Relapsed and Refractory Multiple Myeloma

Arooj Ahmed; Robert Killeen

Relapsed and Refractory Multiple Myeloma

Author: Arooj Ahmed Editor: Robert B. Killeen Updated: 6/8/2023 9:29:25 PM

Introduction

Multiple myeloma (MM) is a malignant disorder of B cells that involves the proliferation of abnormal monoclonal plasma cells in the bone marrow and/or extramedullary sites; it is the second most common hematological malignancy associated with significant morbidity and mortality by causing end-organ damage. Over the last few decades, MM survival rates have been prolonged due to recent advancements by the advent of novel therapies. Targeted agents and combination therapies have resulted in better outcomes, but most MM patients eventually relapse, including those who achieved remission.

Patients who fail to achieve at least minimal response on initial therapy and progress while on treatment are termed "primary refractory." According to the criteria developed by the International Myeloma Working Group (IMWG), relapsed refractory MM (RRMM) is defined as a progressive disease, poor response despite treatment, progression within 60 days of the most recent treatment in a patient who had achieved remission, the absence of at least minimal response (MR), or primary refractory MM.[1][2]

IMWG defines progressive disease as at least a 25% increase in serum or urine paraprotein from nadir, or elevations in the monoclonal protein of free light chains (FLC) or the appearance of any of the CRAB feature even in the absence of biochemical progression.[3][4]

MM is considered "double refractory" if the disease has progressed during or after treatment with a protease inhibitor and an immunomodulatory agent. If the patient is also resistant to the addition of monoclonal antibodies, it is considered a "triple-class" refractory disease, which confers a poor prognosis.[5]

During the treatment course, most MM patients will have several cycles of remissions and relapse, necessitating multiple lines of combination therapies. Various patient, disease, and treatment-related factors have created many challenges in devising the most effective anti-myeloma strategies for RRMM patients.

Etiology

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Etiology

All patients with multiple myeloma will eventually relapse or become resistant to treatment at some point in their lives. The etiology of RRMM is not well understood. Identifying risk factors enables clinicians to implement targeted intervention strategies and preventive measures, reducing the disease burden and minimizing the risk of relapse.

Multiple risk factors have been identified as contributing to relapse or resistance to therapy, including short duration of previous remission, aggressive progression or relapse, high-risk genetic mutations, inadequate response to previous therapies, plasma cell leukemia, and dysregulation in the immune system.[6][7]

Almost 20% of the patients have an aggressive relapse with high-risk cytogenetics like del17p, add 1q/del1p, t(4;14), t(14;16). Involvement of any 2 high-risk abnormalities is considered a "double-hit myeloma," whereas having 3 or more high-risk abnormalities is deemed a "triple-hit myeloma." On the other hand, patients having trisomies, t(11;14) or t(6;14), are considered to have standard risk myeloma.[8]

Poor performance status and toxicities due to combination therapies may indirectly delay or interrupt treatments, resulting in early relapse.

Epidemiology

Multiple myeloma constitutes 1.8% of all new cancer cases and 2.1% of all cancer deaths yearly in the United States, with an incidence of 4.5 to 6 per 100,000 annually. The median age of diagnosis is 70 years.[9][10] The incidence of MM has increased by 126% globally and by over 40% in the US since 1990 and is highly variable among different countries. The highest age-standardized incidence rate of MM was observed in Australia, Western Europe, and North America.[11]

Conversely, mortality has decreased by 14% in the US but increased by 94% globally. With the advent of new advanced therapies, the 5-year survival rate in the US has more than doubled in the past few decades.

According to an analysis carried out at an institution in 2016, the outcomes for 511 multiple myeloma patients treated with novel therapies between 2006 and 2014 showed a total of 82 patients (16%) developed early relapse within 8 months of initiation of the treatment vs 429 patients ( 84%) who either relapsed after a year or had a continued response to therapy for the duration of the study. The median overall survival rate was worse in these patients than in those with late relapse. Median overall survival in patients who received autologous stem cell transplantation and relapsed within 12 months was 23.1 months, compared to 122.2 months in the remaining patients indicating early relapse as a poor prognostic factor.[12]

With each subsequent line of therapy and the successive relapse, the response rate decreases along with a shorter time interval to progression. The proportion of patients achieving complete response decreased from 32% at the first-line to 2% at the fifth-line treatment.[13]

Pathophysiology

In relapsed or refractory MM patients, the clonal evolution of MM cells and changes in the bone marrow microenvironment are major contributing factors in drug resistance.[14] Pathophysiology leading to resistance involves 2 main mechanisms: (1) induction of JAK/STAT and PI3K/AKT signaling by IL-6 resulting in upregulation of antiapoptotic proteins and (2) MM cells binding to fibronectin causing KIP1 and G1 growth arrest leading to cell-mediated drug resistance.

In some cases, the balance between pro-angiogenic and anti-angiogenic genes is disrupted, causing abnormal expression of pro-angiogenic and suppressing anti-angiogenic genes. Upregulation of angiogenesis-promoting factor epidermal growth factors like protein-7 (EGFL7) mediates MM cell proliferation and drug resistance.[15]

Cancer cells develop compensatory protein clearance mechanisms like autophagosomes and aggresomes, resulting in resistance to protease inhibitors, ultimately leading to therapeutic failure and disease relapse.[16]

Another possible mechanism of drug resistance is the clonal evolution of multiple myeloma cells. For example, increased expression of the PSMD4 gene is thought to be associated with bortezomib resistance. Patients with chromosomal abnormalities involving del(13) and t(4;14), who relapsed or developed the refractory disease and received lenalidomide and dexamethasone, had lower response rates with shorter median progression-free survival.[14]

History and Physical

Relapsed or refractory MM patients on treatment are monitored closely; the relapsed disease is usually diagnosed with an increase in the M-protein or free light chains only, called biochemical progression. During follow-up visits and even after achieving complete remission, patients may present with a wide range of symptoms, varying from general fatigue to more complex manifestations such as widespread metastasis, requiring careful assessment and management by clinicians. Thorough history taking, regular physical examinations, and targeted testing specific to multiple myeloma are crucial in facilitating early diagnosis and effective treatment planning for patients. The most commonly reported symptoms include bone pain, fatigue, and shortness of breath.[17]

In the early stages, patients with multiple myeloma may appear physically healthy, while those with advanced disease may present as visibly ill. Patients can have severe pancytopenia, bone fractures even from minor trauma, hypercalcemia, and frequent infections due to the compromised immune system.

Clinicians face challenges in managing the effects of relapsed and treatment-resistant diseases on patients' physical and mental health, emphasizing the need for continuity of care and regular follow-up visits with the myeloma care team. This approach helps identify and address relapse or resistance to the ongoing drug regimen for multiple myeloma patients, promoting a holistic approach to their care.

Evaluation

Certain features indicate relapse or resistance to MM treatment in a patient who has been in remission. Clinical relapse with new or worse CRAB features requires immediate treatment or modification in the treatment plan. In 2016, the International Myeloma Work Group (IMWG) released an updated version of the perimeters to monitor the treatment response in MM patients.[18]

Biochemical relapse with or without symptoms also warrants treatment. Therefore, diligent monitoring is essential to mitigate the progression of the disease. In patients achieving minimal residual disease status or complete response, information from whole-body imaging for identifying focal infiltration has proven beneficial for monitoring disease relapse. Whole-body diffusion-weighted MRI is preferred over PET/CT, but both imaging modalities are commonly used.[19]

A comparison of the follow-up imaging with initial whole-body scans should be used to identify the progression of bony lesions. Sometimes the new fractures may be due to the earlier disease course rather than the disease progression. Minimal residual disease (MRD) assessment is recommended regularly as studies have shown improved response and overall survival in patients with MRD-negative status.[20]

MRD assessment in the bone marrow involves multiparametric flow cytometry (MFC) and molecular methods like next-generation sequencing. Extra-medullary disease evaluation for the minimal residual disease is performed by fluorodeoxyglucose positron emission tomography (FDG-PET). However, the role of MRD status in treatment decision-making is still investigational, and MRD positivity might not mean a change in the treatment outside a clinical trial at this point.

International Myeloma Work Group recommends initiation/modification of treatment if the following perimeters are met:[4]

Clinical Relapse

Hypercalcemia (serum calcium ≥11.5mg/dL)
Decrease in hemoglobin of ≥2g/dL
Rise in serum creatinine by ≥2 mg/dL due to myeloma
Hyperviscosity requiring therapeutic intervention (deep venous thrombosis, pulmonary embolism)
Definite increase ≥50% in the size of existing plasmacytoma or bone lesions
Development of new soft-tissue plasmacytomas or bone lesions

Biochemical Relapse in Patients Without Clinical Relapse

Doubling of M-component in 2 consecutive measurements separated by 2 months with the reference value of 5g/L, or
In 2 consecutive measurements, any of the following increases:
- The absolute levels of serum M protein by ≥10g/L, or
- An increase of urine M protein by ≥500 mg/24 h, or
- An increase of involved serum-free light chain by ≥20 mg/dL or 25% increase (whichever is greater)

Treatment / Management

Most patients with MM will respond well to the first line of therapy, but most will relapse as conventional treatment is not curative. A small percentage of patients will have a primary refractory disease to the first line of treatment. Therapies can be repeated in RRMM depending on prior efficacy and length of remission on the initial response. Clinicians must consider the possibility of cross-resistance among drugs from the same therapeutic group.[21]

Devising a treatment plan for each RRMM patient is a highly individualized task using different combinations and dosages that may be needed to determine the most effective. While choosing treatment options, resistance to a specific class of the drug, the patient's age and other comorbidities, and prior or residual toxicities should be considered to achieve a good response to therapy. During the present COVID era, vaccinations and boosters should be kept updated.[22] This is especially true as the antibody response to the vaccine is adversely affected by the myeloma treatment.[23]

Besides infections, such treatment that might expose the patient to thrombosis (eg, thalidomide) can have this threat compounded by COVID.[24]

Indications to Initiate Therapy

Recognizing the relapse or progression of multiple myeloma is crucial for initiating or modifying treatment approaches to reduce patient morbidity and mortality. On evaluation, if the criteria mentioned above for clinical or biochemical relapse are not met, close monitoring of IMWG-recommended perimeters at least every 2 to 3 months is recommended.

If clinical relapse features are absent, checking the biochemical markers of disease progression is imperative. Patients with evidence of biochemical relapse of progression should be started on treatment or have a change in the drug regimen.

In case of clinical relapse, particularly with high-risk cytogenetic abnormalities, high plasma cell proliferation index, elevated lactate dehydrogenase, and elevated M-protein, treatment should be initiated or modified immediately, considering RRMM to be an aggressive disease at that point.[22][25]

Selection of Regimen

Treatment is tailored by considering various aspects, including:

Patient-related factors: Age, frailty, compliance, transplant eligibility and history, comorbidities, and response to previously used therapies.
Disease-related factors: Stage according to R-ISS, presence of refractory disease, bone involvement, the aggressiveness of current relapse, Revised-Myeloma Comorbidity Index (R-MCI).
Treatment-related factors: Single/dual/triple/quadruple combination, availability, cost, bone marrow reserve, immunodeficiency/risk of infections, and thromboembolic events.

Frail patients are usually treated with monotherapy or dual therapy due to higher R-MCI scores with an increased risk of treatment-related morbidity and mortality. However, triple or quadruple therapy can be considered for fit or intermediate-fit patients.

Treatment Options

Various anti-myeloma drugs and their combinations are used to select treatment plans for RRMM patients. These include autologous stem cell transplantation, protease inhibitors (PIs), immunomodulatory drugs (IMiDs), targeted agents like monoclonal antibodies (mAbs), antibody-drug conjugates, chimeric antigen receptor T-cells (CAR-T-cells), biphasic T-cell engagers (BiTEs), selinexor, venetoclax, and many others.

First Relapse

Relapsed MM treatment is usually based on the response to lenalidomide. If the patient progresses within 60 days of standard lenalidomide therapy, it is considered lenalidomide refractory disease. Otherwise, patients are considered lenalidomide sensitive if the relapse or progression is noted after more than 60 days of lenalidomide treatment or if patients are on maintenance lenalidomide only.

Triplet regimens are the current standard of care in relapsed or refractory settings. Lenalidomide and dexamethasone serve as the backbone in commonly used triplet regimens (KRD, DRd, IRD, Elo-Rd). Four-drug regimens like DARA-KPD (Daratumumab, carfilzomib, pomalidomide, and dexamethasone) are usually used in patients with aggressive disease and progression on bortezomib, lenalidomide, and dexamethasone. Triple or quadruple drug regimens are observed to be superior over the dual combination of thalidomide-dexamethasone in patients who relapsed or developed the refractory disease after auto-HCT.[26][27](A1)

Despite its drawbacks in terms of curative potential, autologous stem cell transplant (auto-SCT) is still favored for the safe short-term management of RRMM. For patients eligible for autologous hematopoietic cell transplantation (auto-HCT) who did not undergo auto-HCT as part of their initial treatment, high-dose chemotherapy followed by auto-HCT at the time of first relapse has been recommended. Retrospective studies have shown improved progression-free survival following a second auto-HCT in MM patients who relapsed after the previous auto-HCT.[28]

For relapsed myeloma, consecutive HLA-identical sibling donor transplantation carries a significant overall survival (OS) of 35% at 5 years.[29] For those patients who experienced graft failure, the OS (of retransplant) was 41% at 2 years. Survival with auto-SCT was deemed better than could be obtained with a salvage allo-SCT.[30] "Safety," as such, was a key issue as the relapse mortality for auto-SCT was 5%, contrasted with the 45% for an allo-SCT. Allo-SCT, it seems, is less safe.

Allogenic stem cell transplantation (allo-SCT) has been used as a curative treatment option for MM patients, but its use is limited due to high treatment-related mortality. The 3 main problems when using allo-HCT are graft failure, great versus myeloma effect, and infections. A graft failure occurs with the primary (initial) or secondary (delayed) failure to engraft.[31] This may be due to various factors, including poor infusate (low CD34 cells), viral infections such as CMV, or antibody-mediated mechanisms. Early identification with transplantation presents the best countermeasure.[32] Chronic graft-versus-myeloma disease (GVMD) is favored (over acute GVMD) regarding its protective effect.[33] (B2)

Chronic GVHD (post-day 100 of transplantation) is evidenced by autoimmune-like sequelae included with such findings as lichen planus, fasciitis, myositis, xerostomia, jaundice, sicca, anorexia, and vaginal sclerosis/ulcerations.[34][35] Non-myeloablative conditioning regimens can induce GVHD but at the cost of a higher relapse rate.[36][37][21] Allo-HCT is fraught with infectious problems. The list of pathogens includes Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Aspergillus and Candida species, Pneumocystis jirovecii, herpes simplex, CMV, EBV, and zoster.[36][38][39]

The presence of graft-versus-host disease and non-relapse-related mortality have raised concerns regarding this treatment option.[36] Considering all these factors, allo-SCT has little support in treating RRMM outside of a clinical study and, even then, for the utmost fit, young patients (with the threat of high-risk cytogenetics). Unfortunately, myeloma is a disease in older patients.[40] Auto-HCT has been observed to be more effective than allo-SCT due to a better safety profile and higher overall survival (OS) rates.[30] Many sources do not consider all-SCT a standard of care.[40]

Daratumumab (anti-CD38), lenalidomide, and dexamethasone (DRd) is the preferred treatment combination to treat lenalidomide-sensitive multiple myeloma. Usually, the recommendation is to use the subcutaneous form of daratumumab in a real-life setting, as it has comparable efficacy to the intravenous formulation and fewer infusion-related reactions. POLLUX trial showed higher overall response rates and superior PFS with DRD vs Rd.[41][42] No difference in overall survival. Compared to Rd, DRd resulted in higher rates of neutropenia (59% vs 43%), diarrhea (43% vs 25%), and upper respiratory tract infection (32% vs 21%).

Carfilzomib, lenalidomide, and dexamethasone (KRd) is another preferred regimen in lenalidomide-sensitive multiple myeloma. The ASPIRE trial showed improved OOR, PFS, and superior overall survival with KRd vs Rd. KRd showed higher rates of respiratory infections, hypokalemia, and muscle spasms when compared to Rd. There is a higher incidence of cardiac toxicity, so an echocardiogram and electrocardiogram (EKG) are performed before starting treatment to assess baseline cardiac function.

Ixazomib, lenalidomide, and dexamethasone (IRd) showed better PFS and duration of response in tourmaline-MM1 compared to Rd alone. The benefit was observed in both high-risk and standard-risk groups. Longer follow-up of a median of 85 months showed similar OS in both groups. The IRd group had a higher rate of grade 3 or 4 thrombocytopenia. Other notable adverse effects in the IRd group were diarrhea, constipation, nausea, vomiting, peripheral neuropathy, peripheral edema, and rash.[43]

Elotuzumab and lenalidomide/dexamethasone (ERd) are primarily used in less aggressive diseases. ELOQUENT-2 trial showed ERd improves PFS and OS, compared to Rd alone. Patients receiving elotuzumab were pretreated with diphenhydramine, ranitidine, acetaminophen, or their equivalents. ERd showed an increased incidence of opportunistic infection, including fungal and herpes zoster infections. ERd also had a higher rate of invasive second primary malignancies (9% vs 6%).

For patients with lenalidomide-refractory MM, future regimens are influenced by whether the disease is refractory to bortezomib and/or daratumumab. The disease, which is refractory to both lenalidomide and bortezomib, can respond to a different proteasome inhibitor like carfilzomib or a different immunomodulator like pomalidomide in combination with dexamethasone and daratumumab. For patients with lenalidomide-refractory MM, treatment options include daratumumab, bortezomib, and dexamethasone (DVd); daratumumab, pomalidomide, and dexamethasone (DPd); bortezomib, pomalidomide and dexamethasone (VPd); or isatuximab, pomalidomide, and dexamethasone (IsaPd).

For patients with MM refractory to both lenalidomide and daratumumab, treatment options include carfilzomib, pomalidomide, and dexamethasone (KPd); bortezomib, pomalidomide, and dexamethasone (VPd); bortezomib, cyclophosphamide, and dexamethasone (VCd or CyBorD) as studied in the EVOLUTION Trial; or selinexor, bortezomib, and dexamethasone (SVd) as studied in the BOSTON Trial.[44][45] Patients on selinexor should get antiemetic prophylaxis and monitor for thrombocytopenia, neutropenia, and hyponatremia.(A1)

The Castor Trial showed improved PFS with DVd compared to Vd alone (16.7 months vs 7.1 months). LEPUS trial showed similar PFS benefits in Chinese patients. Higher rates of thrombocytopenia, lymphopenia, neutropenia, and peripheral sensory neuropathy were noted.[46] OPTIMISM trial showed improved PFS (11 months vs 7 months) with VPd vs Vd. Higher rates of febrile neutropenia and thromboembolic events were noted with VPd.(B2)

The CANDOR trial showed a 37% reduction in the risk of progression or death in a population with DKd (daratumumab, carfilzomib, and dexamethasone) compared to Kd alone.[47] Efficacy is noted to be similar between twice weekly and weekly dosages according to CANDOR and EQUULEUS trial. APOLLO trial showed 12 month PFS benefit of 52% vs 35% between Daratumumab, pomalidomide, and dexamethasone (DPd) vs pomalidomide and dexamethasone (Pd), respectively.[48](B2)

Second Relapse or Subsequent Relapse

Any drug class considered for the first relapse the patient did not receive can be tried in the second or subsequent relapse.[27]

Disease refractory to lenalidomide and bortezomib: In these cases, some therapeutic options are Dara + pomalidomide + dexamethasone, Dara + carfilzomib + dexamethasone, elotuzumab + pomalidomide + dexamethasone.

In cases where multiple myeloma is refractory to both lenalidomide and bortezomib, therapeutic options include combinations such as daratumumab, pomalidomide, and dexamethasone; daratumumab, carfilzomib, and dexamethasone; and elotuzumab, pomalidomide, and dexamethasone. These treatment regimens offer alternative strategies to manage the disease in patients who have not responded adequately to lenalidomide and bortezomib.

In cases of triple-class refractory disease, where patients have failed multiple lines of treatment, including PIs, IMiDs, and mAbs against CD38, recently approved therapies are selinexor and dexamethasone; VdT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide); melflufen-dexamethasone and CAR-T-cells, idecabtagene, and belantamab mafoditin. The HORIZON study has shown that melflufen plus dexamethasone demonstrates a modicum of activity in relapsed and refractory myeloma, especially in triple-class refractory disease.[49]

Novel immunotherapies like CAR-T-cell and bispecific T-cell engagers (BiTE) have revolutionized the treatment of RRMM. Multiple studies have shown the efficacy of CAR-T-cell therapy as a potential treatment for long-term disease control with a higher response rate in patients with high-risk cytogenetics, progressive disease, or extra-medullary disease at baseline.[50]

Response rates of approximately 67% to 83% have been observed with CAR-T-cell therapies in patients refractory to previous treatments.[51] Bispecific antibodies tend to bind 2 antigens simultaneously by binding the molecule on an immune cell and the target on the tumor cell, initiating tumor lysis.

In 2022, the FDA approved teclistamab, the first bispecific T-cell engager antibody against CD38 expressed on the myeloma cells, for patients with relapsed or refractory multiple myeloma who have failed 4 prior lines of therapy. Belantamab mafodotin is anti-BCMA humanized immunoglobulin G (IgG) antibody conjugated with monomethyl auristatin. The drug received accelerated approval in the US for patients who had progressed on at least 4 lines of therapy. It is being withdrawn from the market based on the results of randomized phase 3 trials (DREAMM-3), as it did not show clinical benefit compared to pomalidomide and dexamethasone.

The penta-refractory disease is resistant or refractory to Anti-CD38 monoclonal antibodies, bortezomib, lenalidomide, pomalidomide, and carfilzomib. This is mainly encountered in the third- or fourth-line setting. If any of these agents have not been used before, it is reasonable to use that agent at any time. Patients with the penta-refractory disease have options of BMCA-targeted therapy (Ida-Cel, Cilta-Cel, or teclistamab); alkylator-based combination (VDT-PACE, DCEP, bendamustine); or combination regimens incorporating selinexor, venetoclax (only in cases with t(11;14) or panobinostat). Clinical trials or investigational agents are also encouraged.

Differential Diagnosis

Signs and symptoms of MM can mimic those of many other diseases; therefore, a vast array of tests, including invasive and noninvasive tests, are required to reach the diagnosis and determine the stage. The following conditions should be considered during the initial presentation and work-up of the patients with specific features that differentiate them from multiple myeloma.[52][53]

Monoclonal Gammopathies of Undetermined Significance (MGUS)

Monoclonal protein spike <3 g/dL
Clonal plasma cells <10% of the bone marrow

Lack of CRAB features

Smoldering Multiple Myeloma

Monoclonal protein spike >3 g/dL
Clonal plasma cells >10% of the bone marrow
Lack of CRAB features

Waldernstrom Macroglobulinemia

Presence of IgM monoclonal protein in the serum
Lymphoplasmacytic lymphoma with lymphoid cells in the bone marrow
End-organ damage (peripheral neuropathy, lymphadenopathy, hepatosplenomegaly, hyperviscosity syndrome)
Most common genetic abnormality: MYD88 L265P

Solitary Or Isolated Plasmacytoma

Localized mass of monoclonal plasma cells in the bone or extramedullary site vs diffuse infiltration in multiple myeloma
Absence of CRAB features.
Bone marrow biopsy results: normal if performed outside of the lesion

AL Amyloidosis

Plasm cell clones in bone marrow: secrete unstable monoclonal kappa and lambda light chains forming amyloid fibrils
Monoclonal immunoglobulin deposition in various organs of the body like the heart, kidneys, and gastrointestinal tract)
Less than 20% plasma cell infiltration of bone marrow
Lack of lytic lesions
Apple green birefringence on congo red staining of the affected tissue

Surgical Oncology

MM causes osteolytic lesions with born resorption leading to pathological fractures and bone pain. Bone lesions causing neurological complications or impending fractures require surgical intervention to improve the quality of life of MM patients and reduce morbidity and mortality due to skeletal complications.[54]

Radiation Oncology

Adjuvant radiation therapy of bone lesions is used as a palliative measure. The goal of radiation therapy is to damage the DNA of the cancer cells and halt their multiplication by causing double-strand breaks. Free radical generation destroys the neoplastic cells by apoptosis. Indications for radiation therapy are the treatment of post-fracture pain, intramedullary disease, or signal cord compression by large osteolytic lesions.

In a retrospective analysis, it was observed that one-third of the patients required radiation therapy during the course of their disease, mainly for neurological complications, pain control, prevention, or treatment of fractures. Radiation therapy improved pain in more than 80% of the patients.[55]

Pertinent Studies and Ongoing Trials

Thus far, MM remains an incurable disease, with a significant number of patients relapsing due to evolving genetic mutations in tumor cells resulting in treatment resistance. Therefore, continuous efforts in understanding the pathophysiology of MM can lead to a remarkable breakthrough in preventing relapse and managing multiple refractory myeloma.[2] Latest trends and emerging cutting-edge therapies are being investigated in clinical trials to develop more effective therapeutic options for RRMM.

Bispecific antibodies (bsAbs) have shown promising results in early clinical trials. A bispecific T-cell engager (BiTE) enhances the interaction of T-cells and MM cells by targeting BCMA on MM cells and CD3 receptors on the T-cells causing tumor lysis.[56]

Rpn13 has high expression in MM cells and is involved in the regulation, proliferation, and survival of MM cells; therefore, inhibitors that target Rpn13 may play a significant role in treating MM and increasing survival.[57]

Bromodomain and extra-terminal (BET) proteins employ tandem bromodomains on acetylated histones, which leads to enhanced transcriptional activity in refractory hematological malignancies, including MM. Preclinical studies have shown the anti-tumor effects of highly specific BET protein inhibitors making MM cells more vulnerable to degranulation by NK cells opening a new perspective on treating RRMM.[58][57]

The use of NK-cell-based immunotherapy and combinations of CAR-NK cell therapy with other drugs are still being studied in many trials.

The current use of carfilzomib, bortezomib, and ixazomib by targeting the ubiquitin-proteosome pathway has proven an effective treatment strategy in MM patients; however, patients can develop relapse due to drug resistance. Newer agents like proteolysis targeting chimera (PROTAC) are being studied in the latest clinical trials as molecules that target the disease-related protein to induce its proteasomal degradation.

Toxicity and Adverse Effect Management

Although newer anti-MM agents have significant benefits in treating RRMM, they are not free of adverse effects. Every drug has its unique adverse effect profile and needs to be considered while treating the patient for prompt identification and management. Sometimes the adverse effects are so severe that treatment must be changed or temporarily discontinued.[59] Some of the toxicities of medications being used are as follows:

Neurotoxicity: CAR-T cell therapy
Ocular toxicity: belantamab mafodotin
Cardiotoxicity: carfilzomib, doxorubicin
Gastrointestinal toxicity: selinexor, lenalidomide
Nephrotoxicity: lenalidomide, zoledronic acid
Immune impression: Auto-HCT, CAR-T cell therapy, dexamethasone
Myelosuppression: daratumumab, carfilzomib, selinexor, CAR-T cell therapy
Peripheral neuropathy: thalidomide, protease inhibitors

During the course of treatment, patients are closely monitored for adverse effects and treated accordingly.

In addition to anti-myeloma drugs, supportive care plays a significant role in symptomatic relief for RRMM patients. Besides radiotherapy and surgery, bisphosphonates and denosumab are used to manage bone disease.[60]

MM patients are at a much higher risk of infections than the general population due to impaired immune systems. Therefore, vaccinations are recommended along with prophylactic medications to prevent herpes zoster, pneumocystis, and other infections.[61]

Staging

In 1975, the Durie-Salmon Staging System was developed to determine the stage of MM; it demonstrated the correlation between the amount of myeloma and the damage it causes, such as anemia and bone disease.[53][62]

Durie-Salmon Staging

Stage I: All of the following must be present (hemoglobin >10g/dL, serum calcium ≤12mg/dL, absence of bone disease or solitary plasmacytoma, serum paraprotein <5g/dL if IgG or <3g/dL if IgA, urinary light chain excretion <4g/24h)

Stage II: Not fulfilling criteria of Durie-Salmon stage I or III

Stage III: Any of the following may be present (hemoglobin <8.5g/dL, serum calcium >12 mg/dL, skeletal survey with >2 lytic lesions, serum paraprotein >7g/dL if IgG, >5g/dL if IgA, urinary light chain excretion >2g/24h)

In 2005, the International Myeloma Work Group (IMWG) introduced the International Staging System (ISS) that uses serum albumin and beta-2 microglobulin for staging the disease.

International Staging System

Stage I:

Serum beta-2 microglobulin <3.5 mg/L
Serum albumin ≥3.5g/dL

Stage II:

Serum beta-2 microglobulin <3.5 mg/L
Serum albumin <3.5g/dL

Or serum beta-2 microglobulin 3.5 to 5.5 mg/L irrespective of serum albumin

Stage III: serum beta-2 microglobulin >5.5 mg/L

In 2015, IMWG incorporated genetic risk assessed by fluorescence in-situ hybridization(FISH) and lactate dehydrogenase (LDH) called Revised-ISS (R-ISS):

Revised-International Staging System

Stage I:

Serum beta-2 microglobulin <3.5 mg/L
Serum albumin ≥3.5 g/dL
Standard-risk chromosomal abnormalities by FISH
Normal LDH

Stage II: Not R-ISS stage I or III

Stage III: Serum beta 2-microglobulin ≥5.5 mg/L and either high-risk chromosomal abnormalities by FISH OR high LDH.

Prognosis

Despite the remarkable progress in treatment strategies for multiple myeloma, relapse and resistance to treatment remain significant challenges, often leading to a poor prognosis. Hence, patient-specific and disease-specific factors are extremely important in the risk stratification of MM patients to determine the prognosis and guide the best treatment strategy.[10]

Factors determining MM patients' survival duration include tumor burden(stage), host factors, cytogenetic abnormalities, and response to treatment.[63][64] The RISS helps determine the prognosis of MM patients by combining elements of tumor burden, beta-2-microglobulin, serum lactate dehydrogenase, serum albumin, and risk assessment of cytogenetic abnormalities.

Factors Associated With Poor Prognosis

Cytogenetic abnormalities: More than one cytogenetic abnormality, IgH translocations t(4:14), t(14:16), t(14:20), and genomic imbalances like deletion in 17p or gain in 1q.[65]
Tumor burden: R-ISS stage II/III, renal insufficiency, elevated LDH, presence of extramedullary disease, plasma cell leukemia, high serum beta-2-microglobulin.
Response to treatment: Resistance or failure to first-line therapy, relapse occurring within 1 year of autologous stem cell transplantation or primary therapy.
Previous lines of therapies.

The median survival rate in relapsed MM patients improved from 12 months before 2000 to 24 months after the year 2000 with the availability of modern therapies like protease inhibitors, immunomodulatory drugs, and auto-HCT.[66]

Complications

Advanced multiple myeloma or relapsed disease can lead to complications such as renal impairment, compromised immune function, anemia, and skeletal manifestations, including bone pain and pathological fractures. Due to prolonged drug exposure with multi-drug regimens, the number of complexities can increase exponentially.

Postoperative and Rehabilitation Care

Establishing functionally based goals and recognizing the need for skilled therapy services are critical for patients with advanced multiple myeloma. Patients with relapsed and refractory MM may benefit from self-management workshops and group sessions to help them cope with adverse effects on their physical and psychological well-being.

Consultations

A multidisciplinary approach brings multiple healthcare teams together to manage MM patients. Coordination among all the teams is crucial in curating a treatment plan.[67][68][69] The following teams are most commonly involved:

Medical oncology
Orthopedic oncology
Radiation oncology
Nephrology
Palliative care team
Physical therapy and occupational therapy

Deterrence and Patient Education

A cancer diagnosis is a traumatic experience for the patient, especially when the condition is treatable but not curable. Initial and follow-up visits should allow sufficient time to answer all the patient's concerns and questions and those of the family involved in care.

Enhancing Healthcare Team Outcomes

Relapsed and refractory multiple myeloma is challenging to treat due to poor prognosis secondary to treatment resistance and complications. Therefore, effective communication and collaboration among physicians, advanced practice practitioners, nurses, pharmacists, lab technicians, mental health caregivers, and social workers are essential in developing and implementing a comprehensive treatment plan for patients with multiple myeloma, resulting in improved patient outcomes and quality of care.

Involving palliative care in the management of multiple myeloma patients has demonstrated positive outcomes, including improved medication compliance, enhanced symptom management, and increased survival rates.[70]

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