Treatment of Patients with Newly-Diagnosed Multiple Myeloma

Abstract

Multiple Myeloma is an incurable disease. It is responsible for 1.8% of all cancers. The median age is 69–71 years. The treatment of MM is challenging and is affected by several factors such as the patient’s age, comorbidity index, and fitness. The main combination regimen consists of the addition of proteasome inhibitors and IMIDs to steroids. In all studies conducted to date, the results obtained in transplanted patients are better than in patients who did not proceed into transplantation. Before starting treatment, risk stratification should be performed for all patients, and they should be treated accordingly. Recently, there have been advances in the treatment with the introduction of new agents, particularly monoclonal antibodies.

1. Introduction

Multiple myeloma (MM) is characterized by clonal malignant plasma cell increase in the bone marrow. Clinical manifestations are anemia, low back pain, and infections. Hypogamoglobulinemia, osteolytic bone disease, hypercalcemia, and renal dysfunction are common in symptomatic patients. MM is responsible for 10% and 1.8% of hematologic and all malignancies, respectively. The median age for the disease is 69 and it is rare under the age of 45 [1]. The most frequent morbidity cause is bone disease due to osteolysis. It can be detected by using fluoro-deoxyglucose and (FDG) positron emission tomography/computed tomographic scans (PET/CT), whole-body computed tomography (WB-CT), or magnetic resonance imaging (MRI). PET/CT may offer anatomical and metabolic information with a sensitivity of approximately 80–90% and a specificity of 80–100% [2].

In the 1980s, MM could only be treated with alkylating agents and steroids. Later, in the 1990s, the availability of autologous stem cell transplantation (ASCT) improved the course of the disease. In the 2000s, advances were made with the first immunomodulatory (IMID’s) agent thalidomide, In time, the new generation of IMIDs (lenalidomide and pomalidomide) with fewer adverse effects, proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), monoclonal antibodies and histone deacetylase inhibitors have positively impacted the survival of MM patients.

Stratification of the patients is essential for the appropriate management of newly diagnosed multiple myeloma (NDMM). Treatment can be performed according to the following subjects:

1. Treatment of smoldering MM (controversial).

2. Treatment for transplantation-eligible (TE) patients.

3. Treatment for transplantation-ineligible (TI) patients.

4. Treatment of fragile patients.

2. Risk stratification

The survival of MM patients varies: Some patients demonstrate more than 10 years of survival, while some patients have a limited lifespan of 2–3 years. The main reason for this is the patient’s comorbidities and the biology of the disease. Age is an important factor in treatment selection. However, there is still debate about which patient should be considered elderly [3]. The majority of authors believe that age is not the only determinant for treatment. Today, it is considered more decisive whether the patients are fit or not in the choice of treatment method. For this purpose, the Eastern Cooperative Oncology Group (ECOG) performance status can be used as a useful guide. Patients with ECOG performance status 0–1 are candidates for ASCT. The presence of comorbidities can optimally be determined by the Charlson comorbidity index. Chromosomal abnormalities demonstrated by the fluorescent in situ hybridization are also important for risk stratification which should be performed as soon as MM diagnosis is made. Table 1 demonstrates the association of cytogenetic abnormalities with prognosis, survey, and treatment.

Cytogenetic abnormality	Risk	Prognosis	Survey (years)	Treatment relation
All types of trisomies	Standard	Favorable	7–10	Good response to lenalidomide
t(11;14) (q13;q32)	Standard	Favorable	7–10	—
t(6;14) (p21;q32)	Standard	Favorable	7–10	—
t(4;14) (p16;q32)	High	Adverse	5	ASCT recommended
t(14;16) (q32;q23)	High	Adverse	5	25% risk of renal failure
t(14;20) (q32;q11)	High	Adverse	5	ASCT recommended
Gain of 1q21	High	Adverse	5	ASCT recommended
Del 17 p	High	Adverse	5	ASCT recommended
Trisomy+ del 14	Unknown	Unknown	Unknown	Negativity due to del 17p, 14. chromosome translocations can disappear
None	Low	Good	7–10	Indicate to low tumor burden

Table 1.

The association of cytogenetic abnormalities with prognosis, survey, and treatment.

Treatment of patients with a high Revised-International Scoring System (R-ISS) requires a more aggressive approach. Proteosome inhibitors are especially effective in patients with a high-risk cytogenetic risk. Patients with renal involvement may also benefit from bortezomib treatment. Other factors that are effective in determining the treatment algorithm are the patient’s life expectancy, treatment preference, and the presence of extramedullary disease. Geriatric assessment is crucial for frail patients and consists of age, the activity of daily living (ADL), the Charlson Comorbidity Index (CCI), and instrumental activity of daily living (IADL) (Table 2) [4].

Age

> 80

76–80; Plus at least 1 of the following; ADL ≤ 4; IADL ≤4; CCI ≥ 2

≤ 75; Plus at least 2 of the following; ADL ≤ 4; IADL ≤4; CCI ≥ 2

Table 2.

Geriatric assessment index for frail patients with MM.

3. Treatment of transplant-eligible patients

Therapy with high-dose melphalan and ASCT is very effective in patients with MM. Intergroupe Francophone du Myelome (IFM) and EMN/H095 studies have shown that bortezomib, which is used in the induction regimen, is a beneficial drug for TE patients. TE patients were treated with at least 4 cycles of chemotherapy. Thereafter, the patients were evaluated for response. PFS with ASCT was found better than the bortezomib-melphalan-dexamethasone group (567.7 vs. 41.9 months, p = 0.0001) [5, 6].

Many centers perform transplantation when patients achieve a very good partial remission (VGPR). If patients have not achieved VGPR, two more cycles of chemotherapy can be given. The best induction regimen includes a proteasome inhibitor plus IMID plus dexamethasone. Moreau et al. compared Bortezomib, cyclophosphamide, and dexamethasone (VCD) versus bortezomib, thalidomide, and dexamethasone (VTD) combinations in induction. The overall response rate (ORR) with VTD was detected higher than VCD (92.3% vs. 83.4%, P = 0.01) [7]. Peripheral neuropathy is higher with thalidomide treatment. Lenalidomide was used instead of thalidomide in PETHEMA/GEM2012 study. VGPR or better rate was higher with VRD regimen, but neuropathy rate was lower (3.9%) [8]. Endurance Study compared VRD with carfilzomib-lenalidomide and dexamethasone regimen (CRD). ORR was similar to VRD and CRD regimens [9]. The addition of monoclonal antibodies to VTD (Cassisopea and Griffin Studies) or VRD regimen can improve transplantation results [10, 11]. Improved results with daratumumab are correlated with minimal residual disease negativity rate. These results suggest that Dara-VRD is the best regimen for induction treatment. Other effective regimens are Dara-VTD, VRD, VTD, and VCD, respectively.

The standard conditioning regimen for ASCT includes melphalan 200 mg/m². Another drug addition to melphalan such as busulfan or bortezomib has not been found beneficial. In patients with renal dysfunction or failure, the dose of melphalan can be adjusted according to creatinine clearance [12]. The aforementioned induction regimens are summarized in Table 3.

Study	Regimen	n	≥ VGPR; %	≥ CR; %	PFS; (m)	OS (m)	Author
IFM 2009	VRD+ SCT; VRD	350; 350	88 vs. 78	59; 47	50; 36	81; 82	Attal, N Eng J Med 2017
IFM 2013–2014	VTD vs. VCD	169; 169	66 vs. 56	13; 8.9	—	—	Moreau, Blood 2016
PETHEMA 2012	VRD	458	66	33	—	—	Rosinol, Blood 2019
GRIFFIN	Dara-VRD	104; 103	90 vs. 73; 22 months	42; 32	—	—	Wooererhes, Blood 2020
CASSIOPEIA	Dara-VTD; VTD	543; 542	83; 78	39; 26	—	—	Moreau, Lancet 2019
ENDURANCE	KRD; VRD	527; 526	74; 65	18; 15	34.6; 34.4		Kumar, Lancet Oncology 2020

Table 3.

Treatment regimens for TE patients.

4. Consolidation treatment after ASCT

Is consolidation treatment necessary after ASCT in patients with NDMM? Straka et al. evaluated the impact of bortezomib consolidation following ASCT in patients aged between 61 and 75 [13]. Consolidation treatment consisted of 4 cycles bortezomib (1.6 mg/m² IV on days 1, 8, 15, 22) or observation only. Median PFS with bortezomib consolidation was 33.6 months while it was 29.0 months in the observation arm. They showed that consolidation treatment is useful for PFS in older patients because they received less intensive induction treatment. The generally accepted opinion today is that the agents used in the induction regimen should be given 2–4 more times post-ASCT. A randomized phase 3 study indicates that bortezomib-thalidomide-dexamethasone (VTD) is superior to thalidomide-dexamethasone (TD) as consolidation therapy after ASCT. After consolidation, the CR rate was 60.6 months in VTD while it was 46.6% months in the TD arm. Ultimately, VTD was found superior to TD as consolidation therapy [14]. A study that investigates the effect of Daratumumab in consolidation is also ongoing [15]. Cassiopeia study showed that 2 cycles of Dara-VTD consolidation treatment had a positive effect on PFS in patients with NDMM [10].

5. Treatment of transplant-ineligible patients

Several factors determine the choice of treatment in TI patients. Some authors consider the age limit as 65 years. However, some patients above the age of 65 can have a very good organ function. Therefore, age alone should not be considered the sole determinant for transplantation. Charlson comorbidity index, geriatric assessment scale, and hematopoietic comorbidity index can be used to determine the intensity of treatment. Melphalan is the first agent used in the treatment of elderly myeloma patients. Melphalan and prednisolone (MP) combination can be added to thalidomide (MPT) or bortezomib (VMP). PFS varies between 14 and 62 months among the studies involving MPT [16, 17, 18, 19]. PFS rate is 24 months in Vista Study (bortezomib plus MP treatment) [20].

In a meta-analysis comparing VMP versus MPT, it was found that the CR rate was 21% vs. 13%, PFS 32 months vs. 23 months, and overall survival was 79 months vs. 45 months [21]. One of the most important studies is the SWOG S0777 study in which VRD and RD treatments were compared. PFS rate was 41 months in the VRD group while 29 months in the RD group [22]. Therefore, it supports that bortezomib is one of the most important drugs in induction therapy.

The prognosis has improved with the introduction of lenalidomide as first-line therapy. With the addition of daratumumab to MPV (ALCYON study) or lenalidomide-dexamethasone treatments (MAIA study) as a first-line regimen, the success rate has increased significantly [23, 24]. Today, proteasome inhibitor-IMID-dexamethasone plus a monoclonal antibody combination seems to be the most successful treatment in TI patients. However, it should be emphasized that this treatment is an expensive approach. The results of the studies regarding transplantation in TI patients are presented in Table 4.

Study	n	≥ CR; %	PFS; (m)	OS (m)	Author
MPT vs. MP	850 vs.; 772	4–16 vs.; 1–8.8	20.3 vs.; 14.9	39 vs.; 32	Fayers, Blood 2011
VMP vs. MP; (VISTA)	344; 338	30 vs. 4	24 vs. 16	56 vs. 43	San Miguel, NEJM 2008, JCO 2013
VMP vs. VTD (GEM2005)	130 vs. 130	20 vs. 28	32 vs. 23	63 vs. 43	Mateos Blood 2014
MP vs. MPR; vs. MPR-R; (MM-015)	154 vs. 152; vs. 153	5 vs. 13; vs. 18	12 vs. 15 vs. 31	For 3 years 66% vs. 62% vs. 70%	Palumbo, NEJM 2012
RdC vs. RD 18; MPT 12; (FIRST)	535 vs. 541 vs. 547	15 vs. 14 vs. 9	25.5 vs. 20.7 vs. 21.2	59 vs. 56 vs. 51	Benboubker, N Eng J Med 2014
VRD vs. RD; (SWOG S0777)	216 vs. 214	15 vs. 8	41 vs. 29	Not reached vs. 69	Durie, Lancet 2015 and Blood Cancer Journal 2020
KMP vs. VMP; (CLARION)	478 vs. 477	25.9 vs. 23.1	22.3 vs. 22.1	Not reached in all group	Facon, Blood 2019
IRD vs. RD; Tourmaline 2	73 vs. 74	25.6 vs. 14.1	35.3 vs. 21.8	Not reached	Facon, Blood 2021
VTD vs. TDxSCT; (Gimema-MMY-3006)	241 vs. 239	—	60 vs. 41	110 months; 60% vs. 46%	Tahetti, Lancet Hematol, 2020
Dara-LenDex vs. Lendex; (MAIA)	346 vs. 354	47.6% vs. 24.9	Not reached; 31.9	Not reached in all groups	Facon, N Eng J Med 2019
Dara-MPV vs. MPV; (ALCYON)	350 vs. 356	42% vs. 24%	For 36 months 50% vs. 18.5%	Not reached vs. 46 months	Mateos, N Eng J Med 2020

Table 4.

Treatment regimens for TE patients.

m: month (s), n: number, vs.: versus.

6. Maintenance treatment

Maintenance treatment with thalidomide has improved overall survival nonsignificantly. PFS is improved with thalidomide maintenance, but thrombosis risk and peripheral neuropathy incidence are also higher with thalidomide vs. no maintenance. Lenalidomide has also been found a very effective agent for maintenance. PFS and OS were improved in First Study. PFS for Rd. Continue, Rd18, and MPT groups were 16.0, 21, and 21.9 months, respectively. The median OS was found similar in both Rd. Continue, and Rd18 groups (59.1 months vs. 62.3 months) while 49.1 months in the MPT group [25]. Lenalidomide maintenance results are demonstrated in Table 5. The STAMINA study debated the dose and duration of lenalidomide use. In this study, better results were reported in patients who received 15 mg daily lenalidomide treatment continuously [26]. Huang et al. investigated the effect of lenalidomide versus bortezomib maintenance treatment after ASCT. They showed that there is no difference in both arms although adverse effects in the bortezomib arm were higher than in the lenalidomide arm [27].

Study	n	Regimen	PFS; (m)	OS (m)	Author
MM0015 IFM	153 vs. 154	Lenalidomide vs. no Lenalidomide	31	%77 for 3 years	Palumbo N Eng J Med 2012
ECOG	231 vs. 229	Lenalidomide vs. no Lenalidomide	46 vs. 27	—	McCharty
Myeloma XI	1137 vs. 834	Lenalidomide vs. no Lenalidomide	39 vs. 20	87% vs. 74% for 3 years	Jackson Lancet Oncol 2019
Tourmaline MM3	395 vs. 261	Ixazomib vs. Placebo	26.5 vs. 21.3	—	Dimopoulos Lancet 2019
HOVON	213 vs. 219	VAD vs. PAD	28 vs. 35	—	Sonneveld J Clin Oncol 2012

Table 5.

Maintenance treatment regimens in patients with NDMM.

m: month(s), n: number, vs.: versus.