Exceptional 30-year survival of a patient with multiple myeloma – quality of life and management of disease-related symptoms

INTRODUCTION

Multiple myeloma (MM) is a plasma cell malignancy characterised by the proliferation of abnormal clonal plasma cells in the bone marrow, leading in most cases to the production of monoclonal proteins. Uncontrolled growth of aberrant plasma cells and accumulation of monoclonal protein result in pathophysiological consequences such as anaemia, bone lesions, hypercalcaemia, renal failure, recurrent infections, fatigue, and pain [1].
The introduction of new pharmacotherapy methods in recent years has improved survival in patients; therefore, MM is more willingly considered a chronic disease characterised by multiple relapses and remissions, rather than an incurable disease. However, relapse is still inevitable, and patients require subsequent lines of treatment, negatively affecting their quality of life (QoL). Patients suffering from MM struggle with many disease-related problems, such as bone pain, pathological bone fractures, mobility difficulties, chronic immunodeficiency, anaemia and the need for transfusion of blood products, and toxicity of anticancer treatment, in particular, drug- induced neuropathy and haematological toxicity. The psychosocial burden of a diagnosis of cancer is also evident [2].
According to the latest statistics from the Global Cancer Observatory, MM constitutes 0.9% of all cancer diagnoses. New cases occur more frequently in men, with a cumulative risk of being diagnosed from birth to age 74 years of 0.25% among men and 0.15% among women [3]. The median age at diagnosis hovers around 69 years, with 37% of patients younger than 65 years, 26% in the 65–74 age bracket, and 37% at 75 years or older [4]. The median survival is approximately 8–10 years [5]. In recent years, overall survival in MM of up to 10–15 years has become more common [6], but survival of up to 30 years is still rare.
Today, the standard of treatment for patients with myeloma is multi-drug regimens containing steroids, typically dexamethasone, and antimyeloma agents with different mechanisms of action: immunomodulatory agents (e.g. thalidomide lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and monoclonal antibodies (daratumumab, isatuximab, elotuzumab) [7]. The development of new drugs has improved survival in patients with MM and changed the natural course of the disease, from an incurable haematological malignancy to a chronic disease characterised by multiple alternating periods of remission and relapse. As the survival of patients with MM extends, their QoL should also be taken care of.
In this case, we present an exceptionally long survival in MM, which is 3 times greater than the median survival in MM. This case shows that today patients can achieve long overall survival even when faced with diseases considered life-shortening. New drug classes are promising for long overall survival. Supportive care is implemented to achieve good symptom control.

CASE REPORT

In 1994, a 35-year-old man was admitted to the Haematology Clinic at the University Hospital of Jagiellonian University Medical College in Kraków, Poland, with suspected haematological neoplasm. The patient had been experiencing severe pain in the lumbar-sacral area radiating to the knees, which significantly limited his movements. His medical history was unremarkable for any chronic diseases, and he did not take any permanent medications. The results of the blood test on admission were as follows: red blood cells 3 × 10⁶/µl, haemoglobin 9.9 g/dl, haematocrit 28%, white blood cells 37 × 10³/µl, and platelets 98 × 10³/µl. No young forms of the granulocyte system were detected in the leukogram. Serum protein electrophoresis showed an increased gamma globulin fraction and the presence of a monoclonal protein zone. Bone marrow biopsy revealed 80% domination of abnormal plasma cells with an intense cluster of differentiation 138 (CD138) antigens expression. X-rays of the lumbar-sacral spine revealed severe osteoporosis, a compression fracture of the L3 vertebral body, and a fracture of the L1, L2, and L5 vertebral bodies. The diagnosis of MM IgG kappa was confirmed. The patient was treated with chemotherapy COP (cyclophosphamide, vincristine, prednisone) in combination with melphalan, resulting in resolution of bone pain and improvement in proteinogram results. Complementary radiation therapy of lesions in the lumbar spine was administered with a total dose of 2400 cGy, and the patient was secured with a back brace.
Many treatment regimens were used in the following years (Fig. 1): CTX + VBL (cyclophosphamide with vinblastine) in 1996, CTX + VCR (cyclophosphamide with vincristine) in 1998, VAD (vincristine, doxorubicin, and dexamethasone) in 2000, and DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) in 2001. In 2001, an unsuccessful attempt was made to mobilise haematopoietic cells to perform auto-HSCT. Due to progression, thalidomide treatment was initiated with very good results. Until 2005, thalidomide was administered at intervals due to hepatotoxicity. From November 2005 to March 2006, 5.5 cycles of bortezomib were administered and stopped due to polyneuropathy. In December 2007 CTD (cyclophosphamide, thalidomide, and dexamethasone) was started, then CD and VMBCP (vincristine, melphalan, carmustine, cyclophosphamide, prednisone) in 2008. The patient was then treated with EDAP (etoposide, dexamethasone, cytarabine, cisplatin), which ended with progression in February 2009, and PAD (bortezomib, doxorubicin, and dexamethasone) from March 2009 until September 2009, with a very good partial response. The longest period of remission lasted for 11 years, between 2012–2023, when the patient received maintenance therapy with lenalidomide.
During the 30 years of MM treatment, numerous chemotherapy regimens were used. Pamidronic acid and erythropoietin stimulating agents were used supportively. Treatment was complicated by peripheral polyneuropathy. The patient required periodic transfusion of packed red blood cells. One year after the diagnosis of MM, hepatitis B virus manifested by elevated aminotransferases and jaundice was detected and tenofovir was administered. Additionally, the patient suffered from pulmonary embolism and proximal right lower limb deep vein thrombosis. In periods of deepening immunodeficiency, preventive antibiotic therapy was used – levofloxacin. He was hospitalised several times for pneumonia.
After the last progression in June 2023, the patient was assigned to isatuximab treatment in combination with pomalidomide and dexamethasone. Transient grade 2 and 3 neutropaenia, grade 1 anaemia, and grade 1 thrombocytopaenia were observed. The patient achieved remission and continues therapy.

DISCUSSION

The quality of life of patients with MM appears to deteriorate with prolongation of the duration of the disease, and improvements are limited. The presented patient, during the long 30-year duration of the disease, has struggled with many problems that affect his QoL, which cannot be eliminated and can only be treated symptomatically, such as spine pain secondary to vertebral compression fractures. Pamidronic acid was used supportively to strengthen the bone structure. Immune impairment is the result of immunoglobulin disorders that occur in MM, but treatment may also cause leukopaenia and exacerbate the initial immune deficit. Antibiotic prophylaxis is helpful but does not eliminate the risk of infections. The presented patient was hospitalised several times due to pneumonia. One of the main adverse events of myeloma treatment is polyneuropathy, which often remains symptomatic despite discontinuation of the inducing drug. The haematological toxicity of treatment is manifested by cytopaenia, which, when severe, may require temporary discontinuation of treatment. The presented patient had anaemia that required periodic transfusion of packed red blood cells. A history of pulmonary embolism, deep vein thrombosis of the right lower extremity, and viral hepatitis additionally impaired the patient’s QoL. Due to the treatment of MM with modern drugs, including monoclonal antibodies, the patient achieved exceptionally long survival. Supportive treatment and rehabilitation are used to improve his QoL.
Quality of life in patients with MM is affected in several ways: disease-related physical symptoms, drug-induced adverse events, and emotional distress. In the study that evaluated the QoL of MM patients, the authors reported a lower overall QoL, more burdensome pain and fatigue, reduced physical functioning, and limitations in role functioning in MM patients compared to age-matched controls [8]. The quality of life of patients with MM reflects the activity of the disease and the depth of response. Quality of life improves when patients are successfully treated and deteriorates at the time of progression. High-dose anticancer therapy transiently reduces QoL. Maintenance treatment during periods of remission, such as lenalidomide, is not believed to negatively affect QoL [9]. The principles of supportive care for patients with MM cover the management of bone disease, renal impairment, anaemia, polyneuropathy, immune deficits, and venous thrombosis [10].
The median survival in MM is approximately 8–10 years. Among patients over 75 years old, median survival is lower and is estimated at 5 years [5]. To our knowledge, this case report presents one of the longest survival periods in MM. Table 1 summarises the publications on long survival in MM. As a criterion for long survival in MM, the authors adopted a survival above average (more than 10 years).
According to the National Comprehensive Cancer Network guidelines, in first-line therapy, patients should be treated with a triplet regimen, which contains 2 classes of drugs and steroids. In case of refractoriness or relapse, a new triplet regimen should include drug classes that patients have not been exposed to for at least 6 months [17]. Multiple myeloma generally responds well to first-line chemotherapy, but most patients eventually relapse and become increasingly refractory due to the formation of drug-resistant clones. Double-refractory patients to standard treatment regimens, including immunomodulatory agents and proteasome inhibitors (PI), were observed to have a particularly poor prognosis [17]. Therefore, there was an increasing need to develop a new class of antimyeloma drugs. Monoclonal antibodies are the proposed answer to this demand and are a promising class of drugs for the treatment of refractory and relapsed MM.
Isatuximab is a monoclonal antibody that acts against the transmembrane glycoprotein CD 38 expressed on the surface of malignant plasma cells and is the second drug in this class after daratumumab. Isatuximab, in combination with pomalidomide and low-dose dexamethasone, is registered for the treatment of adult patients with refractory and relapsed MM who were previously treated with at least 2 lines of therapies, including lenalidomide and PI, and progressed with the last therapy [18]. Isatuximab was first approved in the US in March 2020, then in Europe [18]. In the multicentre randomised phase 3 ICARIA-MM study, the addition of isatuximab to pomalidomide and dexamethasone benefited from a significant improvement in progression-free survival (11.5 vs. 6.5 months, during the 11.6-month follow-up) [19]. Isatuximab is generally well tolerated. The prevalence of haematological isatuximab toxicity in all grades is 96%, 84%, and 99% for neutropaenia, thrombocytopaenia, and anaemia, respectively. In most patients, anaemia and thrombocytopaenia occur in grade 1 or 2. In contrast, grade 4 neutropaenia is observed in 61% of patients [19]. In the presented patient, transient grade 2 and 3 neutropaenia, grade 1 anaemia, and grade 1 thrombocytopaenia were observed in the first period of isatuximab treatment. No interruption of treatment was required. The blood count parameters normalised subsequently and therapy was continued.

CONCLUSIONS

For decades, MM was considered an incurable disease. In recent years, dramatic improvement in clinical outcomes has been observed in patients with MM and has accompanied the introduction of new drug classes that are used mainly in triplet drug regimens that mix the pharmaceutics of different mechanisms of action. Although no drug has yet been found to stop the progression of MM, long-term survival with periods of remission that can last many years may currently be observed. Immunotherapy is a new promising direction in the treatment of MM. Supportive care is an integrated part of the treatment of patients with MM. Overall survival of 30 years, which is 3 times greater than median survival in MM, is still rare, but achievable, and new drugs offer a chance, especially for heavily pretreated patients who have experienced many relapses of the disease. Supportive care improves the QoL for patients and is a crucial factor to improve their survival. Our patient achieved this long 30-year overall survival thanks to both modern antimyeloma therapy and supportive care such as treatment for anaemia, infection, bone fractures, and pain.

DISCLOSURES

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

REFERENCES