<h2>Multiple copies of chromosome 1 (1q+) is a frequent CA in MM</h2>
<ul>
 <li>MM is characterized by CAs in plasma cells1</li>
 <li>Frequent gains include 1q, 6p and 11q1</li>
 <li>1q+ is one of the most common CAs in MM</li>
</ul>

<h2>1q+ abnormalities are defined by copy number</h2>
Chromosome 1q abnormalities terminology3

<table border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td>+1q</td>
 <td>Additional copies of any part of the long arm of chromosome 1 (1q), irrespective of copy number or DNA segment gained</td>
 </tr>
 <tr>
 <td>Gain(1q)</td>
 <td>Gain of only 1 extra copy of chromosome 1q (3 total copies)</td>
 </tr>
 <tr>
 <td>Amp(1q)</td>
 <td>“Amplification” of 1q, with 2 additional copies of chromosome 1q (4 or more total copies)</td>
 </tr>
 </tbody>
</table>

In MM, 1q+ is frequently denoted as 1q21+, which refers to a specific location – region 2, band 1 on the long arm of chromosome 1

<h2>Overexpression of certain genes in the 1q arm may drive pathogenesis and drug resistance4,5</h2>

<table border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td>Key genes located in the 1q21 band:
 <ul>
 <li>BCL9: Cell growth</li>
 <li>ILF2, ADAR:&nbsp;RNA metabolism</li>
 <li>MCL1:&nbsp;Anti-apoptosis</li>
 <li>CKS1B:&nbsp;Cell proliferation</li>
 </ul></td>
 <td rowspan="2">Resistance to PIs through the upregulation of the proteasome genes, including PSMD6</td>
 </tr>
 <tr>
 <td>
 <ul>
 <li>PSMD4:&nbsp;Anti-PI</li>
 </ul></td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td>Other key genes outside of the 1q21 band include:
 <ul>
 <li>SLAMF7, SLAMF3:&nbsp; 
 Immunomodulatory receptors</li>
 <li>FCRH5, NEK2:&nbsp;Cell development</li>
 <li>CD1D:&nbsp;T-cell responses</li>
 </ul></td>
 <td rowspan="2">Resistance to drugs that rely mainly on CDC through upregulation of complement inhibitors, such as CD557</td>
 </tr>
 <tr>
 <td>
 <ul>
 <li>CD55, CD46:&nbsp;CDC inhibition</li>
 </ul></td>
 </tr>
 </tbody>
</table>

<h2>1q+ terminology when co-occurring with/without other high-risk cytogenetic abnormalities (HRCA)8</h2>

<h2>1q+ increases throughout the MM disease course4,9</h2>

<h2>Prognosis worsens with increasing copy number</h2>

<h2>Incorporating 1q+ testing into clinical practice remains challenging</h2>

New staging systems, such as R2-ISS, MASS and R-ISS-1q,12–14&nbsp;are including gain/amp(1q), alongside other high-risk factors when defining disease stage, in order to refine predictions of clinical outcomes and highlight the prognostic impact of gain/amp(1q)

Although most guidelines include 1q+ in their HRCA definitions, the recommendations for FISH panel testing for 1q+ are inconsistent and there is little treatment guidance specific to gain/amp(1q)15–17

<div>
 <table border="1" cellpadding="1" cellspacing="1" style="width: 100%;">
 <tbody>
 <tr>
 <td>
 IMWG guidelines&nbsp;include gain/amp(1q) in their definition of HRCAs, but&nbsp;do not&nbsp;include it as part of their recommended routine FISH panel15</td>
 </tr>
 </tbody>
 </table>
</div>

Abbreviations

References

Multiple Myeloma: Chromosome 1q+ cytogenetic abnormalities

MULTIPLE-MYELOMA

HEMATOLOGY

Welcome to the first edition of the Sanofi quarterly newsletter for 2023! These newsletters, created by Sanofi, aim to provide education to healthcare providers in relevant topics in multiple myeloma (MM). In this edition, we look at the increasing challenge of lenalidomide (len)-refractory disease in relapsed/refractory MM (RRMM), highlighting how widespread use of len-based regimens early in the treatment pathway has resulted in the emergence of a difficult-to-treat patient population with unmet medical need.

Early treatment for MM often includes len-based regimens as part of induction, consolidation, or as long-term maintenance. Therefore, many patients with RRMM have been previously exposed to and/or are refractory to len. Len-refractory MM is associated with poor clinical outcomes, as well as high disease burden, with few effective therapeutic options available.
<div>
 <table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>
 In this issue
 <ul>
 <li>The role of lenalidomide in MM</li>
 <li>Lenalidomide-refractoriness in MM</li>
 <li>Unmet needs in lenalidomide-refractory MM</li>
 <li>Summary</li>
 </ul></td>
 </tr>
 </tbody>
 </table>
</div>

<h2>The role of len in MM</h2>
The substantial efficacy and manageable toxicity of len has resulted in this agent becoming the backbone of many combination regimens throughout the MM continuum and one of the most commonly used immunomodulatory drugs (IMiDs) worldwide.1,2&nbsp;Len is used across frontline treatment for both transplant-eligible and -ineligible patients, including during induction, consolidation, as well as for maintenance therapy.3,4
Given the extensive use of len in the treatment of MM, most patients are exposed to len, frequently early in the course of therapy. In the latest data from the CoMMpass global prospective observational study (conducted in the US, Canada, Spain, and Italy), 52% of 1150 patients had a len-based first-line regimen and 45% had len-based second-line therapy (Figure 1).5
&nbsp;
Figure 1: The proportion of patients receiving first-line (induction) or second-line treatment including len in the CoMMpass study (N=1150)5

C, cyclophosphamide; d, dexamethasone; K, carfilzomib; len/R, lenalidomide; V, bortezomib&nbsp;
When maintenance regimens are taken into account, the proportion of patients receiving len for newly diagnosed MM (NDMM) rises even further. Data for 149 transplant-eligible patients treated&nbsp;from 2017 to 2020/2021 in France, Germany, Spain and Italy found that 93% of patients overall received len for NDMM (Figure 2).6
&nbsp;
Figure 2: Induction and maintenance regimens used amongst Te NDMM patients in France, Germany, Spain and Italy (N=149)6

C, cyclophosphamide; d, dexamethasone; len/R, lenalidomide; NDMM, newly diagnosed multiple myeloma; T, thalidomide; Te, transplant-eligible; V, bortezomib
Prolonged therapy with len is common 
 Maintenance regimens are typically given until disease progression or intolerance, therefore treatment is often prolonged. In a retrospective study of 139 patients who received len maintenance&nbsp;during frontline therapy, the median duration of treatment was 21 months, and 25% of patients received len for &gt;31 months (Figure 3).7
&nbsp;
Figure 3: Real-world duration of len maintenance in NDMM patients (N=139)7

len, lenalidomide; NDMM, newly diagnosed multiple myeloma
Duration of len-based treatment can also be lengthy in RRMM. In the INSIGHT MM prospective observational study, 821 patients received one or more lines of Rd-based therapy for RRMM, with median therapy durations up to ~14 months (Figure 4).8
&nbsp;
Figure 4: Median duration of len treatment in RRMM patients in the INSIGHT MM observational study (N=821)8

<h2>Len-refractoriness in MM</h2>
The widespread use of prolonged len-based regimens in frontline treatment has resulted in a high proportion of patients becoming len-refractory.9 According to the International Myeloma Working Group (IMWG), refractory MM is defined as disease that is nonresponsive to primary or salvage therapy (failure to achieve minimal response or development of progressive disease while on therapy) or progresses within 60 days of last therapy.10
The global prevalence of len-refractory patients is unclear as practices vary between countries; however, local registries provide some insights. In a retrospective, real-world UK study of patients with relapsed MM who were treated with len, 72% of 158 evaluable patients acquired len-refractory status.9 Similarly, a Danish retrospective study analyzing a population of NDMM and RRMM patients (N=303) found that 78% had previously received len, and 45% were considered len-refractory.11
Mechanisms of len-resistance&nbsp; 
 The mechanisms of len-resistance are complex and are not completely understood. However, the protein cereblon (CRBN) is the primary target for len and triggered downstream mechanisms elicit the vast majority of the pharmacological effects responsible for its anti-myeloma properties. Therefore, it has been suggested that acquired abnormalities in CRBN-related pathways in malignant plasma cells are likely to result in decreased len sensitivity or development of&nbsp;drug resistance.1 As such, low CRBN expression has been found to be associated with len-resistance in both preclinical studies and patients with MM.1,12&nbsp;
A number of other mechanisms are also thought to contribute to len-resistance;1 however, further research is required to fully understand these pathways with hopes to aid in the development of future therapeutic strategies.12&nbsp;

<h2>Unmet needs in len-refractory MM</h2>
Prognosis in len-refractory disease&nbsp; 
 The most important effect of len-refractory status in MM is its association with poor outcomes.9 A US retrospective analysis of medical records showed that patients who had len-refractory disease after first-line len-based therapy had both a shorter progression-free survival (PFS) and overall survival (OS) (Figure 5) than those who relapsed but were non-refractory.13
&nbsp;
Figure 5: PFS (A) and OS (B) from start of second-line therapy in patients with len-refractory and len-relapsed disease in a retrospective study (N=279)13

OS, overall survival; PFS, progression-free survival; R/len, lenalidomide
Similarly, a retrospective study of 312 patients who progressed on/after receiving frontline therapy with len found significantly shorter PFS at next line in patients refractory to len (regardless of dose received), compared with those who were non-refractory (Figure 6). These data suggest that resistance to len is not dose dependent.14
&nbsp;
Figure 6: PFS at next line in patients refractory to low- and standard-dose len (N=312)14

*Standard dose len = 25 mg daily, in combination with other agents or otherwise, low dose len = 10 mg daily. 
 CI, confidence interval; HR, hazard ratio; Len, lenalidomide; PFS, progression-free survival 
 &nbsp;
Higher disease burden associated with len-refractory disease&nbsp; 
 In addition to their poor prognosis, patients with len-refractory disease may have further characteristics that increase their level of unmet medical need. The CRAB features (hyperCalcemia,&nbsp;Renal failure,&nbsp;Anemia, and&nbsp;Bone lesions) are symptoms of end-organ damage commonly&nbsp;associated with MM.15 Comparison of medical records data from 279 patients who received len-based first-line therapy found that CRAB symptoms were more frequent in those with len-refractory than non-refractory disease at the initiation of second-line therapy, indicating a higher disease burden (Figure 7).13
&nbsp;
Figure 7: Prevalence of CRAB symptoms in len-refractory and non-refractory MM at initiation of second-line therapy (N=279)13

Similarly, significant levels of comorbidities are present in patients with len-refractory disease; US real-world data from claims and electronic health records found high levels of conditions such as hypertension and fluid/electrolyte disorders (Figure 8).16
&nbsp;
Figure 8: Comorbidities seen in real-world populations of patients with len-refractory MM16

Additional challenges in len-refractory MM 
 Patients with len-refractory disease represent an ever-increasing proportion of the RRMM population, but there are a number of challenges associated with treatment selection that make this group difficult to treat. Although rechallenge with a drug that has previously proved effective can be a potential treatment strategy for those who are len-exposed but non-refractory,17 len-refractory status prevents the use of len in subsequent lines.18 Additionally, as the choice of therapy in RRMM needs to consider comorbidities (such as renal or&nbsp;cardiac failure) as well as the response to previous treatment,17 the higher disease burden in len-refractory MM further reduces the pool of potential options. Further, as the use of len in NDMM is so widespread, the len-refractory subgroup is highly heterogeneous,18 so it is possible that a single solution will not meet the needs of all patients. There is, therefore, a high unmet need for effective regimens in this increasing population of patients with poor prognosis, a high disease burden, and a limited number of available therapies (Figure 9).9,19&nbsp;
&nbsp;
Figure 9: Unmet needs in len-refractory MM9,13,16,18-20

<h2>SUMMARY</h2>
Since its approval in MM approximately two decades ago, len has become the backbone of many standard-of-care regimens, with the majority of patients being exposed to this agent early in their treatment journey. The widespread and prolonged use of len has resulted in a high number of patients developing len-refractory disease.
Len-refractory disease is associated with poor outcomes, and as such, patients tend to have a higher disease burden than those without len-refractory MM. It is therefore important to ensure that approved regimens are accessible to patients in this hard-to-treat population.

Reference

Lenalidomide Refractory Patients

<h2>Exploring the True and Complete Cost of Multiple Myeloma</h2>
The financial burden multiple myeloma patients face is often greater than expected when you factor in the cost of caregiving and loss of income.
Sanofi partnered with the International Myeloma Foundation (IMF) to conduct a research study to help haematologists further understand the health system and patients’ financial burdens and provide a new way to look at treatment options.
The True Cost of Multiple Myeloma (MM) report started with a systemic literature review and then discussed those findings in roundtables featuring patients, caregivers, and a variety of leaders in the MM space to gather further insights.

<h3>31% Increase</h3>
<h4>Hospitalized MM patients face an economic burden 31% larger than hospitalized colon cancer patients.1</h4>

<h3>An Economic Burden Higher Than Other Cancers</h3>
One of the biggest expenses of MM is the amount of hospital admissions, both unplanned and planned. These admissions are a significant driver behind the total cost.1
On average the&nbsp;number of multiple myeloma-related hospital admissions&nbsp;per patient is almost 3 times higher&nbsp;than those of colon cancer&nbsp;(4.5 vs 1.4, respectively).

Another consideration is the burden associated with significant productivity loss. The chart below shows the top burdens on patients and caregivers, all of which carry increased direct and indirect costs to patients and society.2
These burdens take a significant toll on patients’ productivity. A diagnosis with multiple myeloma resulted in an approximate productivity loss of €290,601 per patient over a 20-year period.3

Only&nbsp;11% of patients remain working&nbsp;post-diagnosis and treatment, with&nbsp;48% of patients not working&nbsp;due to their disease. The research indicates that 32% of MM patients were forced into early retirement.2
<h3>More Efficacious is More Cost Efficient</h3>
The way healthcare costs for MM have been calculated historically does not paint the whole picture. It is time to tell a complete view because the continued progress of treatments coupled with patients being longer time on therapies, makes healthcare resource utilization and costs associated with the treatments increase, simply due to better treatments and longer time spent on therapies.
<h4>Here’s what we know:</h4>
<ul>
 <li>Patients are now spending a longer time in a progression-free state because of better treatments</li>
 <li>The cost offsets associated with more efficacious treatments are not well documented</li>
 <li>A disproportionate emphasis is being placed on drug treatment costs without the consideration of potential offsetting benefits associated with treatment</li>
</ul>

In a study by Ashcroft et al. 2018, maintenance therapy was shown to delay progression to further lines of therapy and reduce resource use in a 15-month time horizon.4&nbsp;For 2017:

Maintenance patients cost:
<h3 style="text-align: center;">€238-€638</h3>
per month

Non-maintenance patients cost:
<h3 style="text-align: center;">4328-€1001</h3>
per month

Unplanned hospital admissions represented only 10% of all MM admissions, but accounted for 55% of the total hospitalization costs.1
<h3>Optimal Treatment Pathway May Be Translated in Savings</h3>
The findings indicated that the depth and durability of tumor response to treatment can reduce overall disease cost. If the remission period is prolonged, it’s possible to achieve less active treatment and unplanned hospitalizations.5
Improved treatment outcomes may reduce the overall healthcare resource utilization and related costs.5

The evidence suggests that finding&nbsp;the optimal treatment pathway&nbsp;for patients, including selecting the optimal treatment as well as the optimal structural model,&nbsp;has the potential to generate cost savings for payers and patients, while improving patient experience.4

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">"Depending on the insurance system the patient has, it can be difficult to access more expensive treatments such as monoclonal antibodies. -&nbsp;KOL interviewee"</td>
 </tr>
 </tbody>
</table>

The Impact of Access Barriers
<ul>
 <li>
 Medical systems vary widely by country. For many, innovative medicines are not adequately reimbursed or easily available</li>
 <li>
 The global discrepancies in access are equally important to the cost burden but are not well-described factors in publications</li>
 <li>
 New strategies are needed to improve access and outcomes for MM patients worldwide</li>
</ul>

<h2>Reducing the Cost Burden of MM</h2>
Governments, healthcare professionals, patient advocates, and industry must dedicate themselves to practical efforts that address patient cost.
<ul>
 <li>Commit to researching how the variety of healthcare systems implemented globally can affect MM care and patient burden</li>
 <li>Develop tailored solutions, not ‘one-size fits all’ programs that cannot cater to the specific needs of all MM patients</li>
 <li>Use direct and indirect cost data to implement region-specific benefit programs to help improve access to and reimbursement of innovative treatments</li>
 <li>Industry and governments must work together to develop frameworks that ensure available medications are efficient at reducing the economic burden on patients and society</li>
</ul>

True Cost of Multiple Myeloma

<h2>It May Be Time for a New Standard for Measuring Depth of Response in Multiple Myeloma</h2>
Deeper response assessments are needed to keep pace with therapeutic advancements1-3
Although the assessment of MRD is not universally employed in clinical practice, numerous studies have demonstrated the considerable strength of MRD- as a reliable predictor of long-term outcomes, including the potential to supersede the prognostic value of CR.&nbsp;
MRD negativity continues to be investigated as a surrogate endpoint for survival in clinical trials and evaluated as a tool in clinical practice for informing individualised treatment decisions1,2

<h2>The evaluation of MRD in clinical trials may help accelerate regulatory approvals—especially in NDMM2,3,7</h2>
Given that recent therapeutic advances have significantly extended survival in multiple myeloma, a new surrogate endpoint is needed that predicts clinical benefit and accelerates drug development and approvals.2,3,5
Ongoing and future clinical trials in NDMM using the traditional primary endpoint of PFS may require ≥ 5 years to collect mature data, potentially delaying access to increasingly efficacious treatments.3
While there is not yet consensus among regulatory agencies, there are ongoing efforts to gather the necessary evidence to more clearly elucidate the role of MRD in clinical trials, clinical practice, and new drug registration.8

<h3>In NDMM and RRMM&nbsp;at least&nbsp;35&nbsp;ongoing phase&nbsp;3&nbsp;clinical trials include MRD assessment as a primary or second endpoint8</h3>
‘MRD has been found to be a surrogate endpoint for PFS in patients receiving first-line treatment. Therefore, MRD may be used as an endpoint to accelerate drug development.’
MA Dimopolous et al, Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up,&nbsp;Ann Oncol, 2021

<h2>Achieving MRD- should be considered a goal in first-line therapy6</h2>
The development of increasingly sensitive techniques for assessing treatment response have begun to challenge the conventional therapeutic goals of achieving CR or even sCR alone, particularly&nbsp;in&nbsp;NDMM.4-6
Treating to the deepest molecular response with MRD- as the ultimate goal represents a strategy of maximising outcomes for as many patients as possible4,6

<h3>mPFS 7.2 years seen in patients with NDMM when treating to achieve MRD negativity6</h3>
<ul>
 <li>Results from a retrospective analysis of real-world outcomes from a single US academic center (2005-2018), with patients primarily receiving triplet regimens followed by ASCT and maintenance therapy6</li>
 <li>Patients with NDMM (N=159) treated to achieve the deepest response per IMWG criteria saw considerably longer mPFS (86.4 months) than prior reports in similar settings (≤50 months)6,9,10</li>
 <li>Of 159 patients with NDMM, 98% achieved CR prior to MRD assessment and 59% achieved MRD- at 10-5 6</li>
</ul>
Evaluating therapies by demonstrated rate of MRD negativity may be crucial for maximising outcomes early for as many patients as possible6

<h2>In the future, MRD- may be used to guide therapeutic decisions11,12</h2>
Although evaluation of MRD is not yet a widespread factor in routine clinical decision-making, due in part to limited access to testing and still unresolved questions about the best use of MRD status in clinical practice, there is evidence to support further investigation of its role in treatment decisions.11
In a retrospective analysis of PFS in patients with NDMM, a clinical decision to change therapy was made in 17% of patients based on their MRD status (MRD- or MRD+ at 10-5).12
Patients for whom a change in therapy was made based on MRD status had prolonged PFS compared to those for whom a change in therapy was not made.12
Retrospective analysis of 400 patients with NDMM12

Adapted from Martinez-Lopez J, et al. J Hematol Oncol. 2021.
As MRD negativity continues to be investigated as a surrogate endpoint for PFS in NDMM clinical trials, there is clear and mounting evidence that MRD negativity is emerging as one of the most important clinical tools in the treatment of MM1,2,4-6

The assessment of MRD negativity is needed in the clinical setting to improve prognosis, maximise outcomes, and inform treatment decision-making1,7

The Future of MRD

<h2>Renal Impairment’s Effect on MM Patients</h2>
Although renal impairment is a common complication in patients with multiple myeloma these patients are often excluded from or underrepresented in clinical trials because of1:
<ul>
 <li>Restrictive renal exclusion criteria</li>
 <li>Failure to collect data in renally impaired patients</li>
 <li>Difficulty in translating results to real-world practice.</li>
</ul>
50%&nbsp;of patients with multiple myeloma have&nbsp;renal impairment&nbsp;and it forms a core part of the&nbsp;CRAB criteria&nbsp;used to diagnose multiple myeloma2,3

<h2 style="text-align: center;">C</h2>
calcium 
 (hypercalcemia)

<h2 style="text-align: center;">R</h2>
Renal 
 impairment

<h2 style="text-align: center;">A</h2>
Anemia

<h2 style="text-align: center;">B</h2>
Bone 
 lesions

<h2>Underrepresentation Putting Patients at Risk4</h2>
<ul>
</ul>

<h2 style="text-align: center;">&lt;65</h2>
years

<h2 style="text-align: center;">65-75</h2>
years

<h2 style="text-align: center;">75+</h2>
years

How do you treat a patient population effectively that is underrepresented in clinical trials? While multiple myeloma is predominantly a disease of the elderly,5&nbsp;there is still a reluctance to include elderly cancer patients in clinical trials because of reduced performance, comorbidities, and organ dysfunction.6,7&nbsp;That leaves this difficult-to-treat population with a lack of robust treatment guidelines.4
50 percent of elderly patients will need 3 or more GP visits before diagnosis, and this contributes to a 6-month delay in an average diagnosis of MM.6

<h2>Patients &gt;65 years of age have worse survival rates than younger patients5</h2>

<h2>Characteristics commonly found in elderly patients make treatment difficult4,8-10</h2>
<ul>
 <li>Reduced fitness for treatment</li>
 <li>Decreased resilience to treatment-related toxicity</li>
 <li>Fraity</li>
 <li>Difficulty of Diagnosis&nbsp;</li>
 <li>Reduced treatment choices</li>
 <li>Underrepresentation in clinical trials</li>
</ul>

<h2>The Relationship between Multiple Myeloma and Cytogenetic Abnormalities</h2>
The presence of high-risk cytogenetic features has been well documented as a negative prognostic factor and these patients typically have poorer outcomes compared with standard risk patients.11,12
Patients with high-risk cytogenetics are not always captured in clinical trials or real-world studies, resulting in subgroup analyses on a relatively small sample size.1,13,14&nbsp;Because of this, it is important that these patients be encouraged to participate in randomized trials so more data can be collected.14

The presence of multiple cytogenetic abnormalities further decreases prognosis compared with individual high-risk abnormalities11,13,15

There remains a detrimental gap between high-risk and standard-risk cytogenetic patients14,16

With more than 130,000 new diagnoses of multiple myeloma a year globally, it's important to recognize the signs and symptomps of MM.

Patients Factors & Impacts

<h2>Why Early Detection of MM is Crucial</h2>
As incidence continues to increase, early detection may help provide patients more treatment options1.&nbsp;Despite current available treatments, multiple myeloma remains incurable and most patients will relapse and become refractory to these treatments2.&nbsp;In some patients, the cancer may respond to initial treatment, but not to treatment following a relapse2.
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>
 New agents are necessary so that patients and physicians can have options as the disease progresses and patients relapse and become refractory to treatments.</td>
 </tr>
 </tbody>
</table>

<h2>Multiple Myeloma Shows No Signs of Slowing Down</h2>
<ul>
 <li>For the EU as a whole, multiple myeloma incidence is projected to increase from approximately 35,000 new cases in 2015 to over 43,000 by 20303.</li>
 <li>Each year there are more than 130,000 new diagnoses of multiple myeloma worldwide4.</li>
 <li>In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year5.</li>
 <li>This disease is most frequently diagnosed in people aged 65-75 years6.</li>
 <li>Relapsed and refractory multiple myeloma (RRMM) is a complicated and heterogeneous disease, as it is continuously developing resistance to treatments7.</li>
</ul>
Almost all people with multiple myeloma will still relapse on or after treatments. Once these patients relapse, they become more difficult to treat2.&nbsp;There is a need for new agents so that patients and physicians can have options as the disease progresses.

<h2>Signs and Symptoms of Multiple Myeloma8</h2>
Often, multiple myeloma causes no symptoms until it reaches an advanced stage. Sometimes, it might cause vague symptoms that at first seem to be caused by other diseases1.
<ul>
 <li>Bone Pain&nbsp;that is persistent or recurrent, and fractures</li>
 <li>Persistent tiredness&nbsp;due to anemia or kidney failure</li>
 <li>Recurrent unexplained Infections,&nbsp;such as pneumonia</li>
 <li>Nervous system disorders</li>
 <li>Shortness of breath&nbsp;or evidence of heart or kidney failure</li>
</ul>

Bone Pain that is persistent or recurrent, and fractures

Persistent tiredness due to anemia or kidney failure

Recurrent unexplained Infections,&nbsp;such as pneumonia

Nervous system disorders

Shortness of breath or evidence of heart or kidney failure

Myeloma Facts

<h2>What is MRD?</h2>
MRD describes the low level of malignant cells that persist in the bone marrow after treatment but cannot be detected with conventional outcome measures and which eventually lead to relapse. A patient who is MRD negative has achieved clinical remission with the absence of aberrant clonal cells by NGF or NGS per at least 100,000 nucleated cells.1,2

<h2>How does MRD- compare to other clinical endpoints?</h2>
Studies have shown MRD- as an important measurement for depth of response, acting as a surrogate marker for longer PFS and OS. Studies have also demonstrated that the prognostic value of MRD- is superior to CR for PFS and OS across the disease spectrum, regardless of treatment or a patient's risk profile.1,3,4

<h2>Has MRD- been studied in clinical trials?</h2>
MRD- has been studied in clinical trials evaluating response rates in NDMM and RRMM. MRD- has been associated with significantly improved PFS.3

<h2>Many of my patients with multiple myeloma are high risk. Can they achieve MRD- as well?</h2>
Studies have demonstrated that patients with high-risk cytogenetics can achieve MRD- and that this depth of response is associated with improved rates of OS and PFS, similar to standard-risk populations.1,5
Data support that MRD- can be used to inform treatment decisions regardless of a patient’s risk profile or disease stage.4

<h2>Should I consider MRD when making treatment decisions?</h2>
As ongoing clinical trials consider MRD- as an exclusive or additional primary endpoint, MRD- may eventually be used to guide treatment decisions.1,6
Even among patients who have achieved a CR, assessing MRD and finding a treatment that can help more patients achieve MRD- is increasingly important.4,8

MRD FAQs

See why MRD negativity may be the most powerful indicator of long-term outcomes1-6

Importance of MRD

Is MRD negativity the new standard for measuring depth of response?1,2,7

The Future of MRD

What is MRD? 
 Discover the importance of MRD

About MRD

Minimal Residual Disease 
 Frequently Asked Questions

MRD FAQs

Minimal Residual Disease 
 Achieving deeper responses

MRD

Minimal Residual Disease

<h2>The Deepest Level of Treatment Response in Multiple Myeloma</h2>
<h3>Deeper treatment responses drive improved outcomes1-3</h3>
MRD describes the low level of malignant cells that persist in the bone marrow after treatment but cannot be detected with conventional outcome measures and which eventually lead to relapse. A patient who is MRD negative has achieved clinical remission with the absence of aberrant clonal cells by NGF or NGS per at least 100,000 nucleated cells.3,4

Numerous studies suggest that MRD negativity may surpass CR as a prognostic marker for PFS and OS. Results demonstrating the prognostic superiority of MRD negativity have been seen across treatment regimens and regardless of patient characteristics, including cytogenetic risk, in NDMM and RRMM.1,5

<h2>MRD- is associated with improved rates of survival in NDMM and RRMM1</h2>
In a large meta-analysis evaluating patients with NDMM and RRMM, patients achieving MRD- experienced significantly longer OS and PFS vs MRD+ patients1
<h3>OS by MRD status in NDMM</h3>
<h4>Transplant-eligible NDMM: MRD- is associated with prolonged OS vs MRD+</h4>

Adapted from Munshi NC et al.&nbsp;Blood Adv. 2020.
Five-year OS rates were 70.9% for MRD- patients vs 50.5% for MRD+ patients.
The same trend toward improved survival was observed among patients with transplant-ineligible NDMM (N=1268) where MRD- was also associated with significantly improved OS vs MRD+ (HR=0.40; 95% CI: 0.31, 0.51;&nbsp;P&lt;0.001). In the meta-analysis, a pooled Kaplan-Meier curve for OS by MRD status was not generated because it was only reported in 1 study.

<h3>PFS by MRD status in NDMM</h3>
<h4>Transplant-eligible NDMM: MRD- is associated with prolonged PFS vs MRD+</h4>

Adapted from Munshi NC et al.&nbsp;Blood Adv. 2020.
Five-year PFS rates were 51% for MRD- patients vs 24% for MRD+ patients.
The same trend toward improved PFS was observed among patients with transplant-ineligible NDMM (N=2350) who achieved MRD- vs patients who were MRD+ (HR=0.32; 95% CI: 0.27, 0.39;&nbsp;P&lt;0.001).
<h3>OS by MRD status in RRMM</h3>
<h4>RRMM: MRD- is associated with prolonged OS vs MRD+</h4>

Adapted from Munshi NC et al.&nbsp;Blood Adv. 2020.
Three-year OS rates were 86.4% for MRD- patients vs 58.1% for MRD+ patients.
<h3>PFS by MRD status in RRMM</h3>
<h4>RRMM: MRD- is associated with prolonged PFS vs MRD+</h4>

Adapted from Munshi NC et al.&nbsp;Blood Adv. 2020.
Three-year PFS rates were 71.8% for MRD- patients vs 23.4% for MRD+ patients.

<h2>MRD- may surpass CR as the most powerful indicator of long-term outcomes1,5,6</h2>
With treatment advances in MM leading to an increasing proportion of patients achieving CR, particularly in first-line therapy, the development of MRD testing has given investigators a tool to detect even deeper treatment responses for a more accurate prognostic assessment.1,2
As superior outcomes have been observed in patients achieving MRD- compared to patients achieving CR with persistent residual disease, MRD- may supersede the prognostic value of CR.1,5,6

A pooled analysis of patients with NDMM who achieved CR but remained MRD+ showed a greater risk of relapse and disease progression vs patients who achieved CR and MRD-5
<ul>
 <li>Patients in CR with persistent MRD (MRD+)&nbsp; = 27 months</li>
 <li>Patients in CR with undetectable MRD (MRD-) = 63 months</li>
</ul>
Compared to achieving CR alone, achieving MRD negativity can significantly prolong disease control and delay relapse1,5,6

<h2>Achieving MRD- can overcome the poor prognosis of high-risk cytogenetics7</h2>
Although patients with both standard and high-risk cytogenetics achieve similar CR rates, the latter typically experience significantly earlier relapse.
However, a recent study of patients with transplant-eligible NDMM showed that treatment leading to MRD- overcame the poor prognosis conferred by high-risk cytogenetics, with 3-year PFS rates &gt;90% for patients achieving MRD-, regardless of cytogenetic risk status.
Rate of PFS at 36 months by cytogenetic risk and MRD status7

Patients with high-risk cytogenetics who achieve MRD negativity may have outcomes that are comparable to standard risk patients, depending on MRD status7

Looking to treatments that achieve high rates of MRD negativity for patients is increasingly important to ensure better outcomes4,8

Importance of MRD

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