaoyang Hospital, presented findings from a study on the efficacy of the SPVD quadruple therapy as a first-line treatment for NDMM patients with renal impairment. The research offers a novel and promising solution to a pressing clinical challenge. Hematology Frontier invited Dr. Wen Gao to provide an in-depth analysis of this study and its significant implications for clinical practice.

Hematology Frontier: During this year’s ASH meeting, you presented results from a Phase II study on the SPVD quadruple therapy as a first-line treatment for NDMM patients with renal impairment (Abstract #1978). Could you share the background and key findings of this research?

Dr. Wen Gao: In recent years, the MM field has seen the emergence of numerous new drugs, significantly improving patient survival. For transplant-eligible MM patients, the combination of novel therapies and transplantation has extended the median survival to over 10 years. For transplant-ineligible patients, new drugs have also markedly enhanced treatment outcomes. However, there are still some high-risk subgroups, particularly NDMM patients with renal impairment, whose prognosis remains poor.

Previously, a retrospective study conducted by our hospital in collaboration with Peking University First Hospital and the General Hospital of the People’s Liberation Army (301 Hospital) included over 300 patients treated with novel therapies, including more than 60 who underwent transplantation. The overall survival (OS) for these patients was only 3–4 years, and for those reliant on dialysis, the OS was as low as 2 years. This highlights the urgent unmet therapeutic needs for NDMM patients with renal impairment.

Against this backdrop, we initiated a series of studies. Initially, we evaluated the efficacy of bortezomib (V) combined with pomalidomide (P) and dexamethasone (D) in NDMM patients with renal impairment. This combination achieved an overall renal response rate (ORR) of 78%, with results published in Blood Advances. Despite these promising outcomes, 20% of patients did not achieve renal response. Renal response not only signifies the recovery of a major organ function but also has a substantial impact on overall survival. Patients achieving renal response exhibit better prognosis and longer OS, while those without renal response have significantly worse outcomes.

To address this, we conducted a second study by adding selinexor (S) to the VPD regimen. Selinexor, an XPO1 inhibitor, demonstrated an overall response rate (ORR) exceeding 30% in the STORM study, targeting heavily refractory patients, including those resistant to three-drug regimens, with a progression-free survival (PFS) of 3–4 months. Based on these findings, selinexor was approved for the treatment of MM. The subsequent BOSTON study confirmed that SVD therapy outperformed VD in terms of patient survival. Further analysis revealed that SVD also showed superior efficacy in patients with renal impairment, as selinexor is metabolized in the liver rather than the kidneys.

Following selinexor’s approval, we initiated the SPVD study. Preliminary results were presented at last year’s ASH meeting as a poster, and the study received another poster presentation opportunity at this year’s ASH.

In this year’s study, we enrolled over 50 patients and analyzed data from 49 who completed at least one treatment cycle. Results showed that the renal ORR exceeded 80%, with the best renal ORR nearing 90%. More than 50% of patients achieved major renal response, demonstrating highly promising efficacy.

Regarding selinexor’s toxicity profile, concerns have been raised since its approval, particularly about hematologic and non-hematologic toxicities. In our study, we used a low-dose regimen (40 mg/week) combined with robust supportive care. Overall, the treatment was well-tolerated. Some patients experienced adverse events such as nausea and vomiting, primarily during the first two treatment cycles. However, most patients tolerated the regimen well after this initial period.

In the future, we aim to validate these findings through real-world studies to further assess the treatment’s efficacy and safety. This is the next step we are eager to pursue.

Hematology Frontier: In your study, high-risk events such as severe liver function impairment were mentioned. What specific monitoring and management measures were implemented to address these risks? Have these measures effectively reduced the incidence and severity of adverse events?

Dr. Wen Gao: At the beginning of the study, we observed cases of liver function impairment in a few enrolled patients. In fact, one patient at our center, who was dialysis-dependent and in relatively poor general condition, unfortunately passed away after treatment. Notably, this patient had no prior history of hepatitis B or liver dysfunction. Additionally, a few other cases of liver impairment were reported at other centers.

Since selinexor’s approval, it has been extensively studied in combination therapies such as SKD, SDD, and SPD, without identifying any clear contraindications. However, we hypothesize that the increased hepatic burden, due to the liver metabolism of these drugs, may have contributed to liver impairment in these cases.

Importantly, no subsequent cases of liver impairment or severe liver dysfunction were observed in patients enrolled later in the study. Therefore, we consider these early occurrences to be isolated incidents. Nonetheless, we remain vigilant and recommend that patients with existing liver dysfunction or high hepatitis B viral loads be excluded from enrollment in similar studies to further ensure patient safety.

Hematology Frontier: Based on the results of this study, what is your outlook on the clinical application of the SPVD regimen? Are there any plans for follow-up studies to further verify its efficacy, safety, and suitability?

Dr. Wen Gao: That’s an excellent question. Among the patients we enrolled, renal impairment in multiple myeloma (MM) typically signifies a very high tumor burden and a poor prognosis. The two studies we conducted, involving VPD and SPVD regimens, included extremely high-risk patients. These cohorts comprised a significant proportion of double-hit and triple-hit patients, as well as those with extramedullary disease and peripheral plasma cell issues, representing an exceptionally challenging MM population.

For such high-risk groups, treatment paradigms are shifting from three-drug combinations to quadruple regimens. Both newly diagnosed transplant-eligible and transplant-ineligible patients, as well as standard- and high-risk patients, are believed to benefit from quadruple therapy. However, considering real-world factors such as financial constraints and treatment accessibility, quadruple therapies are often reserved for the most high-risk cases. For these patients, conventional treatment approaches frequently yield suboptimal results, underscoring the urgent need for innovative strategies.

Quadruple therapies, such as SPVD, offer a promising avenue for exploration. Looking ahead, I believe the SPVD regimen holds substantial potential as a treatment option for high-risk patients, particularly those with concurrent renal impairment.

About Dr. Wen Gao

Position:

• Deputy Director, Department of Hematology, Beijing Chaoyang Hospital
• Chief Physician, Associate Professor, and Master’s Supervisor

Academic Roles:

• Member of the Asia Myeloma Network
• Standing Committee Member and Secretary General of the Hematology Committee, Chinese Medical Education Association
• Vice Chair of the Myeloma Committee, Chinese Medical Education Association
• Member of the Multiple Myeloma Expert Committee, CSCO
• Member of the Tumor Hematology Committee, Chinese Anti-Cancer Association

Research Focus: Dr. Wen Gao specializes in the pathogenesis, clinical trials of novel drugs, and prognostic research in multiple myeloma. Her expertise spans the comprehensive management of hematologic malignancies such as myeloma, amyloidosis, Waldenström’s macroglobulinemia, plasmacytomas, plasma cell leukemia, lymphomas, and leukemias, including stem cell transplantation and immunotherapy.

Research Contributions:

• Principal Investigator for 5 CDE-approved clinical trials and over 10 IIT studies
• Recipient of grants from the National Natural Science Foundation, Beijing Natural Science Foundation, and Beijing Municipal Health Bureau’s Sailing Plan Fund
• Associate Editor of Chinese Journal of Hematology