# Understanding High-Risk Multiple Myeloma: A Patient's Guide to Diagnosis, Treatment, and New Hope

**Summary:** This patient-friendly guide translates a comprehensive medical review about newly diagnosed high-risk multiple myeloma (MM), a blood cancer that affects plasma cells in the bone marrow. The review explains how doctors identify high-risk disease through genetic testing, compares the latest treatment combinations for both transplant-eligible and transplant-ineligible patients, and explores the role of stem cell transplantation and emerging therapies. Key findings highlight that roughly 20%–25% of newly diagnosed patients carry high-risk genetic abnormalities, and that newer quadruplet drug regimens, early stem cell transplantation, and deeper response rates are changing the outlook for this challenging patient population.

# Understanding High-Risk Multiple Myeloma: A Patient's Guide to Diagnosis, Treatment, and New Hope

## Table of Contents

- Key Points
- Introduction: What Is High-Risk Multiple Myeloma?
- How Doctors Define High-Risk Disease
- Treatment Options for Transplant-Eligible Patients
- Treatment Options for Transplant-Ineligible Patients
- The Role of Stem Cell Transplantation (ASCT)
- What These Findings Mean for Patients
- Study Limitations
- Recommendations for Patients and Families
- Frequently Asked Questions
- Source Information

## Key Points

- About 20–25% of newly diagnosed myeloma patients have high-risk genetic abnormalities that make the disease more aggressive.
- FISH testing identifies high-risk markers such as del(17p), t(4;14), t(14;16), gain(1q), and del(1p).
- In trials, quadruplet regimens like DVRd and IsaKRd achieved deeper responses, including in high-risk patients.
- Early autologous stem cell transplant improved progression-free survival compared to no early transplant in high-risk patients.
- Achieving MRD-negativity is a strong predictor of longer survival and is now a key treatment goal.

## Introduction: What Is High-Risk Multiple Myeloma?

Multiple myeloma (MM) is a blood cancer that begins when plasma cells—a type of white blood cell responsible for producing antibodies—transform into malignant cells. These abnormal cells grow out of control in the bone marrow, crowding out healthy blood cells and causing a range of complications. MM is the second most common blood cancer, after non-Hodgkin lymphoma, and accounts for about 20% of all deaths from blood-related malignancies.

The past two decades have brought remarkable progress in treating MM. Newer medications have dramatically improved survival for many patients. However, MM is not a single disease—it is highly varied. The same treatment that works brilliantly for one person may offer little benefit to another. This variability is largely driven by the genetic characteristics of the cancer cells themselves.

Roughly 20%–25% of patients with newly diagnosed multiple myeloma (NDMM) have what doctors call **high-risk cytogenetic abnormalities (HRCAs)**—specific genetic changes in the cancer cells that make the disease more aggressive. These abnormalities include deletions or rearrangements of chromosomes, such as del(17p), t(4;14), t(14;16), and gain(1q). Patients with these genetic markers tend to experience more frequent relapses and shorter progression-free survival (the time a patient lives without the disease worsening) and overall survival.

However, the story is not all grim. This review article, published in *Advances in Hematology*, examines the rapidly evolving treatment landscape for high-risk MM and shows that newer, more intensive treatment strategies are giving patients with high-risk disease reasons for hope.

## How Doctors Define High-Risk Disease

Doctors categorize the prognosis of multiple myeloma by looking at three main groups of factors: the biology and characteristics of the disease itself, host-related factors (such as the patient's age, overall health, and other medical conditions), and the interaction between the tumor and the patient's body.

For disease-related factors, genetic testing plays a central role. Doctors use a technique called **fluorescence in situ hybridization (FISH)** to examine the chromosomes inside myeloma cells. This testing looks for specific chromosomal abnormalities that indicate how aggressive the disease may behave.

### Staging Systems: R-ISS and R2-ISS

The **Revised International Staging System (R-ISS)** is now the preferred staging system for multiple myeloma. It combines four key pieces of information:

- Beta-2 microglobulin level (a protein that reflects tumor burden and kidney function)
- Serum albumin level (a blood protein that reflects nutritional status and inflammation)
- Serum lactate dehydrogenase (LDH) level (an enzyme that can indicate rapid cell turnover)
- Bone marrow FISH results (genetic abnormalities in the cancer cells)

A newer system, called the **R2-ISS**, builds on the R-ISS by adding gain(1q)—an extra copy of part of chromosome 1—into the scoring. This is important because gain(1q) is a common high-risk feature that was not included in the older system. The R2-ISS has demonstrated better ability to distinguish outcomes, particularly for the large group of patients with intermediate-risk disease. Its straightforward additive calculation method also makes it easier to incorporate new prognostic factors in the future.

### Key Genetic Abnormalities and What They Mean

Genetic abnormalities in myeloma are classified as either primary translocations (where pieces of chromosomes swap places) or secondary high-risk abnormalities (acquired later as the disease evolves).

Among primary translocations:

- t(11;14) is generally considered **standard-risk** disease and responds well to many treatments
- t(4;14), t(14;16), and t(14;20) are considered **high-risk** features

Secondary abnormalities that worsen prognosis include:

-
**del(17p)**—a deletion on chromosome 17 that removes the TP53 tumor suppressor gene. This is frequently associated with biallelic loss (both copies of the gene are lost) and is a strong indicator of aggressive disease. It is highly associated with t(4;14) in about 71% of cases.
-
**gain(1q) / amp(1q)**—an extra copy of the long arm of chromosome 1. This is found in about 30%–40% of patients. When amplified, it increases genomic instability and treatment resistance.
-
**del(1p32)**—a deletion on the short arm of chromosome 1, seen in about 10%–15% of patients, associated with worse response to standard therapies.
-
**MYC rearrangements**—genetic changes often coexisting with t(14;16) or del(17p), linked to advanced disease and plasma cell leukemia.

Patients with **double-hit MM** (two or more high-risk abnormalities) and **triple-hit MM** (three or more) experience particularly poor survival rates, even with intensive treatment. However, the review emphasizes that newer treatments—such as venetoclax (a BCL-2 inhibitor) for t(11;14), bortezomib (a proteasome inhibitor) for t(4;14), and CAR-T therapy or bispecific antibodies for ultra-high-risk patients—are opening the door to more personalized treatment approaches.

Another important factor is **extramedullary disease**, where myeloma cells spread outside the bone marrow into other tissues or organs. This affects approximately 15% of MM patients over the course of their disease and is associated with a poor prognosis in both newly diagnosed and relapsed patients. Detecting extramedullary involvement early is clinically important because it changes treatment planning.

## Treatment Options for Transplant-Eligible Patients

For patients who are healthy enough to undergo high-dose chemotherapy and stem cell rescue, the choice of induction therapy (the first treatment given) is critical. Several regimens have been studied, and the review provides a detailed breakdown of the evidence.

### Bortezomib, Lenalidomide, and Dexamethasone (VRd)

VRd combines **bortezomib** (a proteasome inhibitor that blocks cancer cells from breaking down proteins they need to survive), **lenalidomide** (an immunomodulatory drug that helps the immune system attack cancer cells), and **dexamethasone** (a steroid that reduces inflammation and directly kills myeloma cells).

The **SWOG S0777 trial** compared VRd against lenalidomide plus dexamethasone (Rd) alone in newly diagnosed patients, with approximately one-third having high-risk disease. Among high-risk patients, those receiving VRd experienced a median progression-free survival of **38 months versus 16 months** for Rd—a striking improvement, though the difference did not reach statistical significance, likely because the study included only a limited number of high-risk patients.

The **IFM2008 trial** provided further support for VRd. High-risk cytogenetic features (del(17p) or t(4;14)) were present in seven patients (27%). This small group showed an estimated 3-year PFS of **86% (95% CI: 33%–98%)**. The authors caution that this finding should be interpreted carefully given the very small sample size and limited statistical power.

### Bortezomib, Cyclophosphamide, Dexamethasone (VCd)

The **EVOLUTION study** compared VRd, VCd (replacing lenalidomide with cyclophosphamide, a chemotherapy drug), and VDCR (all four drugs combined). VCd is considered a reasonable alternative to VRd, particularly for patients at higher risk of kidney toxicity. In this study, 17% (24 patients) had high-risk features, defined as del(13)/−13q14, t(4;14), t(14;16), −17p13, or hypodiploidy.

Notably, high-risk patients in the VCd group achieved a **1-year PFS of 100%**, suggesting that VCd may be especially effective in this population—though again, the small sample size warrants caution.

### Bortezomib, Thalidomide, Dexamethasone (VTd)

The **IFM2013-04 trial** showed superior outcomes with VTd compared to VCd in transplant-eligible patients with high-risk features (del(17p) and/or t(4;14)).

The **GIMEMA MM-BO2005 trial** provided important insights into VTd's effectiveness in high-risk disease. VTd consolidation was particularly beneficial for patients with t(4;14), achieving superior 3-year PFS compared to thalidomide-dexamethasone (Td) consolidation: **66% versus 20% (p=0.001)**. Most strikingly, VTd appeared to completely overcome the negative prognosis of t(4;14), with nearly identical PFS curves regardless of t(4;14) status (3-year estimates: 65% vs. 61%; p=0.936). In contrast, Td consolidation showed poor outcomes in t(4;14)-positive patients (median PFS: **12 vs. 44 months** in t(4;14)-positive vs. negative patients; p<0.0001), highlighting the specific benefit of proteasome inhibition in this high-risk subset.

### Daratumumab + VRd (DVRd)

The **GRIFFIN study** compared DVRd (adding daratumumab, a monoclonal antibody that targets CD38 on myeloma cells) with VRd in transplant-eligible patients. Among 30 patients (14%) with high-risk cytogenetics (del(17p), t(14;16), t(4;14)), subgroup analysis revealed lower rates of stringent complete response (sCR) and MRD-negativity compared to standard-risk patients, though these differences were not statistically significant—the small number of high-risk patients limits definitive conclusions.

The larger **PERSEUS trial** provided stronger evidence. Among 709 patients, 21.7% had high-risk cytogenetics (del[17p], t[4;14], t[14;16]). Preplanned subgroup analyses showed a consistent PFS advantage for DVRd over VRd across all clinically relevant subgroups, **including patients with high-risk cytogenetics**. This supports the use of this quadruplet regimen even in adverse-risk disease.

### Daratumumab + VTd (D-VTd)

The **CASSIOPEIA trial** randomized 1,085 transplant-eligible patients to D-VTd versus VTd. High-risk cytogenetics (del[17p] or t[4;14]) were present in 15% of the D-VTd group. Importantly, the benefit of adding daratumumab was attenuated in high-risk patients: there was no significant advantage for achieving stringent CR (HR, 0.83; 95% CI, 0.42–1.66) or reducing the risk of progression or death (HR, 0.67; 95% CI, 0.35–1.3). This suggests that high-risk patients may need alternative or more intensive approaches beyond simply adding daratumumab to VTd.

### Daratumumab + Carfilzomib + Lenalidomide + Dexamethasone (Dara-KRd)

The **MANHATTAN cohort** included 41 patients, 20 of whom (49%) had high-risk features (1q+, t(4;14), t(14;16), t(14;20), and/or 17p−). High-risk patients achieved MRD-negativity rates similar to standard-risk patients (odds ratio, 1.7; 95% CI, 0.36–8.6; p=0.50), suggesting that Dara-KRd may overcome adverse cytogenetic features.

The **MASTER trial** provided more robust evidence with 123 patients: 37% had one HRCA and 20% had two or more HRCAs. MRD-negativity rates were maintained across risk groups: 78% (0 HRCAs), 82% (1 HRCA), and 79% (≥2 HRCAs). However, the 3-year PFS showed clear risk stratification: **88% (no HRCAs), 79% (1 HRCA), and 50% (≥2 HRCAs)**. This indicates that while deep responses are achievable in ultra-high-risk patients, those with two or more high-risk abnormalities still experience inferior long-term outcomes despite intensive therapy.

### Daratumumab + Cyclophosphamide + VRd (Dara-CVRd)

The **OPTIMUM trial** specifically targeted 107 transplant-eligible patients with ultra-high-risk disease, defined by two or more high-risk genetic markers (including t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p), and/or SKY92 gene expression profiles). This intensive five-drug approach (**pentuplet therapy**) achieved MRD-negativity in **41% after induction and 64% after autologous stem cell transplantation (ASCT)**. The study provides proof-of-concept that even ultra-high-risk patients can achieve deep responses with sufficiently intensive therapy.

### Carfilzomib, Lenalidomide, Dexamethasone (KRd)

The **FORTE trial** compared three treatment strategies in 474 transplant-eligible patients. High-risk features (t(4;14), t(14;16), del(17p), gain(1q), del(1p), or 1q amplification) were present in 34% (one HRCA) and 26% (two or more HRCAs) of patients. The 4-year PFS was 60% for patients with one HRCA versus 39% for those with two or more, confirming clear risk stratification.

Importantly, KRd plus ASCT consistently outperformed other strategies in high-risk patients:

- For patients with 1 HRCA: 4-year PFS of **67%** versus 57% (KRd alone) and 55% (KCd plus ASCT)
- For patients with ≥2 HRCAs: 4-year PFS of **55%** versus 31% and 33%, respectively

KRd plus ASCT also achieved superior sustained MRD-negativity regardless of cytogenetic profile, establishing it as the preferred approach for high-risk disease in this trial.

### Isatuximab + KRd (IsaKRd)

The **IsKia trial** randomized 302 transplant-eligible patients to IsaKRd versus KRd. High-risk features (del(17p), t(4;14), t(14;16)) were present in 18%–19% of patients, and double-hit disease (≥2 HRCAs including 1q abnormalities) was present in 8%–9%. IsaKRd demonstrated superior MRD-negativity in high-risk patients: **76% versus 58%** for those with 1 HRCA, and **77% versus 53%** for those with ≥2 HRCAs. Notably, ultra-deep MRD-negativity (at the 10⁻⁶ level, meaning one cancer cell in a million normal cells) was achieved in 72% and 77% of IsaKRd patients with 1 and ≥2 HRCAs respectively—indicating profound disease control even in adverse-risk patients.

The **GMMG-CONCEPT trial** confirmed IsaKRd's efficacy in an exclusively high-risk population of 125 patients. MRD-negativity was achieved in **68% of transplant-eligible** and **54% of transplant-ineligible** patients, with sustained MRD-negativity (lasting at least one year) in 63%.

## Treatment Options for Transplant-Ineligible Patients

Not all patients are healthy enough for high-dose chemotherapy and stem cell transplantation. For these patients, the goals of treatment are to achieve deep responses while managing side effects and preserving quality of life.

### Daratumumab + Lenalidomide + Dexamethasone (DRd)

The **MAIA trial** randomized 737 transplant-ineligible patients to DRd versus Rd, with high-risk cytogenetics (del(17p), t(14;16), t(4;14)) present in about 15% of patients. High-risk patients derived significant benefit from DRd:

- Median PFS: **45.3 months** versus 29.6 months with Rd
- Median overall survival: **55.6 months** versus 42.5 months

These results establish DRd as an effective frontline option for transplant-ineligible high-risk patients, providing both progression-free and overall survival advantages.

### VRd-Lite (Dose-Adjusted VRd)

The **VRd-Lite study** treated 53 transplant-ineligible patients with a dose-reduced version of VRd. High-risk features were present in 6 patients (12%), though specific outcomes for this subgroup were not reported. This regimen represents a reasonable option for frail or older transplant-ineligible patients, particularly when considering kidney function and overall tolerability.

### Daratumumab + Bortezomib + Melphalan + Prednisone (DVMP)

The **ALCYONE trial** randomized 706 transplant-ineligible patients to DVMP versus VMP, with high-risk cytogenetics (del(17p), t(4;14), t(14;16)) present in 15%–17%. Subgroup analysis showed a favorable trend for DVMP in high-risk patients (hazard ratio 0.78), though this did not reach statistical significance. The study suggests potential benefit, particularly for patients with R-ISS stage III disease (HR 0.75).

### Isatuximab-Based Regimens: IsaVRd and Isa-VRd

The **BENEFIT trial** compared isatuximab + lenalidomide + dexamethasone (Isa-Rd) versus the same regimen plus bortezomib (IsaVRd) in 270 transplant-ineligible patients. High-risk features (del(17p), t(4;14), t(14;16)) were present in 8%–10%. The addition of bortezomib significantly improved:

- MRD-negativity: **53% versus 26%**

- Complete response rates: **58% versus 33%**

Importantly, MRD benefits were consistent across all subgroups, including high-risk patients, indicating that adding a proteasome inhibitor is beneficial even in adverse-risk transplant-ineligible patients.

The **IMROZ study** randomized 446 transplant-ineligible patients to Isa-VRd versus VRd, with high-risk cytogenetics in 15%–19% of patients. While Isa-VRd improved MRD-negativity and complete response rates in high-risk patients (**55.5% vs. 40.9%; p=0.003**), the PFS benefit was less pronounced in this subgroup (HR 0.97) and did not reach statistical significance. This suggests that high-risk transplant-ineligible patients may require alternative intensification strategies beyond adding an anti-CD38 antibody to VRd.

## The Role of Stem Cell Transplantation (ASCT)

**Autologous stem cell transplantation (ASCT)**—a procedure where the patient's own stem cells are collected before high-dose chemotherapy and then returned to the body to rebuild the bone marrow—remains a cornerstone of first-line therapy for transplant-eligible newly diagnosed patients. For high-risk patients characterized by cytogenetic abnormalities such as del(17p), t(4;14), and t(14;16), ASCT provides significant benefits, though these patients typically have shorter progression-free and overall survival than standard-risk patients and often require additional maintenance therapy and novel agents for optimal long-term disease control.

### Key Trial Evidence

The **IFM2009 trial** demonstrated that early ASCT was associated with superior PFS in high-risk patients: median PFS of **47.2 months** in the ASCT group compared with **35 months** in the VRd-alone group (HR 0.70, 95% CI 0.59–0.83).

The **DETERMINATION trial** further confirmed these benefits, showing improved PFS in high-risk patients with ASCT versus VRd alone: median PFS **56 vs. 17 months** (HR 1.99, 95% CI 1.21–3.26). Overall survival differences remain modest due to the effectiveness of salvage therapies, including second-line ASCT and novel agents.

ASCT also enhances the depth of response in high-risk patients. MRD-negativity rates were significantly higher in the ASCT group: **29.8% versus 20%** in the VRd-alone group (p=0.01). MRD-negativity serves as a powerful predictor of long-term survival, suggesting that the intensive conditioning regimen helps overcome some of the resistance mechanisms associated with adverse cytogenetics.

### The Timing of Transplant Matters

For high-risk patients, the timing of ASCT is particularly crucial. While the choice between early and delayed ASCT can depend on patient and physician preferences in standard-risk disease, the evidence strongly favors **upfront ASCT for high-risk patients**. The IFM2009 trial showed that high-risk patients experienced improved PFS with early ASCT compared to delayed strategies, supporting the recommendation for early transplantation in this population.

### Tandem ASCT: A Promising Intensification Strategy

**Tandem ASCT**—receiving two sequential transplants—represents a promising intensification approach for high-risk patients. The **EMN02/HO95 study** demonstrated that tandem ASCT significantly prolonged PFS compared to single ASCT in high-risk patients (HR 0.59, 95% CI 0.38–0.91; p=0.02). This provides robust evidence that the graft-versus-myeloma effect and increased tumor cell kill achieved through tandem transplantation may be particularly beneficial for patients with adverse cytogenetic features.

## What These Findings Mean for Patients

The review delivers several important messages for patients and their families:

**First, genetic testing matters.** Knowing whether your myeloma carries high-risk features isn't just academic—it directly guides treatment intensity. Patients with high-risk cytogenetics may benefit from more aggressive initial therapy, including quadruplet regimens and early transplantation.

**Second, deeper responses translate to better outcomes.** MRD-negativity—meaning no detectable cancer cells even with highly sensitive testing—is becoming an essential treatment goal. The review highlights that achieving MRD-negativity may help overcome the negative effects of high-risk cytogenetics. As one study noted, MRD-negativity is now considered a valid predictor of progression-free and overall survival.

**Third, more drugs can mean better outcomes.** Data from trials like PERSEUS, FORTE, and IsKia show that quadruplet regimens incorporating monoclonal antibodies or carfilzomib achieve deeper responses—even in high-risk patients. For the most challenging ultra-high-risk patients, five-drug regimens (like OPTIMUM's pentuplet approach) can produce MRD-negativity in nearly two-thirds of patients after transplant.

**Fourth, transplant is worth considering early.** For eligible patients, the evidence strongly supports early ASCT for high-risk disease. Tandem transplant is also emerging as a viable intensification strategy. Even among high-risk patients, ASCT produces significantly higher MRD-negativity rates than chemotherapy alone.

**Fifth, emerging treatments are on the horizon.** While the main body of this review focuses on approved therapies, the authors emphasize that **bispecific antibodies** (lab-engineered molecules that link T-cells to myeloma cells) and **CAR-T therapy** (where a patient's own immune cells are genetically modified to attack the cancer) are being studied in earlier lines of treatment. These therapies may further transform the standard of care for high-risk MM patients.

## Study Limitations

It is important to understand what this review can and cannot tell us:

-
**This is a review article, not a single study.** It synthesizes findings from multiple clinical trials, each with its own patient population, design, and limitations.
-
**Many high-risk subgroup analyses have small sample sizes.** For example, only 7 to 30 patients with high-risk features were included in some trials (IFM2008, GRIFFIN, VRd-Lite). This limits the statistical power to detect differences reliably.
-
**Several trials showed numerical improvements in high-risk patients that did not reach statistical significance.** This does not mean the treatments don't work—it often means the number of high-risk patients studied was too small to prove it.
-
**Results are not always consistent across trials.** For example, the CASSIOPEIA trial showed that high-risk patients did *not* derive significant benefit from adding daratumumab to VTd, while the PERSEUS trial showed consistent benefit when daratumumab was added to VRd. This highlights that not all quadruplet regimens are equally effective in high-risk disease.
-
**Overall survival data are still maturing.** Some trials show PFS benefits that have not yet translated into proven overall survival benefits, due to the effectiveness of subsequent treatments (salvage therapies).
-
**Definition of "high-risk" varies across studies.** Some trials used one set of cytogenetic markers, others used different ones. This makes cross-study comparisons challenging.

## Recommendations for Patients and Families

Based on this review and standard medical guidelines, here are actionable points to discuss with your healthcare team:

1.
**Ask about FISH testing.** Make sure your bone marrow sample was tested for high-risk cytogenetic abnormalities, including del(17p), t(4;14), t(14;16), t(14;20), gain(1q), and del(1p). Knowing your risk status changes treatment decisions.
1.
**Ask about R2-ISS staging.** Newer staging systems that include gain(1q) provide a more complete picture of your disease.
1.
**Discuss whether a quadruplet induction regimen is right for you.** If you are transplant-eligible, options such as DVRd, IsaKRd, or KRd plus transplant may offer the best chance of deep responses. If you are not transplant-eligible, DRd or isatuximab-based combinations are supported by strong evidence.
1.
**Consider early stem cell transplant if eligible.** The evidence clearly favors upfront ASCT for high-risk disease. Ask your doctor about whether tandem transplant might be appropriate in your case.
1.
**Ask about MRD testing.** MRD-negativity is a powerful predictor of long-term outcomes. Ask whether your treatment response will be monitored with MRD testing and what the results mean for your next steps.
1.
**Stay informed about clinical trials.** Because high-risk myeloma is challenging to treat, clinical trials of new approaches—including CAR-T therapy, bispecific antibodies, and novel combinations—may offer access to cutting-edge treatments. The review specifically notes that ongoing trials investigating the early use of these therapies may change the standard of care.
1.
**Pay attention to maintenance therapy.** The review notes that high-risk patients often require additional maintenance therapies for optimal long-term disease control. Ask about your maintenance plan after induction and transplant.
1.
**Consider a second opinion at a myeloma center of excellence.** High-risk myeloma is complex, and treatment outcomes improve when care is provided by specialists who see large numbers of myeloma patients.

## Frequently Asked Questions

### What does it mean if my doctor says my multiple myeloma is high-risk?

High-risk multiple myeloma means your cancer cells have specific genetic abnormalities, such as del(17p), t(4;14), t(14;16), gain(1q), or del(1p), that tend to make the disease more aggressive, with more frequent relapses and shorter survival. About 20% to 25% of newly diagnosed patients have these features, and your treatment plan is often adjusted accordingly.

### Why is FISH genetic testing important for newly diagnosed multiple myeloma?

FISH testing examines the chromosomes inside your myeloma cells to look for high-risk genetic changes. Knowing whether your disease carries these abnormalities directly guides treatment intensity, such as whether a quadruplet drug combination, early stem cell transplant, or more intensive maintenance therapy is most appropriate for your situation.

### If I am eligible for a stem cell transplant, should I have it early for high-risk myeloma?

In trials, early autologous stem cell transplantation improved progression-free survival in high-risk patients compared to not having early transplant. For example, in one study median progression-free survival was 47.2 months with early transplant versus 35 months without. Ask your doctor whether early transplant and possibly tandem transplant is right for you.

### What treatment options are available if I am not eligible for a stem cell transplant?

For transplant-ineligible patients, combinations such as daratumumab plus lenalidomide and dexamethasone (DRd) have improved survival. In one trial, high-risk patients lived a median of 55.6 months with DRd versus 42.5 months with Rd alone. Isatuximab-based combinations are also supported by evidence for this group.

### What is MRD-negativity and why does it matter for high-risk myeloma?

MRD-negativity means no detectable cancer cells even with highly sensitive testing. In several trials, achieving MRD-negativity was linked to longer progression-free and overall survival, and some intensive regimens achieved it in high-risk patients at rates similar to standard-risk patients. Ask whether your response will be monitored with MRD testing.

### Are there effective treatments for ultra-high-risk multiple myeloma, such as double-hit or triple-hit disease?

Yes. In the OPTIMUM trial, a five-drug regimen in ultra-high-risk patients achieved MRD-negativity in 41% after induction and 64% after autologous stem cell transplant. The MASTER trial showed that patients with two or more high-risk abnormalities still had lower long-term progression-free survival, so intensive therapy followed by maintenance is often recommended.

### What should I discuss with my healthcare team about maintaining remission in high-risk myeloma?

Ask about FISH testing, R2-ISS staging, whether a quadruplet induction regimen is appropriate, early transplant if eligible, MRD testing to monitor response, maintenance therapy after induction and transplant, and clinical trials for new approaches like CAR-T therapy or bispecific antibodies, which are being studied in earlier lines of treatment.

## Source Information

**Original Article:** "Newly Diagnosed High-Risk Multiple Myeloma: Outcomes and Management"

**Authors:** Fatma Zehra Yasar and Elan Gorshein

**Publication:** *Advances in Hematology*, Volume 2025, Article ID 6622365, 16 pages (published by John Wiley & Sons Ltd)

**DOI:** https://doi.org/10.1155/ah/6622365

**Affiliations:** Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey; and Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, North Haven, Connecticut, USA

**Publication Timeline:** Received 19 April 2025; Revised 24 August 2025; Accepted 2 September 2025

**Academic Editor:** Suraiya Saleem

**Access:** This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace individualized medical advice from your healthcare team. Always discuss your specific treatment plan with your doctor.*


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