A patient with minimal myeloma treatment who survived for 20 years

We describe a patient who lived for 20 years after a strategy of minimal myeloma treatment. If treated according to current treatment algorithms, this patient would have been heavily overtreated and might have felt under pressure to accept side effects without any benefit. With this case report, we focus on the risk of overtreatment of myeloma patients.

Since 2000, approximately 15 new drugs have been approved for multiple myeloma (MM),¹ and combinations of drugs have been moving from double to triple, and now quadruple combinations. Furthermore, additional treatment strategies include consolidation therapy, maintenance therapy, and sequencing of regimens. Survival has approximately doubled in population-based studies,² and today, long-lasting remission is a highly realistic expectation for younger myeloma patients. In addition, bispecific antibodies and chimeric antigen receptor (CAR) T-cell treatment will be added to the armamentarium and may further increase expectations. MM demonstrates considerable variation in overall survival (OS). Despite this, treatment principles have remained largely unchanged except for autologous stem cell transplantation (ASCT) and the adaption of treatment for frail and high-risk patients. This is a concern, because it is very unlikely that the same treatment principles will be optimal for those patients with a life expectancy of three months and those of 20 years, and good predictive markers for treatment effect are lacking.

A 50-year old man was referred to hospital in 1999 with stiffness in the back and general fatigue. Tests showed IgG 59.6 g/L in serum, no light chains in urine, and normal values of hemoglobin, creatinine and calcium. He had osteolytic lesions in the skull, th8 and os pubis. Performance status was estimated to be WHO 2. Bone marrow (BM) aspirate showed 45% plasma cells and he was diagnosed with MM. An overview of treatment and responses is given in Figure 1. His first ASCT, given with vincristine, adriamycin, dexamethasone (dex) induction and high-dose melphalan (HDM), produced a complete remission. Maintenance treatment was given with interferon alpha for nine months within a clinical trial. M protein reappeared in serum after four years, reaching 5 g/L (progressive disease) after five years. The patient received a second ASCT seven years after diagnosis when backpain and small osteolytic lesions appeared. He obtained partial remission and stopped treatment, whereafter M protein started to rise slowly. The next relapse, four years later, was treated with bortezomib to which he did not respond. Treatment was changed to lenalidomide-based therapy. Altogether, four separate treatment sequences were given. Treatment was continued as long as the M protein level declined and was stopped as soon as the M protein leveled off. After termination of treatment, M protein began to rise, and new treatment was started when the patient experienced relevant symptoms or according to CRAB criteria. He had grade 1-2 side effects which disappeared every time he stopped lenalidomide. The patient was informed that he had growing indolent myeloma without treatment, and we had no defined level of M protein that could suggest starting treatment. Altogether, he was sensitive to intermittent treatment with lenalidomide for a period of 77 months (Figure 1), which also included 44 months of treatment-free intervals.

Figure 1.M protein (IgG) in serum from peripheral blood as measured by protein electrophoresis. Treatments including duration of therapy are seen at the top of the figure. Autologous stem cell transplantation (ASCT) here refers to VAD + high-dose therapy (melphalan) + ASCT. VAD: vincristine + doxorubicine + dexamethasone; IFNα: interferon alpha; Btz: bortezomib; MPL: melphalan + prednisone + lenalidomide; Ld: lenalidomide + dexamethasone; Dara: daratumumab; Pom: pomalidomide; CTD: cyclophosphamide + thalidomide + dexamethasone; Carf: carfilzomib; cyclo: cyclophosphamide.

During the 4^th lenalidomide-based therapy, M protein rose during treatment, demonstrating resistance. Dara-tumumab was administered, but after approximately four months with stable disease (SD) as best response, the M protein level increased during treatment. Pomalidomide was chosen as the next drug to which he was sensitive for ten months. The disease had now changed character and the tumor growth was more rapid. He had still significant responses to CTD and carfilzomib-cyclophosphamide lasting altogether for 12 months. However, the patient was at this point increasingly frail and fatigued, and he decided to discontinue cancer-targeted therapy. The patient passed away 20 years after being diagnosed with MM. Altogether, he had active myeloma therapy for 6.5 years and had been off myeloma drugs for 13.5 years. He received triplet myeloma drug treatment including one of the novel drugs for ten months and otherwise doublet therapy including steroids. He developed immunoparesis (suppression of normal polyclonal immunoglobulins) after ten years and had increasing problems with bacterial infections. Altogether, his general well-being was mostly good (WHO 0-2) and he had a physically active life for 18 of the 20 years with MM.

To determine the status of the tumor microenvironment (TME) in this patient with intermittent treatment and an indolent tumor, we analyzed four BM aspirates that had been taken, fractionated and frozen 13, 16, and 19 (two samples) years after diagnosis. Their relation to treatment and disease status can be seen in Figure 1 (BM1-4).

Exome sequencing revealed a hyperdiploid tumor. Transcriptional analysis of CD138-positive tumor cells showed that the tumor remained stable until the last sample (BM4) when the proliferative index³ increased (Figure 2A). Mass cytometry analysis of the CD138-negative cells showed that the proportion of T cells (CD3⁺) was similar in BM1-3, but a drop was seen during the last two months before death (BM4) (Figure 2B). We also found that the CD4/CD8 ratios were not markedly different in BM1-3, whereas the ratio increased in BM4 (Figure 2B). We found no increase in the myeloid CD11b⁺CD14⁺HLA^-DR^- population in BM4 (data not shown). An increased proportion of T regulatory CD4 (T_reg) cells was found at that time point (Figure 2C), as well as an elevated proportion of exhausted CD4 T cells (Figure 2E). There was no increase in proportions of exhausted and senescent CD8 T cells in BM4 (Figure 2D). A slight increase in TCF1⁺ memory CD8 and CD4 T cells was seen in the last sample (BM4) (Figure 2F, G). TCR sequencing showed comparable clonality until BM4 where the hyperexpanded T-cell clones disappeared with a concurrent decrease in clonality (Figure 3A, B). Clonotype tracking revealed that the 10 most expanded TCR clones in BM1 remained relatively stable in BM1-3 but diminished or disappeared in BM4 (Figure 3C).

In summary, the T cells in the TME remained relatively stable in the period 13-19 years after diagnosis and we anticipate that this was the case also prior to the first BM sample. Two months before death (BM4), considerable changes in T-cell populations were observed with an increase in the CD4/CD8 ratio, T_reg cells and exhausted CD4 T cells, as well as the disappearance of hyperexpanded T-cell clones and loss of clonality, indicating a shift in the T-cell environment at this stage. Similar changes had previously been described in patients with advanced disease.^1,3,4 This coincided with transcriptional changes with an increase in PI.⁵ However, these data suggest that the tumor expansion seen in the last couple of months of the patient’s life was not associated with an increase in senescence or exhaustion in CD8 T cells, or a drop in TCF1⁺ memory T cells.^4,6 Generally speaking, T-cell immunity is important for controlling tumor growth. Changes in the TME coincided with a worsening of the disease; however, at present we can only speculate on the causal relationship between these events.

Immunoparesis is commonly seen in MM demonstrating a serious deficiency in B cells producing normal immunoglobulins. In this patient, this occurred ten years prior to deterioration of the T-cell system, indicating that the disease-induced changes in these two components of the immune system may not be related.

Myeloma treatment has definitely improved but is still hampered by the lack of cure. Even bispecific antibodies and CAR T-cells have yet to prove their efficiency. In the meantime, we have to face the challenging task of treating residual indolent disease with the aim of prolonging survival without unacceptable side effects. Over time it has clearly been a tendency to intensify treatment with triplet and quadruplet drug combinations, prolonged by consolidation and maintenance. This has partly been motivated by a strong wish to remove the last myeloma cell. However, we should discern between the two very different treatment aims of cure and chronic disease. For the great majority of patients, chronic disease is still the most realistic treatment goal that often lasts for several years with a high quality of life. We should strive to give these patients optimal, not maximal, treatment. Preventing serious myeloma events has been a concern that argues for early treatment and prolongation of treatment. This cannot be totally neglected; however, it should not over-rule all other considerations.

Figure 2.Investigation of the patient’s tumor microenvironment by bulk and single-cell analysis. (A) Proliferative index³ of the CD138-positive tumor cells as found by bulk RNA sequencing. (B-G) Single-cell mass cytometry using a custom 37-marker panel was performed on CD138-negative cells from the patient’s bone marrow (BM). Gating was performed to investigate percentages of different immune cell populations across BM1-4. (B) Proportions of T-cell (CD3), B-cell (CD20), myeloid (CD14), and NK-cell (CD56) populations in the live CD45⁺ cell compartment, and proportions of CD8 and CD4 T cells in the T-cell compartment (bottom). (C) Percentage of regulatory T (T_reg) cells (CD4⁺FoxP3⁺CD25⁺) in the T-cell compartment. (D, E) Percentage of exhausted (Eomes⁺PD1⁺TIGIT⁺) and senescent (CD45RO^-CD57⁺) CD8 (D) and CD4 (E) T cells in the T-cell compartment. (F, G) Percentages of different CD8 memory T-cell (F) and CD4 memory T-cell (G) populations in the CD8 and CD4 T-cell compartment, respectively. Central memory T (T_CM) cells (CD45RO⁺CD27⁺), effector memory T (T_EM) cells (CD45RO⁺CD27^-), resident memory T (T_RM) cells (CD45RO⁺CD103⁺), and TCF1⁺ memory T cells (CD45RO⁺TCF1⁺).

Figure 3.Hyperexpanded T cells, clonality, and clonotype tracking of the patient’s T cells. TCRb sequencing of CD138-negative cells was performed across samples BM1-4. (A) Abundance of hyperexpanded T-cell clones, i.e., clones making up ≥1% of all TCRb sequences. (B) Productive clonality of T-cell receptors (TCR) as measured by the Simpson index, where a higher value indicates a more monoclonal TCR repertoire, and a lower value indicates a more polyclonal TCR repertoire. (C) Tracking of the top 10 clonotypes in BM1 across BM1-4.

Although only a case study, this patient demonstrates that there is a group of patients in whom, at best, continuous and combinatory treatment only has a marginal effect. By promoting personalized medicine, we should aim to avoid treatment that is not needed, and this aspect deserves a greater research focus in future clinical trials. MRD negativity is emerging as an excellent marker of good prognosis and may serve as a reasonable basis of selection to such studies.⁷ Discontinuation studies have successfully been carried out in other blood cancers, such as chronic myelogenous leukemia,⁸ and are highly relevant to MM.

Footnotes

• Received June 14, 2023
• Accepted September 26, 2023

Correspondence

*ADB and ENV contributed equally as first authors

A.D. BEHSEN - alenka.d.behsen@ntnu.no

Disclosures

TSS has received honoraria for lectures and educational material from Takeda, Celgene, Amgen, and Janssen-Cilag, consultancy fees from Bristol Myers Squibb, and GSK, and has had an advisory board consultancy role in Amgen, Celgene, GSK, and Janssen-Cilag. ADB, ENV, HHH, PQP, KM, AMS and AW have no conflicts of interest to disclose.

Contributions

ADB, ENV, AMS and KM performed research and data analysis. AW, ADB, ENV and AMS wrote the manuscript. AW, TSS, HHH and PQP treated the patient.