Multiple myeloma (MM) is a haematologic malignancy characterised by abnormal clonal plasma cells in the bone marrow with a potential for uncontrolled growth causing destruction, osseous lesion, acute kidney injury (AKI), anaemia, and hypercalcaemia. The median age of onset for MM is 69 years, and approximately 63% of patients diagnosed with MM are above the age of 651. MM accounts for 176,404 new cases and 1.2% of cancer-related deaths globally2. Bony destruction seen in MM is a result of an increase in osteoclast formation with no bony repair in response to previous bone destruction3. Approximately 1-2% of patients exhibit extramedullary disease (EMD) at the time of the initial diagnosis, and 8% may develop EMD at later stages of the disease4. Relapsed or refractory MM (RRMM) constitutes as an unmet medical need in patients with MM since most of them have a median survival range from 6 to 9 months with remission period becoming shorter after each relapse5,6. Therefore, to address the challenging nature of the RRMM, we have invited Dr. Justin Li, a haematology specialist, to highlight the outstanding issues with RRMM through a case-based sharing and discuss the novel therapeutic options available for patients with RRMM.

An Unusual Case of RRMM
Thalidomide was the first immunomodulatory drug (IMiDs) introduced to treat MM due to its potential anti-angiogenic activity7. The early success of thalidomide prompted an investigation into additional IMiDs, the most notable of which are the Lenalidomide and Pomalidomide8. Dr. Li explained, while cure remains an ultimate goal, converting myeloma into a chronic disease through the sequencing of available therapies, guided by disease biology appears to be within the grasp9. On this note, Dr. Li shared a clinical case of a 79-year-old retired healthcare worker who presented with a two-year history of chest and lower back pain which has worsened since the July 2020. A left-sided supraclavicular mass with apical shadow was seen on the chest x-ray, therefore, the patient underwent a CT thorax to exclude lung carcinoma. The CT reported an extrapulmonary mass with left 1st medial rib bony destruction but no lung parenchymal involvement (Figure 1);

Figure 1.  Chest x-ray and CT revealed extrapulmonary mass on the 1st left rib (red arrow) with lung parachymal sparing. 

in addition, there were lytic lesions involving the 10th thoracic vertebra (T10). Therefore, to assess further, a diagnostic biopsy was offered which the patient declined, according to Dr. Li. Further blood tests showed a haemoglobin (Hb) of 9.2g/dL, with normal serum calcium but mildly deranged serum creatinine (130µmol/L).
 

The serum protein electrophoresis (SPEP) was 42g/dL, mainly involving IgA lambda (λ) and marrow analysis showed around 41% of plasma cells, consistent with a diagnosis of plasma cell myeloma. The fluorescence in-situ hybridisation (FISH) demonstrated chromosome 1 gain (+1q) as per Dr. Li and according to studies, +1q gain is the most common cytogenetic abnormality seen in 20-50% of newly diagnosed cases of MM10. In this case, the patient was eventually diagnosed with the Revised International Staging System (R-ISS) II and underwent a positron emission tomography-computed tomography (PET-CT). The PET-CT findings were consistent with the previous CT thorax showing a left 1st rib bony lesion with T10 lytic lesion, in addition to vertebrae collapse at T10 and 3^rd lumbar (L3) levels. The patient was eventually initiated onto bortezomib/thalidomide/dexamethasone (VTd) treatment in early October 2020 and had around 8 treatment cycles of VTd until the April 2021. According to Dr. Li, “the patient responded well to the VTd treatment as his SPEP levels dropped from 42g to 2g (Figure 2).”

Figure 2.  SPE levels post VTd treatment dropped from 42g to 2g. SPE= serum protein electrophoresis, VTd= bortezomib, thalidomide, dexamethasone. 

Therefore, bortezomib was offered as a maintenance treatment since there was a high-risk of recurrence, but the patient refused. Instead, he opted for the oral treatment and was commenced onto thalidomide 50 mg (nocte). 

During the follow-up, PET-CT was repeated, and new bony lesions were reported. Thus, dexamethasone 20 mg weekly was added to the treatment regimen. The patient reported worsening bone pain in June 2021 after having only 1 treatment cycle, and repeated tests showed uptrending SPEP levels (up to 9g). A further bone marrow aspirate was obtained in September 2021 due to worsening of symptoms and it showed 22% of clonal bone marrow plasma cells, once again consistent with the diagnosis of plasma cell myeloma. 

Hence, the patient was commenced onto ixazomib-based therapy for approximately 5 treatment cycles prior to reporting intolerable generalised rash (Figure 3).

Figure 3.  SPE levels post Ixazomib-based therapy treatment showing an increase in SPE levels after 4th treatment cycle. SPE= serum protein electrophoresis.

Therefore, the treatment was escalated to pomalidomide/dexamethasone (Pom/Dex) and no further rashes were reported. Dr. Li elaborated that the patient was readmitted on two different occasions after being discharged and on his last admission, he presented with persistent headaches. Dr. Li emphasised that the blood cultures revealed disseminated cryptococcal infection even though the patient was not neutropenic. Thus, antifungals (flucytosine and ambisome) were commenced for approximately 4 weeks followed by fluconazole 400 mg for 8 weeks. His MM treatment was temporarily discontinued for three months to allow the underlying disseminated fungal infection to be treated.  
 

To date, the patient remained on maintenance dose of fluconazole 200 mg, nevertheless, repeated tests showed the SPEP levels were rising (up to 7g) shortly after the discontinuation of the Pom/Dex treatment. Therefore, the Pom/Dex treatment was recommenced. After completing 13 treatment cycles of Pom/Dex, the SPEP levels eventually decreased and remained low (Figure 4).

Figure 4.  SPE levels post Pd treatment showing a decline in SPE level at 13th cycle. SPE= serum protein electrophoresis, Pd= pomalidomide, dexamethasone (Pom/Dex)

Dr. Li explained that the patient is due his 14^th dose in August 2023 and so far, he has been responding very well to the Pom/Dex treatment with no major haematological toxicity. 

Clinical Trials to Real-World Effectiveness of Pom/Dex in RRMM:
Even though the therapeutic options for RRMM are increasing, the treatment efficacy for RRMM remains a critical challenge. As the latest IMiD, pomalidomide has shown to be more potent, yet less toxic than thalidomide and lenalidomide¹¹. This was demonstrated in a multi-centred, retrospective registry-based study which reviewed the medical records of 49 consecutive patients who have undergone Pox/Dex treatment for RRMM. The results showed that the overall response rate (ORR) of Pom/Dex was 47.7% with a median progression-free survival (PFS) of 4 months in a real-world setting11. In addition, patients who received two prior lines of treatment had a higher ORR compared to those who received more than two prior lines of treatment (55.2% vs 33.3%; p= 0.045). The study concluded that the primary lenalidomide refractoriness reduced the risk of myeloma progression following Pom/Dex treatment (hazard ratio, 0.14; p= 0.001)¹¹. These findings were also substantiated in a Czech study that analysed the data of patients with RRMM from nine centres between 2013 and 2018. The results showed patients treated with Pom/Dex had ORR of 51.8% with the clinical benefit rate of 67.1%. Furthermore, the median PFS was 8.9 months, and the medial overall survival (OS) was 14.2 months in patients treated with Pom/Dex. These results further elaborated the findings that the efficacy of Pox/Dex in a real-world setting is comparable to that of the clinical trials¹². 

Notably, recent studies have shown that a longer duration of therapy utilising the maintenance treatment strategy being more beneficial in improving the patient outcomes. Moreover, the disease refractory to the novel agents such as the IMiDs and proteasome inhibitors is being encountered more frequently and earlier in myeloma patients¹³. Therefore, a longer duration of treatment may correlate to a higher response rate according to Ailawadhi et al., (2018) who conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of Pox/Dex in patients with RRMM¹³. In this trial, 345 patients were divided into six cohort groups based on the dose (2 mg or 4 mg daily) and types of prior lines of therapies (lenalidomide or lenalidomide and bortezomib or <3 prior regimens) taken. A response rate of 35% was reported in all cohorts with a higher response rate seen in cohorts with a fewer prior lines of therapy¹³. The longest PFS and OS in any cohort were 13.1 and 47.9 months, respectively¹³. The results obtained from the clinical trial justified the longer duration of Pom/Dex used in the case presented by Dr. Li. In this regards, Dr. Li suggested that patients with MM often require more than first line treatment, and Pox/Dex should be one of the key arsenals when treating RRMM. In conclusion, continuing therapy from the first relapse to the disease progression may have the potential to suppress the residual disease, thereby, may extend the overall survival; this represents the paradigm shift allowing MM to be managed as a chronic illness^14. 

References
1. Cowan AJ, et al. JAMA 2022; 327(5): 464-77.  2. Liu J, et al. Chinese Medical Journal 9900: 10.1097/CM9.0000000000002600.  3. Roodman GD. Bone Marrow Transplant 2007; 40(12): 1139-46.  4. Rajkumar SV. Am J Hematol 2022; 97(8): 1086-107.  5. Crawford R, et al. Cancer Rep (Hoboken) 2022; 5(11): e1603.  6. Richardson P, et al. Hematology 2007; 2007(1): 317-23.  7. Kumar S, et al. European Journal of Cancer 2006; 42(11): 1612-22.  8. Bhatt P, et al. Curr Oncol 2023; 30(2): 2322-47.  9. Kumar S, et al. Blood Cancer Journal 2022; 12(6): 98.  10. Shah GL, et al. Leuk Lymphoma 2017; 58(8): 1823-31.  11. Hung YC, et al. Front Oncol 2021; 11: 695410.  12. Sandecka V, et al. Neoplasma 2022; 69(6): 1474-9.  13. Ailawadhi S, et al. Leukemia 2018; 32(3): 719-28.  14. Sonneveld P, et al. Haematologica 2016; 101(4): 396-406.