Salvage Therapy in Relapsed Multiple Myeloma: A Critical Analysis

Long-term data from the phase 3 GMMG ReLApsE trial (2009-013856-61), recently published in Blood, challenges the established role of salvage high-dose chemotherapy (sHDCT) plus autologous stem cell transplantation (ASCT) in treating relapsed/refractory multiple myeloma.The study indicates that adding sHDCT/ASCT to lenalidomide (Revlimid) and dexamethasone did not provide a statistically significant survival advantage.

Key Findings of the GMMG ReLApsE Trial

the multicenter trial, conducted across 16 sites in Germany, involved 282 patients aged 75 and older with relapsed/refractory multiple myeloma who had undergone 1 to 3 prior lines of therapy. Patients were randomized into two arms:

• Transplant Arm (n = 139): Received reinduction with lenalidomide (25 mg daily for 21 days of a 28-day cycle) and dexamethasone (40 mg weekly), followed by sHDCT with melphalan (200 mg/m²), ASCT (minimum of 2 x 10⁶ CD34-positive cells/kg), and lenalidomide maintenance (10 mg daily).
• Control Arm (n = 138): Received continuous treatment with lenalidomide/dexamethasone.

The primary endpoint was progression-free survival (PFS),while secondary endpoints included overall survival (OS) and post-trial treatment strategies.

Progression-Free Survival (PFS) Analysis

Univariate landmark analysis revealed no significant difference in PFS between the two arms:

• Transplant Arm: Median PFS of 23.0 months (95% CI, 17.2-32.2)
• Control Arm: Median PFS of 20.3 months (95% CI, 14.1-30.1)
• Hazard Ratio (HR): 0.91 (95% CI, 0.68-1.22; P = .52)

overall Survival (OS) analysis

Similarly, the OS outcomes did not considerably differ:

• Transplant Arm: Median OS of 76.3 months (95% CI, 58.8-Not Reached [NR])
• Control Arm: Median OS of 66.0 months (95% CI, 49.7-92.9)
• Hazard Ratio (HR): 0.8 (95% CI, 0.56-1.13; P = .2)

Patient Characteristics and Prior Therapies

The baseline characteristics of patients in both arms were largely similar. key features included:

• Predominantly male (Transplant: 57%, Control: 61%)
• WHO performance status of 0 (Transplant: 69%, Control: 76%)
• ISS stage I disease (Transplant: 63%, Control: 60%)
• Normal lactate dehydrogenase levels (Transplant: 83%, Control: 83%)
• One prior line of treatment (Transplant: 94%, Control: 94%)
• Time to progression after first-line therapy (TTP1): 12-24 months (Transplant: 34%, Control: 36%), 24-48 months (transplant: 33%, Control: 39%)

The moast common prior therapies were similar as well:

• Bortezomib (Velcade): 77% in both arms
• Thalidomide (Thalomid): Transplant 22%, Control 18%
• Lenalidomide: Transplant 9%, Control 13%

Challenges and Adverse Events

A notable 29% (41/139) of patients in the transplant arm did not proceed to sHDCT/ASCT, primarily due to disease progression (12%), adverse effects (6%), or withdrawal of consent (5%). The incidence of secondary primary malignancies was also investigated:

• Transplant Arm: 18% (24/135)
• Control Arm: 14% (20/145)
• P = .41 (not statistically significant)

Expert commentary and Clinical Implications

While sHDCT/ASCT has been a cornerstone of myeloma treatment, these findings suggest a need for re-evaluation. The absence of a significant survival benefit raises questions about the risks and benefits of intensive salvage therapy in this patient population. It’s crucial to consider factors such as patient frailty, treatment history, and disease biology when making treatment decisions.

Further research is needed to identify subgroups of patients who may benefit from sHDCT/ASCT in the relapsed/refractory setting.Novel therapies and combination approaches may offer more effective and less toxic alternatives.

Conclusion and Call to Action

The GMMG ReLApsE trial’s long-term data challenge the routine use of sHDCT/ASCT in all patients with relapsed/refractory multiple myeloma. Clinicians should carefully weigh the potential benefits against the risks and explore choice treatment options. For a deeper understanding of myeloma treatment strategies and to stay updated on the latest research, consult with a hematologist-oncologist specializing in multiple myeloma.Share this article to raise awareness and promote informed discussions within the medical community.

How might the potentially increased risk of secondary primary malignancies in patients who receive salvage high-dose chemotherapy impact treatment decision-making for individual patients?

Dr.Anya Sharma is a leading hematologist-oncologist specializing in multiple myeloma at the fictional City General Hospital. She’s here to discuss the recent GMMG ReLApsE trial and its implications for salvage therapy. dr. Sharma,welcome!

Thank you for having me. I’m happy to be here.

The long-term data from the GMMG ReLApsE trial has certainly stirred up quite a discussion in the myeloma community.Could you briefly summarise the key findings for our readers?

Absolutely. The GMMG ReLApsE trial investigated the benefit of salvage high-dose chemotherapy (sHDCT) followed by autologous stem cell transplantation (ASCT) in patients with relapsed/refractory multiple myeloma compared to continuous lenalidomide and dexamethasone. The surprising finding was that adding sHDCT/ASCT didn’t significantly improve progression-free survival (PFS) or overall survival (OS).This challenges the previously assumed benefit of this intensive approach in this patient population.

That’s quite a importent shift in outlook. What patient characteristics were studied to get these findings?

The trial focused on patients aged 75 and under with relapsed or refractory myeloma who had received between one and three prior lines of therapy. These patients typically had a good performance score and a largely standard risk myeloma. It’s vital to remember that this trial has very specific inclusion criteria, and all of the data collected is based on patients receiving the care described in the trial.

The study also mentioned that a ample portion of patients in the transplant arm never made it to the actual transplant. Could you elaborate on why?

Yes,that’s a crucial point to consider.Around 29% of patients randomized to the transplant arm didn’t undergo sHDCT/ASCT. The main reasons were disease progression, adverse effects from the re-induction therapy, or patient withdrawal of consent. This highlights the challenges and potential toxicity associated with the transplant pathway.

based on this data, how should clinicians now approach treatment decisions for patients with relapsed multiple myeloma?

Clinicians need to carefully weigh the potential benefits and risks of sHDCT/ASCT. We should consider factors like patient frailty, previous treatment history, disease biology, and the availability of newer, potentially less toxic therapies. Individualized treatment plans are more critically important then ever. This study suggests that a “one-size-fits-all” approach with salvage transplants may not be optimal. We really need to ask ourselves if the potential benefits outweigh the risks with sHDCT/ASCT.

What are some of those newer, less toxic therapies you alluded to?

There are several exciting developments in myeloma treatment.We now have access to novel agents like daratumumab, selinexor, and other immunotherapies. Manny of these agents are used in combination regimens and have shown promising results in relapsed/refractory myeloma with manageable toxicity profiles, making them viable alternatives to sHDCT/ASCT in certain patients.

The trial reported on secondary primary malignancies. Is there anything there that should raise concern for patients?

The trial did report a higher incidence of secondary primary malignancies in the transplant arm (18%) compared to the control arm (14%), but this difference wasn’t statistically significant. However,this is something that can be caused by Melphalan,the drug used in HDCT and is something that we should always take into consideration when developing long-term care plans for our patients.

What further research do you think is needed to refine our understanding of salvage therapy in multiple myeloma?

We need studies that identify subgroups of patients who might still benefit from sHDCT/ASCT. Biomarker analyses, genetic profiling, and more granular data on post-trial therapies are all important. Also, comparative studies evaluating novel combination therapies against sHDCT/ASCT would be incredibly valuable.

a thought-provoking question for our readers: Considering the evolving landscape of myeloma treatment, what factors, besides survival statistics, should patients prioritize when discussing treatment options with thier doctors? We’d love to hear your thoughts in the comments below.

That’s an excellent question. I think patients should prioritize quality of life, treatment-related side effects, and their personal goals and preferences. it’s about shared decision-making and choosing a treatment plan that aligns with their individual needs and values.

Dr.Sharma, thank you so much for your insights. This has been incredibly helpful.

My pleasure.thank you for having me.